DrSarmaworks

The Core Knowledge onThe Core Knowledge on

Metabolic Syndrome Metabolic Syndrome

DrSarma RVSN DrSarma RVSN MD MSc (Canada)MD MSc (Canada)

Consultant Physician and Chest SpecialistConsultant Physician and Chest Specialist

Thiruvallur ChennaiThiruvallur Chennai

DrSarmaworks

Metabolic Metabolic Syndrome Syndrome

The Hidden The Hidden VolcanoVolcano

DrSarmaworks

142175

23

156225

44

265329

24

1013

33

94141

50

World2000=151 million2010=221 millionIncrease 46

8451323

57

Zimmet P et al Nature 2001414782

Global ProjectionsGlobal Projectionsfor Diabetes 1995-2010 for Diabetes 1995-2010

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World CongressWorld Congress

1First World Congress on Insulin Resistance syndrome ndash Nov 2003

2Second World Congress on IRS ndash 2004

wwwinsulinresistanceus

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Synonyms of Metabolic Synonyms of Metabolic syndromesyndrome

1 Insulin resistance syndrome (IRS)

2 (Metabolic) Syndrome X

3 Dysmetabolic syndrome

4 Multiple metabolic syndrome

5 ICD code 2777

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What is this Syndrome What is this Syndrome

Insulin resistance ndash Hyperinsulinemia

Hyperglycemia ndash IFG IGT DMII

Pro-inflammatory state ( ￪ CRP)

Pro-coagulant changes ( ￪ PAI-1 ￪ Fibrinogen)

Dyslipidemia ( ￪ TG darrHDL)

Premature atherosclerosis IHD CAD

Type 2 diabetes

Hypertension ED

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Definitions of the Metabolic Definitions of the Metabolic SyndromeSyndrome

According to clinical outcomes

According to underlying causes

According to metabolic components

According to clinical criteria

DrSarmaworks

Definition of Metabolic SyndromeDefinition of Metabolic SyndromeAccording to Underlying CausesAccording to Underlying Causes

Insulin resistance (1999 WHO)

Insulin resistance syndrome

Lifestyle especially obesity (NCEP ATP III)

Metabolic syndrome

Sub-clinical inflammation

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

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Causes

Acquired causes Overweight and obesity Physical inactivity High carbohydrate diets (gt60 of energy

intake) in some persons

Genetic causes

Metabolic SyndromeMetabolic Syndrome

Currently 47 million US adults- metabolic syndrome Leading health problem in US

DrSarmaworks

Secondary

10487071048707 Pregnancy

10487071048707 Stress

10487071048707 Infection

10487071048707 Uremia

10487071048707 Glucocorticoid excess

10487071048707 Acromegaly

Metabolic SyndromeMetabolic Syndrome

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The Worsening EpidemicThe Worsening Epidemicof Obesity and Diabetesof Obesity and Diabetes

1999-2000 NHANES Data (JAMA Oct 2002)

31 obese (BMI 30) increase from 23

65 overweight (BMI 25) increase from 56

47 extremely obese (BMI 40) ￪ from 29

No physical activity in 27 No regular activity in additional 28

Each 1-kg increase in weight =remember 9 increase in risk of diabetes

How can lifestyle changes be implemented long term

NHANES=National Health and Nutrition Examination Survey

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How It works How It works

DrSarmaworks

Plausible MechanismsPlausible Mechanisms

Mixed IR ndash CHO IR FFA no IR

Lipotoxic state - ￪ FFA

TNFndashalpha IL -6 ndash Adipocytokine - ￪ FFA

PPARndashgamma ndash nuclear enzyme ￪ darr Adiponectin ndash darrFFA oxidation ￪ FFA ndash

IR

FFA ndash IR ndash JNK mediated

Satiation signaling ndash Leptin Resistance

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

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Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

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ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

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Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

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WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

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DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

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Acanthosis NigricansAcanthosis Nigricans

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Acanthosis NigricansAcanthosis Nigricans

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PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

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Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

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ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

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0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

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Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

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Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

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Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

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Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

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Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

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Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

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Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Metabolic Metabolic Syndrome Syndrome

The Hidden The Hidden VolcanoVolcano

DrSarmaworks

142175

23

156225

44

265329

24

1013

33

94141

50

World2000=151 million2010=221 millionIncrease 46

8451323

57

Zimmet P et al Nature 2001414782

Global ProjectionsGlobal Projectionsfor Diabetes 1995-2010 for Diabetes 1995-2010

DrSarmaworks

World CongressWorld Congress

1First World Congress on Insulin Resistance syndrome ndash Nov 2003

2Second World Congress on IRS ndash 2004

wwwinsulinresistanceus

DrSarmaworks

Synonyms of Metabolic Synonyms of Metabolic syndromesyndrome

1 Insulin resistance syndrome (IRS)

2 (Metabolic) Syndrome X

3 Dysmetabolic syndrome

4 Multiple metabolic syndrome

5 ICD code 2777

DrSarmaworks

What is this Syndrome What is this Syndrome

Insulin resistance ndash Hyperinsulinemia

Hyperglycemia ndash IFG IGT DMII

Pro-inflammatory state ( ￪ CRP)

Pro-coagulant changes ( ￪ PAI-1 ￪ Fibrinogen)

Dyslipidemia ( ￪ TG darrHDL)

Premature atherosclerosis IHD CAD

Type 2 diabetes

Hypertension ED

DrSarmaworks

Definitions of the Metabolic Definitions of the Metabolic SyndromeSyndrome

According to clinical outcomes

According to underlying causes

According to metabolic components

According to clinical criteria

DrSarmaworks

Definition of Metabolic SyndromeDefinition of Metabolic SyndromeAccording to Underlying CausesAccording to Underlying Causes

Insulin resistance (1999 WHO)

Insulin resistance syndrome

Lifestyle especially obesity (NCEP ATP III)

Metabolic syndrome

Sub-clinical inflammation

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

Causes

Acquired causes Overweight and obesity Physical inactivity High carbohydrate diets (gt60 of energy

intake) in some persons

Genetic causes

Metabolic SyndromeMetabolic Syndrome

Currently 47 million US adults- metabolic syndrome Leading health problem in US

DrSarmaworks

Secondary

10487071048707 Pregnancy

10487071048707 Stress

10487071048707 Infection

10487071048707 Uremia

10487071048707 Glucocorticoid excess

10487071048707 Acromegaly

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

The Worsening EpidemicThe Worsening Epidemicof Obesity and Diabetesof Obesity and Diabetes

1999-2000 NHANES Data (JAMA Oct 2002)

31 obese (BMI 30) increase from 23

65 overweight (BMI 25) increase from 56

47 extremely obese (BMI 40) ￪ from 29

No physical activity in 27 No regular activity in additional 28

Each 1-kg increase in weight =remember 9 increase in risk of diabetes

How can lifestyle changes be implemented long term

NHANES=National Health and Nutrition Examination Survey

DrSarmaworks

How It works How It works

DrSarmaworks

Plausible MechanismsPlausible Mechanisms

Mixed IR ndash CHO IR FFA no IR

Lipotoxic state - ￪ FFA

TNFndashalpha IL -6 ndash Adipocytokine - ￪ FFA

PPARndashgamma ndash nuclear enzyme ￪ darr Adiponectin ndash darrFFA oxidation ￪ FFA ndash

IR

FFA ndash IR ndash JNK mediated

Satiation signaling ndash Leptin Resistance

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

142175

23

156225

44

265329

24

1013

33

94141

50

World2000=151 million2010=221 millionIncrease 46

8451323

57

Zimmet P et al Nature 2001414782

Global ProjectionsGlobal Projectionsfor Diabetes 1995-2010 for Diabetes 1995-2010

DrSarmaworks

World CongressWorld Congress

1First World Congress on Insulin Resistance syndrome ndash Nov 2003

2Second World Congress on IRS ndash 2004

wwwinsulinresistanceus

DrSarmaworks

Synonyms of Metabolic Synonyms of Metabolic syndromesyndrome

1 Insulin resistance syndrome (IRS)

2 (Metabolic) Syndrome X

3 Dysmetabolic syndrome

4 Multiple metabolic syndrome

5 ICD code 2777

DrSarmaworks

What is this Syndrome What is this Syndrome

Insulin resistance ndash Hyperinsulinemia

Hyperglycemia ndash IFG IGT DMII

Pro-inflammatory state ( ￪ CRP)

Pro-coagulant changes ( ￪ PAI-1 ￪ Fibrinogen)

Dyslipidemia ( ￪ TG darrHDL)

Premature atherosclerosis IHD CAD

Type 2 diabetes

Hypertension ED

DrSarmaworks

Definitions of the Metabolic Definitions of the Metabolic SyndromeSyndrome

According to clinical outcomes

According to underlying causes

According to metabolic components

According to clinical criteria

DrSarmaworks

Definition of Metabolic SyndromeDefinition of Metabolic SyndromeAccording to Underlying CausesAccording to Underlying Causes

Insulin resistance (1999 WHO)

Insulin resistance syndrome

Lifestyle especially obesity (NCEP ATP III)

Metabolic syndrome

Sub-clinical inflammation

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

Causes

Acquired causes Overweight and obesity Physical inactivity High carbohydrate diets (gt60 of energy

intake) in some persons

Genetic causes

Metabolic SyndromeMetabolic Syndrome

Currently 47 million US adults- metabolic syndrome Leading health problem in US

DrSarmaworks

Secondary

10487071048707 Pregnancy

10487071048707 Stress

10487071048707 Infection

10487071048707 Uremia

10487071048707 Glucocorticoid excess

10487071048707 Acromegaly

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

The Worsening EpidemicThe Worsening Epidemicof Obesity and Diabetesof Obesity and Diabetes

1999-2000 NHANES Data (JAMA Oct 2002)

31 obese (BMI 30) increase from 23

65 overweight (BMI 25) increase from 56

47 extremely obese (BMI 40) ￪ from 29

No physical activity in 27 No regular activity in additional 28

Each 1-kg increase in weight =remember 9 increase in risk of diabetes

How can lifestyle changes be implemented long term

NHANES=National Health and Nutrition Examination Survey

DrSarmaworks

How It works How It works

DrSarmaworks

Plausible MechanismsPlausible Mechanisms

Mixed IR ndash CHO IR FFA no IR

Lipotoxic state - ￪ FFA

TNFndashalpha IL -6 ndash Adipocytokine - ￪ FFA

PPARndashgamma ndash nuclear enzyme ￪ darr Adiponectin ndash darrFFA oxidation ￪ FFA ndash

IR

FFA ndash IR ndash JNK mediated

Satiation signaling ndash Leptin Resistance

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

World CongressWorld Congress

1First World Congress on Insulin Resistance syndrome ndash Nov 2003

2Second World Congress on IRS ndash 2004

wwwinsulinresistanceus

DrSarmaworks

Synonyms of Metabolic Synonyms of Metabolic syndromesyndrome

1 Insulin resistance syndrome (IRS)

2 (Metabolic) Syndrome X

3 Dysmetabolic syndrome

4 Multiple metabolic syndrome

5 ICD code 2777

DrSarmaworks

What is this Syndrome What is this Syndrome

Insulin resistance ndash Hyperinsulinemia

Hyperglycemia ndash IFG IGT DMII

Pro-inflammatory state ( ￪ CRP)

Pro-coagulant changes ( ￪ PAI-1 ￪ Fibrinogen)

Dyslipidemia ( ￪ TG darrHDL)

Premature atherosclerosis IHD CAD

Type 2 diabetes

Hypertension ED

DrSarmaworks

Definitions of the Metabolic Definitions of the Metabolic SyndromeSyndrome

According to clinical outcomes

According to underlying causes

According to metabolic components

According to clinical criteria

DrSarmaworks

Definition of Metabolic SyndromeDefinition of Metabolic SyndromeAccording to Underlying CausesAccording to Underlying Causes

Insulin resistance (1999 WHO)

Insulin resistance syndrome

Lifestyle especially obesity (NCEP ATP III)

Metabolic syndrome

Sub-clinical inflammation

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

Causes

Acquired causes Overweight and obesity Physical inactivity High carbohydrate diets (gt60 of energy

intake) in some persons

Genetic causes

Metabolic SyndromeMetabolic Syndrome

Currently 47 million US adults- metabolic syndrome Leading health problem in US

DrSarmaworks

Secondary

10487071048707 Pregnancy

10487071048707 Stress

10487071048707 Infection

10487071048707 Uremia

10487071048707 Glucocorticoid excess

10487071048707 Acromegaly

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

The Worsening EpidemicThe Worsening Epidemicof Obesity and Diabetesof Obesity and Diabetes

1999-2000 NHANES Data (JAMA Oct 2002)

31 obese (BMI 30) increase from 23

65 overweight (BMI 25) increase from 56

47 extremely obese (BMI 40) ￪ from 29

No physical activity in 27 No regular activity in additional 28

Each 1-kg increase in weight =remember 9 increase in risk of diabetes

How can lifestyle changes be implemented long term

NHANES=National Health and Nutrition Examination Survey

DrSarmaworks

How It works How It works

DrSarmaworks

Plausible MechanismsPlausible Mechanisms

Mixed IR ndash CHO IR FFA no IR

Lipotoxic state - ￪ FFA

TNFndashalpha IL -6 ndash Adipocytokine - ￪ FFA

PPARndashgamma ndash nuclear enzyme ￪ darr Adiponectin ndash darrFFA oxidation ￪ FFA ndash

IR

FFA ndash IR ndash JNK mediated

Satiation signaling ndash Leptin Resistance

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Synonyms of Metabolic Synonyms of Metabolic syndromesyndrome

1 Insulin resistance syndrome (IRS)

2 (Metabolic) Syndrome X

3 Dysmetabolic syndrome

4 Multiple metabolic syndrome

5 ICD code 2777

DrSarmaworks

What is this Syndrome What is this Syndrome

Insulin resistance ndash Hyperinsulinemia

Hyperglycemia ndash IFG IGT DMII

Pro-inflammatory state ( ￪ CRP)

Pro-coagulant changes ( ￪ PAI-1 ￪ Fibrinogen)

Dyslipidemia ( ￪ TG darrHDL)

Premature atherosclerosis IHD CAD

Type 2 diabetes

Hypertension ED

DrSarmaworks

Definitions of the Metabolic Definitions of the Metabolic SyndromeSyndrome

According to clinical outcomes

According to underlying causes

According to metabolic components

According to clinical criteria

DrSarmaworks

Definition of Metabolic SyndromeDefinition of Metabolic SyndromeAccording to Underlying CausesAccording to Underlying Causes

Insulin resistance (1999 WHO)

Insulin resistance syndrome

Lifestyle especially obesity (NCEP ATP III)

Metabolic syndrome

Sub-clinical inflammation

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

Causes

Acquired causes Overweight and obesity Physical inactivity High carbohydrate diets (gt60 of energy

intake) in some persons

Genetic causes

Metabolic SyndromeMetabolic Syndrome

Currently 47 million US adults- metabolic syndrome Leading health problem in US

DrSarmaworks

Secondary

10487071048707 Pregnancy

10487071048707 Stress

10487071048707 Infection

10487071048707 Uremia

10487071048707 Glucocorticoid excess

10487071048707 Acromegaly

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

The Worsening EpidemicThe Worsening Epidemicof Obesity and Diabetesof Obesity and Diabetes

1999-2000 NHANES Data (JAMA Oct 2002)

31 obese (BMI 30) increase from 23

65 overweight (BMI 25) increase from 56

47 extremely obese (BMI 40) ￪ from 29

No physical activity in 27 No regular activity in additional 28

Each 1-kg increase in weight =remember 9 increase in risk of diabetes

How can lifestyle changes be implemented long term

NHANES=National Health and Nutrition Examination Survey

DrSarmaworks

How It works How It works

DrSarmaworks

Plausible MechanismsPlausible Mechanisms

Mixed IR ndash CHO IR FFA no IR

Lipotoxic state - ￪ FFA

TNFndashalpha IL -6 ndash Adipocytokine - ￪ FFA

PPARndashgamma ndash nuclear enzyme ￪ darr Adiponectin ndash darrFFA oxidation ￪ FFA ndash

IR

FFA ndash IR ndash JNK mediated

Satiation signaling ndash Leptin Resistance

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

What is this Syndrome What is this Syndrome

Insulin resistance ndash Hyperinsulinemia

Hyperglycemia ndash IFG IGT DMII

Pro-inflammatory state ( ￪ CRP)

Pro-coagulant changes ( ￪ PAI-1 ￪ Fibrinogen)

Dyslipidemia ( ￪ TG darrHDL)

Premature atherosclerosis IHD CAD

Type 2 diabetes

Hypertension ED

DrSarmaworks

Definitions of the Metabolic Definitions of the Metabolic SyndromeSyndrome

According to clinical outcomes

According to underlying causes

According to metabolic components

According to clinical criteria

DrSarmaworks

Definition of Metabolic SyndromeDefinition of Metabolic SyndromeAccording to Underlying CausesAccording to Underlying Causes

Insulin resistance (1999 WHO)

Insulin resistance syndrome

Lifestyle especially obesity (NCEP ATP III)

Metabolic syndrome

Sub-clinical inflammation

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

Causes

Acquired causes Overweight and obesity Physical inactivity High carbohydrate diets (gt60 of energy

intake) in some persons

Genetic causes

Metabolic SyndromeMetabolic Syndrome

Currently 47 million US adults- metabolic syndrome Leading health problem in US

DrSarmaworks

Secondary

10487071048707 Pregnancy

10487071048707 Stress

10487071048707 Infection

10487071048707 Uremia

10487071048707 Glucocorticoid excess

10487071048707 Acromegaly

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

The Worsening EpidemicThe Worsening Epidemicof Obesity and Diabetesof Obesity and Diabetes

1999-2000 NHANES Data (JAMA Oct 2002)

31 obese (BMI 30) increase from 23

65 overweight (BMI 25) increase from 56

47 extremely obese (BMI 40) ￪ from 29

No physical activity in 27 No regular activity in additional 28

Each 1-kg increase in weight =remember 9 increase in risk of diabetes

How can lifestyle changes be implemented long term

NHANES=National Health and Nutrition Examination Survey

DrSarmaworks

How It works How It works

DrSarmaworks

Plausible MechanismsPlausible Mechanisms

Mixed IR ndash CHO IR FFA no IR

Lipotoxic state - ￪ FFA

TNFndashalpha IL -6 ndash Adipocytokine - ￪ FFA

PPARndashgamma ndash nuclear enzyme ￪ darr Adiponectin ndash darrFFA oxidation ￪ FFA ndash

IR

FFA ndash IR ndash JNK mediated

Satiation signaling ndash Leptin Resistance

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Definitions of the Metabolic Definitions of the Metabolic SyndromeSyndrome

According to clinical outcomes

According to underlying causes

According to metabolic components

According to clinical criteria

DrSarmaworks

Definition of Metabolic SyndromeDefinition of Metabolic SyndromeAccording to Underlying CausesAccording to Underlying Causes

Insulin resistance (1999 WHO)

Insulin resistance syndrome

Lifestyle especially obesity (NCEP ATP III)

Metabolic syndrome

Sub-clinical inflammation

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

Causes

Acquired causes Overweight and obesity Physical inactivity High carbohydrate diets (gt60 of energy

intake) in some persons

Genetic causes

Metabolic SyndromeMetabolic Syndrome

Currently 47 million US adults- metabolic syndrome Leading health problem in US

DrSarmaworks

Secondary

10487071048707 Pregnancy

10487071048707 Stress

10487071048707 Infection

10487071048707 Uremia

10487071048707 Glucocorticoid excess

10487071048707 Acromegaly

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

The Worsening EpidemicThe Worsening Epidemicof Obesity and Diabetesof Obesity and Diabetes

1999-2000 NHANES Data (JAMA Oct 2002)

31 obese (BMI 30) increase from 23

65 overweight (BMI 25) increase from 56

47 extremely obese (BMI 40) ￪ from 29

No physical activity in 27 No regular activity in additional 28

Each 1-kg increase in weight =remember 9 increase in risk of diabetes

How can lifestyle changes be implemented long term

NHANES=National Health and Nutrition Examination Survey

DrSarmaworks

How It works How It works

DrSarmaworks

Plausible MechanismsPlausible Mechanisms

Mixed IR ndash CHO IR FFA no IR

Lipotoxic state - ￪ FFA

TNFndashalpha IL -6 ndash Adipocytokine - ￪ FFA

PPARndashgamma ndash nuclear enzyme ￪ darr Adiponectin ndash darrFFA oxidation ￪ FFA ndash

IR

FFA ndash IR ndash JNK mediated

Satiation signaling ndash Leptin Resistance

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Definition of Metabolic SyndromeDefinition of Metabolic SyndromeAccording to Underlying CausesAccording to Underlying Causes

Insulin resistance (1999 WHO)

Insulin resistance syndrome

Lifestyle especially obesity (NCEP ATP III)

Metabolic syndrome

Sub-clinical inflammation

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

Causes

Acquired causes Overweight and obesity Physical inactivity High carbohydrate diets (gt60 of energy

intake) in some persons

Genetic causes

Metabolic SyndromeMetabolic Syndrome

Currently 47 million US adults- metabolic syndrome Leading health problem in US

DrSarmaworks

Secondary

10487071048707 Pregnancy

10487071048707 Stress

10487071048707 Infection

10487071048707 Uremia

10487071048707 Glucocorticoid excess

10487071048707 Acromegaly

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

The Worsening EpidemicThe Worsening Epidemicof Obesity and Diabetesof Obesity and Diabetes

1999-2000 NHANES Data (JAMA Oct 2002)

31 obese (BMI 30) increase from 23

65 overweight (BMI 25) increase from 56

47 extremely obese (BMI 40) ￪ from 29

No physical activity in 27 No regular activity in additional 28

Each 1-kg increase in weight =remember 9 increase in risk of diabetes

How can lifestyle changes be implemented long term

NHANES=National Health and Nutrition Examination Survey

DrSarmaworks

How It works How It works

DrSarmaworks

Plausible MechanismsPlausible Mechanisms

Mixed IR ndash CHO IR FFA no IR

Lipotoxic state - ￪ FFA

TNFndashalpha IL -6 ndash Adipocytokine - ￪ FFA

PPARndashgamma ndash nuclear enzyme ￪ darr Adiponectin ndash darrFFA oxidation ￪ FFA ndash

IR

FFA ndash IR ndash JNK mediated

Satiation signaling ndash Leptin Resistance

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

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FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Causes

Acquired causes Overweight and obesity Physical inactivity High carbohydrate diets (gt60 of energy

intake) in some persons

Genetic causes

Metabolic SyndromeMetabolic Syndrome

Currently 47 million US adults- metabolic syndrome Leading health problem in US

DrSarmaworks

Secondary

10487071048707 Pregnancy

10487071048707 Stress

10487071048707 Infection

10487071048707 Uremia

10487071048707 Glucocorticoid excess

10487071048707 Acromegaly

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

The Worsening EpidemicThe Worsening Epidemicof Obesity and Diabetesof Obesity and Diabetes

1999-2000 NHANES Data (JAMA Oct 2002)

31 obese (BMI 30) increase from 23

65 overweight (BMI 25) increase from 56

47 extremely obese (BMI 40) ￪ from 29

No physical activity in 27 No regular activity in additional 28

Each 1-kg increase in weight =remember 9 increase in risk of diabetes

How can lifestyle changes be implemented long term

NHANES=National Health and Nutrition Examination Survey

DrSarmaworks

How It works How It works

DrSarmaworks

Plausible MechanismsPlausible Mechanisms

Mixed IR ndash CHO IR FFA no IR

Lipotoxic state - ￪ FFA

TNFndashalpha IL -6 ndash Adipocytokine - ￪ FFA

PPARndashgamma ndash nuclear enzyme ￪ darr Adiponectin ndash darrFFA oxidation ￪ FFA ndash

IR

FFA ndash IR ndash JNK mediated

Satiation signaling ndash Leptin Resistance

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Secondary

10487071048707 Pregnancy

10487071048707 Stress

10487071048707 Infection

10487071048707 Uremia

10487071048707 Glucocorticoid excess

10487071048707 Acromegaly

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

The Worsening EpidemicThe Worsening Epidemicof Obesity and Diabetesof Obesity and Diabetes

1999-2000 NHANES Data (JAMA Oct 2002)

31 obese (BMI 30) increase from 23

65 overweight (BMI 25) increase from 56

47 extremely obese (BMI 40) ￪ from 29

No physical activity in 27 No regular activity in additional 28

Each 1-kg increase in weight =remember 9 increase in risk of diabetes

How can lifestyle changes be implemented long term

NHANES=National Health and Nutrition Examination Survey

DrSarmaworks

How It works How It works

DrSarmaworks

Plausible MechanismsPlausible Mechanisms

Mixed IR ndash CHO IR FFA no IR

Lipotoxic state - ￪ FFA

TNFndashalpha IL -6 ndash Adipocytokine - ￪ FFA

PPARndashgamma ndash nuclear enzyme ￪ darr Adiponectin ndash darrFFA oxidation ￪ FFA ndash

IR

FFA ndash IR ndash JNK mediated

Satiation signaling ndash Leptin Resistance

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

The Worsening EpidemicThe Worsening Epidemicof Obesity and Diabetesof Obesity and Diabetes

1999-2000 NHANES Data (JAMA Oct 2002)

31 obese (BMI 30) increase from 23

65 overweight (BMI 25) increase from 56

47 extremely obese (BMI 40) ￪ from 29

No physical activity in 27 No regular activity in additional 28

Each 1-kg increase in weight =remember 9 increase in risk of diabetes

How can lifestyle changes be implemented long term

NHANES=National Health and Nutrition Examination Survey

DrSarmaworks

How It works How It works

DrSarmaworks

Plausible MechanismsPlausible Mechanisms

Mixed IR ndash CHO IR FFA no IR

Lipotoxic state - ￪ FFA

TNFndashalpha IL -6 ndash Adipocytokine - ￪ FFA

PPARndashgamma ndash nuclear enzyme ￪ darr Adiponectin ndash darrFFA oxidation ￪ FFA ndash

IR

FFA ndash IR ndash JNK mediated

Satiation signaling ndash Leptin Resistance

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

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FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

How It works How It works

DrSarmaworks

Plausible MechanismsPlausible Mechanisms

Mixed IR ndash CHO IR FFA no IR

Lipotoxic state - ￪ FFA

TNFndashalpha IL -6 ndash Adipocytokine - ￪ FFA

PPARndashgamma ndash nuclear enzyme ￪ darr Adiponectin ndash darrFFA oxidation ￪ FFA ndash

IR

FFA ndash IR ndash JNK mediated

Satiation signaling ndash Leptin Resistance

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Plausible MechanismsPlausible Mechanisms

Mixed IR ndash CHO IR FFA no IR

Lipotoxic state - ￪ FFA

TNFndashalpha IL -6 ndash Adipocytokine - ￪ FFA

PPARndashgamma ndash nuclear enzyme ￪ darr Adiponectin ndash darrFFA oxidation ￪ FFA ndash

IR

FFA ndash IR ndash JNK mediated

Satiation signaling ndash Leptin Resistance

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Insulin Resistance Receptor and Postreceptor Defects

Peripheral tissues(skeletal muscle)

Increased glucose

Pancreas

Liver

Impaired insulin secretion

Increased glucoseproduction

X

Insufficient glucosedisposal

Causes of HyperglycemiaCauses of Hyperglycemiain Type 2 Diabetesin Type 2 Diabetes

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Metabolic SyndromeMetabolic Syndrome I Insulin nsulin Resistance and AtherosclerosisResistance and Atherosclerosis

MacFarlane S et al J Clin Endocrinol Metab 200186713-718

Hyperinsulinemiahyperproinsulinemia

Glucoseintolerance

Increasedtriglycerides

DecreasedHDL cholesterol

Increased BPEndothelial dysfunction

Small denseLDL

Atheroscleroticcardiovascular

disease

IncreasedPAI-1

Insulin resistance

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Normal Type 2 Diabetes

Courtesy of Wilfred Y Fujimoto MD

Visceral Fat DistributionVisceral Fat DistributionNormal vs Type 2 DiabetesNormal vs Type 2 Diabetes

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

ThiazolidinedionesThiazolidinediones Adipose tissueAdipose tissue

MuscleMuscle LiverLiver

Decreased FFA and TNFreleaseDecreased tissue triglycerides

Increased adiponectin

Decreasedglucoseoutput

Increasedglucose

utilization

-cell-cell

Increasedinsulin

secretion

VascularVascular

Increasedendothelial

function

PPARPPAR

Adapted from Goldstein BJ Adapted from Goldstein BJ Am J CardiolAm J Cardiol Suppl 2002 Suppl 2002

Effects of Thiazolidinediones Effects of Thiazolidinediones MediatedMediated

via Adipose Tissuevia Adipose Tissue

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

NO reductionVascular constrict

NO reductionVascular constrict

NO productionVascular dilationNO production

Vascular dilation

Adapted from Steinberg H et al Diabetes 2000491231

ThiazolidinedionesThiazolidinediones

Insulin Insulin ResistanceResistance

Shear stressShear stress

Increased visceral fatIncreased visceral fat

Increased lipolysisIncreased lipolysis

Increased FFA levelsIncreased FFA levels

--

EndotheliumEndothelium

Increased TNFIncreased TNF

--

Decreased adiponectinDecreased adiponectin

--

FFA and Adipokines inFFA and Adipokines inEndothelial Endothelial DysfunctionDysfunction

--

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Multiple Factors May Drive Multiple Factors May Drive Progressive Decline of Progressive Decline of -Cell -Cell

FunctionFunction

Adapted from Unger RH Orci L Biochim Biophys Acta 20021585202-212

Hyperglycemia(glucose toxicity)

Proteinglycation -cell

ObesityInsulin resistance

ldquoLipotoxicityrdquo(elevated FFA TG)

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

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FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworksNGT=normal glucose toleranceWeyer C et al Diabetes Care 20002489-94

Insulin Resistance and Insulin Resistance and -Cell Defect-Cell DefectBoth Contribute to Diabetes Both Contribute to Diabetes

ProgressionProgression

4-Year Cumulative Incidence of Diabetes

N=145 Pima Indians with initial NGT

Low HighHigh

Low

Per

cen

t

0

10

20

30

40

Insulin Secretion

Glucose Disposal

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

GeneticsEnvironmentbull nutritionbull obesitybull exercise

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failureInsulin resistance

HyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Onset ofdiabetes

Disability

Death

Impairedglucosetolerance

Ongoinghyperglycemia

Complications

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Therapeutic Implications Therapeutic Implications According to Underlying CausesAccording to Underlying Causes

Insulin resistance

Treat insulin resistance

Lifestyle especially obesity

Prevent and treat obesity

Sub-clinical inflammation

Treat obesity

Statins Thiozolidines etc

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Risk Factor Defining Level

Abdominal obesity(Waist circumference)

MenWomen

gt90 cm (gt40 in) 102 cmgt80 cm (gt35 in) 88 cm

TG 150 mgdl

HDL-C

MenWomen

lt40 mgdllt50 mgdl

Blood pressure 13085 mm Hg (14090)

Fasting glucose 100 mgdl ( gt110)

ATP III The Metabolic SyndromeATP III The Metabolic SyndromeDiagnosis is established when Diagnosis is established when 3 of these 3 of these

abnormalities are present abnormalities are present

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Based on Clinical CriteriaBased on Clinical Criteria

Insulin resistance (type 2 diabetes IFG IGT)

Plus any 2 of the following

Elevated BP (14090 or drug Rx)

Plasma TG 150 mgdl

HDL lt35 mgdl (men) lt40 mgdl (women)

BMI gt30 andor WH gt09 (men) gt085 (women)

Urinary albumin gt20 mgmin AlbCr gt30 mgg

Note that 1999 WHO uses hyperinsulinemic euglycemic clamp whereas 1998 WHO and EGIR use HOMA-IR

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

In patients with Acanthosis Nigricans with or without DMII not taking statins or lipid lowering agents check their lipid panel if their LDL and triglycerides are really low think of cancer The cancers of the endothelium eat up the cholesterol for energy

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Acanthosis NigricansAcanthosis Nigricans

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

PCOSPCOS Chronic ovarian dysfunction found in about 6 of pre-menopausal

Amenorrhea Dysmenorrhea oligomenorrhea abd pain

androgenic characteristics such as low voice and Hirsutism

Acanthosis Enlarged ovaries may have multiple small cysts

Acne infertility seborrhea Acanthosis obesity

Metabolic syndrome Insulin Resistance DMII CVD

HTN Dyslipidemia Infertility Elevated Luteinizing hormone

Low normal FSH May have elevated insulin levels

Low dose hormonal contraceptives and depo-provera ￪ IR

Rx of the co morbidities such as obesity insulin resistance MS

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

NAFLDNAFLD

There are severe fatty changes in liver

USG is diagnostic

No history of alcoholism

This reflects fat deposition intra-abdominally

Non alcoholic fatty liver disease (NAFLD)

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

Metabolic Syndrome Increases Risk Metabolic Syndrome Increases Risk for CHD and Type 2 for CHD and Type 2

DiabetesDiabetes

Coronary Heart DiseaseCoronary Heart Disease

Type 2Type 2DiabetesDiabetes

HighHighLDL-CLDL-C

MetabolicMetabolicSyndromeSyndrome

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Conversion Status at Follow-up

Diabetes (n=18) Normal (n=490) P

BMI (kgm2) 282 11 272 02 472

Centrality 138 009 116 02 472

TG (mmol) 183 012 126 010 006

HDL-C (mmol) 114 007 128 002 045

SBP (mm Hg) 1168 30 1088 08 004

Fasting glucose (mmol)

528 01 500 002 032

Fasting insulin (pmol) 157 27 81 5 006

Increased Metabolic Syndrome in Pre-diabetic Subjects Increased Metabolic Syndrome in Pre-diabetic Subjects Baseline Risk Factors in Subjects with Normal Glucose Baseline Risk Factors in Subjects with Normal Glucose Tolerance at Baseline according to Conversion Status Tolerance at Baseline according to Conversion Status

at 8 Year Follow-up -at 8 Year Follow-up - San Antonio Heart Study San Antonio Heart Study

Haffner SM et al JAMA 19902632893-2898

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Non-diabeticthroughout the study

Prior todiagnosis of

diabetes

Elevated Risk of CVD Prior to Clinical Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes - Diagnosis of Type 2 Diabetes - Nursesrsquo Nursesrsquo

Health StudyHealth Study

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1129-1134Reprinted with permission from The American Diabetes Association

Rela

tive R

isk

11

282282

371371

502502

After diagnosis of

diabetes

Diabetic at

baseline

0

1

2

3

4

5

6

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Risk of Major CHD Event Associated Risk of Major CHD Event Associated with Insulin Quintiles in Non-diabetic with Insulin Quintiles in Non-diabetic Subjects Subjects Helsinki Policemen StudyHelsinki Policemen Study

070

075

080

085

090

095

100

Years5 10 200 15 25

Pyoumlraumllauml M et al Circulation 199898398-404

Log rankOverall P = 001Q5 vs Q1 P lt 001

Q1

Q2

Q3

Q4Q5P

roport

ion w

ithout

Majo

r C

HD

Event

0

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

HOMA-IR

Q1 Q2 Q3 Q4 Q5

HDL-C (mgdl) 517 493 478 450 412

LDL-C (mgdl) 1157 1193 1250 1281 1248

Cholesterol (mgdl) 1880 1916 1979 2008 1990

Triglyceride (mgdl) 1057 1166 1297 1454 1872

Systolic BP (mm Hg) 1149 1165 1183 1193 1230

Diastolic BP (mm Hg) 690 704 719 731 754

CVD Risk Factors across HOMA-IR CVD Risk Factors across HOMA-IR Quintiles Quintiles San Antonio Heart Study San Antonio Heart Study

(Phase II)(Phase II)

All p(trend) lt 00001 quintile cut points 10 16 25 48

Adjusted for age sex ethnicity

Copyright copy 2002 American Diabetes AssociationFrom Diabetes Care Vol 25 2002 1177-1184Reprinted with permission from The American Diabetes Association

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

40ndash49

Prevalence of NCEP Metabolic Syndrome Prevalence of NCEP Metabolic Syndrome N NHANES III by AgeHANES III by Age

Ford ES et al JAMA 2002287356-359

Pre

vale

nce

2020ndash70+70+

Age years20ndash29 3030ndash3939 50ndash59 6060ndash6969 70

Men

Women

24242323

8866

44444444

0

10

20

30

40

50

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

0

10

20

30

40

Prevalence of the NCEP Metabolic Prevalence of the NCEP Metabolic Syndrome Syndrome NHANES III by Sex and NHANES III by Sex and

RaceEthnicityRaceEthnicity

Pre

vale

nce

MenFord ES et al JAMA 2002287356-359

Women

WhiteAfrican AmericanMexican AmericanOthers

2525

1616

2828

21212323

2626

3636

2020

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Prevalence of CHD by the Metabolic Prevalence of CHD by the Metabolic Syndrome and Diabetes in the Syndrome and Diabetes in the NHANES Population Age 50+NHANES Population Age 50+

CH

D P

revale

nce

of Population =

No MSNo DMNo MSNo DM

542542MSNo DMMSNo DM

287287DMNo MSDMNo MS

2323DMMSDMMS148148

87

139

75

192

0

5

10

15

20

25

Alexander CM et al Diabetes 2003521210-1214

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

ATP III Metabolic SyndromeATP III Metabolic SyndromeTherapeutic ImplicationsTherapeutic Implications

Focus on obesity (especially abdominal obesity) as the underlying cause of the metabolic syndrome

Therefore prevent development of obesity in the general population

Also treat obesity in the clinical setting (NHLBINIDDK Obesity Education Initiative)

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

VariableOddsRatio

Lower 95Limit

Upper 95Limit

Waist circumference 113 085 151

Triglycerides 112 071 177

HDL cholesterol 174 118 258

Blood pressure 187 137 256

Impaired fasting glucose 096 060 154

Diabetes 155 107 225

Metabolic syndrome 094 054 168

Different Components of the NCEP Different Components of the NCEP Metabolic Syndrome Predict CHD Metabolic Syndrome Predict CHD

NHANESNHANES

Significant predictors of prevalent CHDSignificant predictors of prevalent CHD

Prediction of CHD Prevalence using Prediction of CHD Prevalence using Multivariate Logistic RegressionMultivariate Logistic Regression

Copyright copy 2003 American Diabetes AssociationFrom Diabetes Vol 52 2003 1210-1214Reprinted with permission from The American Diabetes Association

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

0 2 4 6 8 10

BMI per kgm2

HDL-C per mgdldarr

SBP per mm Hg

FPG per mgdl

Different Components of NCEP Metabolic Different Components of NCEP Metabolic Syndrome Predict Diabetes Syndrome Predict Diabetes San Antonio San Antonio

Heart StudyHeart Study

Stern MP et al Ann Intern Med 2002136575-581

Risk of Type 2 Diabetes per Unit Change in Risk Trait Risk of Type 2 Diabetes per Unit Change in Risk Trait LevelsLevels

88

22

44

77

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Must Insulin Resistance be Must Insulin Resistance be Present for a Patient to Have the Present for a Patient to Have the

Metabolic SyndromeMetabolic Syndrome WHO 1999 clinical definition Yes

ATP III 2001 clinical definition No but it is usually present Multiple metabolic risk factors are sufficient Obesity can produce the metabolic syndrome

without insulin resistance

WHO Definition Diagnosis and Classification of Diabetes Mellitus and Its Complications Report of a WHO Consultation Geneva WHO 1999 | Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults JAMA 20012852486-2497

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

WHO Metabolic Syndrome Definition WHO Metabolic Syndrome Definition 1999 1999 Therapeutic ImplicationsTherapeutic Implications

Focus on insulin resistance as the underlying cause of the metabolic syndrome

More emphasis on the genetic basis of the metabolic syndrome rather than obesity

Leads to increased thinking about the use of drugs to treat insulin resistance in patients with the metabolic syndrome

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Therapeutic Implications of Therapeutic Implications of Definition of Metabolic SyndromeDefinition of Metabolic Syndrome

If focus is on obesity as underlying cause

Prevent and treat obesity

If focus is on insulin resistance as underlying cause

Treat insulin resistance

If focus is on metabolic risk factors

Treat individual risk factors

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Criteria for Comparing Different Criteria for Comparing Different Definitions of Metabolic SyndromeDefinitions of Metabolic Syndrome

Risk of

CHD

DM

Relation to

Insulin resistance

Obesity

Prevalence in community could differ by race

How simple is the definition

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Intensity of Therapy Should be Intensity of Therapy Should be Proportionate to Level of RiskProportionate to Level of Risk

What is the impact of the metabolic syndrome on health outcomes

Cardiovascular disease

Type 2 diabetes

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Prevention of Type 2 Diabetes Prevention of Type 2 Diabetes Completed Trials in IGTCompleted Trials in IGT

31

58

Metformin

Lifestyle changes

N Engl J Med

2002Diabetes Prevention Program (DPP)3

1 Pan XR et al Diabetes Care 199720537-544 2 Tuomilehto J et al N Engl J Med 20013441343-13503 Knowler WC et al N Engl J Med 2002346393-4034 Chiasson JL et al Lancet 20023592072-2077

25AcarboseLancet2002

STOP-NIDDM4

58Intensive lifestyle

N Engl J Med2001

Finnish Prevention Study (FPS)2

31-46Diet +or exercise

Diabetes Care1997

Da Qing IGT and Diabetes Study1

Results (risk darr)TreatmentJournalYearTrial

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Cardiovascular Disease Mortality Increased Cardiovascular Disease Mortality Increased in the Metabolic Syndrome in the Metabolic Syndrome Kuopio Kuopio

Ischemic Heart Disease Risk Factor StudyIschemic Heart Disease Risk Factor Study

Lakka HM et al JAMA 20022882709-2716

Cum

ula

tive H

aza

rd

0 2 6 8 12Follow-up years

YESYES

Metabolic Syndrome

NONO

Cardiovascular Disease Mortality

RR (95 CI) 355 (198ndash643)

4 100

5

10

15

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

NCEP Met Syn WHO Met Syn

Total Population

All Cause 143 (110ndash187) 125 (096ndash163)

CVD 255 (175ndash372) 164 (113ndash237)

Disease Free

All Cause 111 (074ndash167) 087 (057ndash133)

CVD 204 (114ndash363) 077 (038ndash155)

Cox Proportional Hazard Ratios (and 95 Cox Proportional Hazard Ratios (and 95 CI) Predicting All-Cause amp Cardiovascular CI) Predicting All-Cause amp Cardiovascular

Mortality Mortality San Antonio Heart Study 14-Year Follow-San Antonio Heart Study 14-Year Follow-

upup

Hunt KJ et al Diabetes 200352A221-A222

Those without diabetes cardiovascular disease or cancer Adjusted for age gender and ethnic group

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Comparison of NCEP and 1999 WHO Comparison of NCEP and 1999 WHO Metabolic Syndrome to Identify Insulin-Metabolic Syndrome to Identify Insulin-

Resistant Subjects Resistant Subjects IRASIRAS

in L

ow

est

Quart

ile o

f S

i

Hanley AJ et al Diabetes 2003522740-2747

Neither NCEP Only WHO Only Both

Overall

Hispanics

Non-Hispanic whites

African Americans

0102030405060708090

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Rela

t ive R

isk

CRP Adds Prognostic Information at All CRP Adds Prognostic Information at All Levels of Risk as Defined by the Levels of Risk as Defined by the

Framingham Risk ScoreFramingham Risk Score

lt10

hs-CRP(mgL)

Framingham 10-Year Risk ()

10ndash30

gt30

Ridker PM et al N Engl J Med 20023471557-1565

10+ 5ndash9 2ndash4 0ndash10

5

10

15

20

25

Copyright copy 2002 Massachusetts Medical Society All rights reserved Adapted with permission

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Partial Spearman Correlation Analysis of Partial Spearman Correlation Analysis of Inflammation Markers with Variables of IRS Inflammation Markers with Variables of IRS Adjusted for Age Sex Clinic Ethnicity and Adjusted for Age Sex Clinic Ethnicity and

Smoking Status Smoking Status IRASIRASCRP WBC Fibrinogen

BMI 040Dagger 017Dagger 022Dagger

Waist 043Dagger 018Dagger 027Dagger

Systolic BP 020Dagger 008 011dagger

Fasting glucose 018Dagger 013Dagger 007

Fasting insulin 033Dagger 024Dagger 018Dagger

Si ndash037Dagger ndash024Dagger ndash018Dagger

Festa A et al Circulation 200010242ndash47

Plt005 daggerPlt0005 DaggerPlt00001

CRP=C-reactive protein IRS=insulin-resistance syndrome WBC=white blood cell count

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

0

Mean V

alu

e o

f Lo

g C

RP

Mean Values of CRP by Number of Metabolic Mean Values of CRP by Number of Metabolic Disorders (Dyslipidemia Upper Body Disorders (Dyslipidemia Upper Body

Adiposity Insulin Resistance Hypertension) Adiposity Insulin Resistance Hypertension) IRASIRAS

Festa A et al Circulation 200010242ndash47

Number of Metabolic Disorders

1 2 3 4000204060810121416

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Fibrinogen CRP PAI-1

Five-Year Incidence of Type 2 Diabetes Five-Year Incidence of Type 2 Diabetes Stratified by Quartiles of Inflammatory Stratified by Quartiles of Inflammatory

Proteins Proteins IRASIRAS

Inci

den

ce

1st

Festa A et al Diabetes 2002511131-1137

2nd 3rd 4thQuartilesP=006P=006 P=0001P=0001 P=0001P=0001

0

5

10

15

20

25

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

The Effect of Rosiglitazone on CRPThe Effect of Rosiglitazone on CRP

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Ch

an

ge f

rom

Base

line t

o

Week

26

Difference = ndash268 Difference = ndash268 (95 CI ndash397 ndash218)(95 CI ndash397 ndash218)

Placebo

Difference = ndash218 (95 CI ndash347 ndashDifference = ndash218 (95 CI ndash347 ndash56)56)

-50

-40

-30

-20

-10

0n=95 n=124 n=134

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

The Effect of Rosiglitazone on IL-6The Effect of Rosiglitazone on IL-6

Haffner SM et al Circulation 2002106679-684

Rosiglitazone8 mgd8 mgd

Rosiglitazone4 mgd4 mgd

Difference = ndash19 Difference = ndash19 (95 CI ndash113 93)(95 CI ndash113 93)

Placebo

Difference = 00 (95 CI ndash90 100)Difference = 00 (95 CI ndash90 100)

Ch

an

ge f

rom

Base

line t

o

Week

26

-50

-40

-30

-20

-10

0 n=91 n=120 n=132

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

0

1

2

3

4

5

6

hs-

CR

P (

mgL

)ReductionReduction of CRP Levels of CRP Levels

with Statin Therapy (n=22) with Statin Therapy (n=22)

Jialal I et al Circulation 20011031933-1935

AtorvastatiAtorvastatinn

(10 mgd)(10 mgd)

SimvastatinSimvastatin(20 mgd)(20 mgd)

PravastatinPravastatin(40 mgd)(40 mgd)

BaselineBaseline

plt0025 vs Baselineplt0025 vs Baseline plt0025 vs Baselineplt0025 vs Baseline

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Insulin resistance is related to increased PAI-1 fibrinogen and CRP levels in all sections

Increased levels of PAI-1 CRP and fibrinogen predict the development of type 2 diabetes In some analyses these associations are independent of obesity and insulin resistance

Rosiglitazone a TZD decreases levels of PAI-1 CRP and MMP-9

SummarySummary

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Does Lipid and Blood Pressure Does Lipid and Blood Pressure Therapy Work in Subjects with the Therapy Work in Subjects with the

Metabolic SyndromeMetabolic Syndrome

Diabetic subjects

Blood pressure YES

Statin therapy YES

Non-diabetic non lipid subjects

Little data available

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

StudyStudy DrugDrug NoNo

CHD Risk CHD Risk Reduction Reduction

OverallOverall

CHD Risk CHD Risk Reduction in Reduction in

DiabeticsDiabetics

Primary PreventionPrimary Prevention

AFCAPSTexCAPS Lovastatin 155 37 43 (NS)

HPS Simvastatin 2912 24 33 (p=0003)

Secondary Secondary PreventionPrevention

CARE Pravastatin 586 23 25 (p=05)

4S Simvastatin 202 32 55 (p=002)

LIPID Pravastatin 782 25 19

4S Reanalysis Simvastatin 483 32 42 (p=001)

HPS Simvastatin 1981 24 15

CHD Prevention Trials with Statins in CHD Prevention Trials with Statins in Diabetic Subjects Diabetic Subjects Subgroup AnalysesSubgroup Analyses

Downs JR et al JAMA 19982791615-1622 | HPS Collaborative Group Lancet 20033612005-2016 | Goldberg RB et al Circulation 1998982513-2519 | Pyoumlraumllauml K et al Diabetes Care 199720614-620 | LIPID Study Group N Engl J Med 19983391349-1357 | Haffner SM et al Arch Intern Med 19991592661-2667

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Completed Clinical Trials with Completed Clinical Trials with Antihypertensive Agents in Antihypertensive Agents in

DiabetesDiabetesTrial DiabeticTotal Results

SHEP 5834736 Beneficial

GISSI-3 279018131 Beneficial

Syst-Eur 4924695 Beneficial

HOT 150118790 Beneficial

UKPDS 1148 Beneficial

CAPPP 57210985 Beneficial

Curb JD et al JAMA 19962761886-1892 | Zuanetti G et al Circulation 1997964239-4245 | Staessen JA et al Am J Cardiol 19988220Rndash22R | Hansson L et al Lancet 19983511755-1762 | UKPDS Group BMJ 1998317703-713 | Hansson L et al Lancet 1999353611-616

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Isolated Isolated LDL-C LDL-CRR=086 (059ndash126)RR=086 (059ndash126)

0

10

20

30

40

221

ldquoldquoMetabolic Syndromerdquo in 4SMetabolic Syndromerdquo in 4SEven

t R

ate

Ballantyne CM et al Circulation 20011043046-3051

Simvastatin

Placebo

237 261 284

180203190

369

Lipid TriadLipid TriadRR=048 (033ndash069)RR=048 (033ndash069)

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

0

10

20

30

40

50

60

70

80

Hb A1 c lt65

Efficacy of Multiple Risk Factor Intervention Efficacy of Multiple Risk Factor Intervention in High-Risk Subjects (Type 2 Diabetes with in High-Risk Subjects (Type 2 Diabetes with

Micro-albuminuria) Micro-albuminuria) Steno-2Steno-2

Pati

ents

Reach

ing Inte

nsi

ve-

Tre

atm

ent

Goals

at

Mean 7

8 y

(

)

Gaeligde P et al N Engl J Med 2003348383-393

Intensive Therapy

Cholesterollt175 mgdl

Triglyceride lt150 mgdl

Systolic BPlt130 mm

Diastolic BPlt80 mm

Conventional Therapy

P=006

Plt0001P=019

P=0001

P=021

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

0

10

20

30

40

50

60

Composite Endpoint of Death from CV Causes Composite Endpoint of Death from CV Causes Nonfatal MI CABG PCI Nonfatal Stroke Nonfatal MI CABG PCI Nonfatal Stroke Amputation or Surgery for PAD Amputation or Surgery for PAD STENO-2STENO-2

Pri

mary

Com

posi

te

Endpoin

t (

)

Months of Follow-upGaeligde P et al N Engl J Med 2003348383-393

0 24 48 60 9636 847212

Conventional Conventional TherapyTherapy

Intensive Intensive TherapyTherapy

P=0007P=0007

Hazard ratio = 047 Hazard ratio = 047 (95 CI 024ndash073 (95 CI 024ndash073 P=0008)P=0008)

Copyright copy 2003 Massachusetts Medical Society All rights reserved

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

FACTS ABOUT FATS WE EATFACTS ABOUT FATS WE EAT

SaFA Saturated fatty acids Coconut Red meat palm oil butter ghee vanaspati

bakery products TrUFA Trans unsaturated fatty acids

Vanaspati margarine crispy fried food buscuits MUFA Mono unsaturated fatty acids

Olive oil canola Nuts PUFA Poly unsaturated fatty acids

Sunflower oil Omega 3 fatty acids ndash EPA DHA AA ndash Fish oils Reusing cooking oil ndash great peril

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

FAT FACTSFAT FACTSName SAFA MUFA PUFA Chol mg

Canola oil 6 55 28 0

Safflower 8 11 67 0

Sunflower 10 18 60 0

Olive oil 12 66 7 0

Sesame oil 13 36 38 0

Groundnut 15 41 29 0

Palm oil 45 33 3 0

Red meat 46 38 10 93 mg

ButterGhee 48 27 4 207 mg

Coconut oil 79 5 1 0

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

We are What We Eat We are What We Eat

CHO ndash 60 Not simple CHO Complex CHO

Protein intake must be at least 15 of calories

Pulses legumes sprouts nuts milk proteins

Fats ndash quantity darr quality more of MUFA amp PUFA O3F

Fresh vegetables regular diet ndash fibre

Plenty of whole fruits ndash not juices ndash pentoses fibre vit

Avoid junk foods ndash crispy crunchy colas fast foods

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

What should I take home What should I take home

Metabolic syndrome is a hidden volcano

We need to evaluate every one above 25 years of age for MS

All those with any one manifestation should be screened for the rest of the components

Waist circumference IR Dys Lipidemia

There are effective Rx stategies

This MS is the ldquoPRErdquo for DMII and CHD

We should not wait till these killers develop

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Metabolic SyndromeMetabolic SyndromeTherapeutic Objectives

To reduce underlying causes Overweight and obesity Physical inactivity

To treat associated lipid and non-lipid risk factors Hypertension Prothrombotic state Atherogenic dyslipidemia (lipid triad)

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Management of Overweight and Obesity

Overweight and obesity lifestyle risk factors

Direct targets of intervention

Weight reduction Enhances LDL lowering Reduces metabolic syndrome risk factors

Clinical guidelines Obesity Education Initiative Techniques of weight reduction

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Management of Physical Inactivity

Physical inactivity lifestyle risk factor

Direct target of intervention

Increased physical activity Reduces metabolic syndrome risk

factors Improves cardiovascular function

Clinical guidelines US Surgeon Generalrsquos Report on Physical Activity

Metabolic SyndromeMetabolic Syndrome

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Management StrategiesManagement Strategies

1 TLC ndash Diet and Weight reduction

2 Physical activity ndash Abdominal exercises

3 Insulin sensitizers ndash Metformin

4 Insulin ndash CHO Fat metabolizer anti thrombotic anti inflammatoty

5 Glitazones ndash Insulin sensitizer Anti Inflammatory

6 Statins ndash Anti inflamma Anti lipid Anti thrombotic

7 Aspirin ndash anti thrombotic anti inflammatory

8 Nitrates ndash No increase vasodilatory

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Summary Metabolic SyndromeSummary Metabolic Syndrome

The metabolic syndrome predicts the onset of both DM and CHD Insulin resistance and obesity characterize most individuals

subjects with the metabolic syndrome although not required features of the NCEP metabolic syndrome

Initial therapy for the metabolic syndrome should consist of caloric restriction and increased physical activity

Conventional cardiovascular risk factors such as lipids and blood pressure should be treated in individuals with the metabolic syndrome

No consensus exists on whether insulin sensitizers should be used in non-diabetic individuals with the metabolic syndrome

DrSarmaworks

Hope it is informative enough

To set all of us into action

DrSarmaworks

Hope it is informative enough

To set all of us into action