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MACROVASCULAR COMPLICATION & DIABETES

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What Are the Potential Benefits What Are the Potential Benefits of Personalized Medicine?of Personalized Medicine?

Earlier disease protection

Optimize therapeutic selection and dosing

Reduce adverse drug reactions

Increase patient compliance with therapy

Reduce the time, cost, and failure rate of clinical trials by

improving the selection of targets for drug discovery

“Save” therapeutics

Shift the emphasis in medicine from reaction to prevention

Reduce the overall cost of healthcare

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Tools Needed for Prediction and Personalized Care

Dis

ease

Bur

den

Time

Cos

t

1/re

vers

ibili

ty

Typical Current

Intervention

Earliest Clinical

Detection

Earliest Molecular Detection

Initiating Events

Baseline Risk

Decision Support Tools:

Baseline Risk Preclinical Progression

Disease Initiation and Progression

Assess Risk Refine Assessment Predict/Diagnose Monitor Progression

Predict Events

Inform Therapeutics

Sources of New Biomarkers:

Stable Genomics: Single Nucleotide Polymorphisms (SNPs) Haplotype Mapping Gene Sequencing

Dynamic Genomics: Gene ExpressionProteomics Metabolomics Molecular Imaging

Therapeutic Decision Support

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Macrovascular complications

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MACROVASCULAR COMPLICATION

DIABETES

IHDCVD

PVD

Why accelerated

NO Definite Answers

Many factors

Risk factors

Is it preventable or at least delayed

yes

Atherosclerosis: An Inflammatory Disease

III.2© 2002 PPS®

C

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1. Atherosclerotic lesions Fatty streaks.

Gelatinous plaques. Fibrous plaques.

Complicated plaques.2. Theories of atherogenesis

Lipid hypothesis. Thrombogenetic hypothesis.

Mesenchymal hypothesis. Monoclonal hypothesis.

Response to injury hypothesis.

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C – Peptide and atherosclerosis

http://www.hindawi.com/journals/mi/2012/858692/

C-peptide protects endothelial cells from apoptosis and inflammation triggered by high glucose conditions [62]. The situation can be totally different in patients with insulin resistance and type 2 diabetes where high levels of C-peptide could have opposite effects.

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Cardiometabolic Risk

Global Diabetes / CVD Risk

Overweight / Obesity

Inflammation Hypercoagulation

Elevated

Blood Pressure

Smoking

Age, Race, Sex,

Family History

GlucoseBP Lipids

Age Genetics

Insulin Resistance

Abnormal Lipid Metabolism.

LDL or ApoB HDL Triglycerides

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Prevalence of MeS in different Countries

Country Year Sample Prevalence (%)

Arab Americans 2003 542 23

Oman 2001 1419 21

Jordan 2002 1121 36

Saudi Arabia 2004 2250 20.8

Palestine 1998 17*

Qatar 2007 817 27.6

Turkey 2004 1637 33.4*

Iran ? 10368 33.7

* Crude rates Mussallam et al. Int J Food Safety and PH 2008

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What are the clinical outcomes of the metabolic syndrome?

Cardiovascular disease Relative risk = 2x

Type 2 diabetes Relative risk = 5x

Fatty liver Obstructive sleep apnea Cholesterol gallstone Polycystic ovarian disease

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Definitions of the Metabolic Syndrome

We get a new definition about every 2 years

We now have 7 definitions

No definition has been accompanied by data on

its sensitivity, specificity and positive predictive

value

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Metabolic Syndrome: Overview

Metabolic Syndrome is not a disease, but rather a cluster of disorders of your body’s metabolism, including:

o High blood pressureo High insulin levelso Excess body weighto Abnormal cholesterol levels

Each of these disorders is by itself a risk factor for other diseases.

In combination, however, these disorders dramatically boost the chances of developing potentially life-threatening illnesses, such as diabetes, heart disease or stroke.

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What are unresolved questions about the MetS? (Kahn et al. 2005)

Metabolic syndrome name? Existence of metabolic syndrome? More than some of its parts? MetS vs. prediabetes & type 2 diabetes Diagnostic utility? Pathogenesis? Clinical utility?

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Is the metabolic syndromea “syndrome”?

A collection of things Clustering of signs and symptoms Three or more related entities

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Plurametabolic syndrome (Crepaldi) Syndrome X (Reaven) Deadly Quartet (Kaplan) Metabolic syndrome (WHO; NCEP: IDF) Insulin resistance syndrome (EGIR; AACE) Dysmetabolic syndrome Cardiometabolic syndrome CHAOS (Australia)

What should the metabolic syndrome be called?

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What is the metabolic syndrome?

Clustering of

Metabolic Risk Factors (3+) Atherogenic dyslipidemia Elevated blood pressure Elevated plasma glucose Prothrombotic state Proinflammatory state

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Diagnosing Metabolic Syndrome

Waist Circumference o Greater than 35 inches in women and 40 inches in men (abdominal obesity)

Triglycerideo Levels of 150 milligrams per deciliter (mg/dl) or higher

Blood Pressureo 130/85 millimeters of mercury or higher

Fasting blood glucoseo Level of 110 mg/dl or higher

High-density lipoprotein cholesterol (HDL)o Lower than 50 mg/dl in women and 40 mg/dl for men

According to the National Cholesterol Education Program (NCEP), the presence of three or more of the following traits indicates

metabolic syndrome:

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ATP III Clinical Identification of the Metabolic Syndrome

Waist circumference: Men>102 cm (>40 in) Women>88 cm (>35 in)

Triglycerides >150 mg/dL HDL cholesterol: 

Men<40 mg/dL   Women<50 mg/dL

Blood pressure 130/ 85 mm Hg Fasting glucose >110 mg/dL*

* New ADA guidelines suggest >100mg/dl increases risk for Metabolic Syndrome

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International Diabetes Federation (IDF) Definition

Modified ATPIII definition Fasting Glucose > 100mg/dl Adjusted waist circumference based on ethnicity

(i.e. asians with lower waist circumference threshold than pacific islanders)

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Clinical Measure

WHO (1998) AACE (2003)AHA/NHLBI

(2005)IDF (2005)

Insulin resistance

IGT, IFG, T2DM, or ins. resist. And 2 of

the below

IGT or IFG. And any of the below. Clinical judgment

None.

3 of the belowNone

ObesityWHR >0.90 in men or >0.85 in women

and/or BMI >30BMI > 25

Waist ≥102 cm in men or ≥88 cm in

women

Waist (population specific).

And any 2 of the below

TG (mg/dl)TG >150 and/or

HDL-C <35 in men or < 39 in women

TG >150 and HDL-C <40 in men or <50 in

women

≥150 or Rx ≥150 or Rx

HDL (mg/dl)<40 in men, <50 in women or Rx

<40 in men, <50 in women or Rx

Blood pressure (mm Hg)

>140/90 > 130/85 mm Hg≥130 or ≥85 or

Rx ≥130 or ≥85 or

Rx

Glucose (mg/dl) IGT, IFG, or T2DMIGT or IFG (not

diabetes)> 100 or Rx > 100 or Rx

Other MicroalbuminuriaOther features of

insulin resistance

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References

Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). (2)Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.

International Diabetes Federation Insulin-sensitising drugs, The Cochrane Database of

Systematic Reviews Date of last Substantial Update: December 31. 2002

Effects of Rimonabant on Metabolic Risk Factors in Overweight Patients with Dyslipidemia, NEJM. Nov 2005

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Insulin-resistance and Insulin-resistance and ββ-cell function-cell function

Amiloyd storeAmiloyd store

GlucotoxicityGlucotoxicity(hyperglycemia(hyperglycemia))

Hyper-Hyper-insulinaemiainsulinaemia

ProteinProteinGlycosilationGlycosilation

LipotoxicityLipotoxicity((↑ ↑ FFA e TG)FFA e TG)

Insulin-Insulin-resistanceresistance

⇩⇩ ββ-cell-cell

functionfunction

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The new IDF definition focusses on

abdominal obesity rather than insulin

resistance

International Diabetes Federation (IDF) Consensus Definition 2005

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Fat Topography In Type 2 Diabetic Subjects

Intramuscular

Intrahepatic

Subcutaneous

Intra-abdominal

FFA*TNF-alpha*Leptin*IL-6 (CRP)*Tissue Factor*PAI-1*

Angiotensinogen*

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NEFA

Cytokines(TNF &

IL-6)Adiponectin PAI-1

Leptin Resistin

Angioten-sinogen

Adipose Tissue

Adipose Tissue

MetabolicRisk Factors

ElevatedBlood Pressure

AtherogenicDyslipidemia

ElevatedGlucose

Pro-thrombotic

State

Pro-inflammatory

State

How does obesity contribute to MetS?

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Diabetes Obesity

Dia Besity

DiabesityUp–regulation of adiponectin and its receptor, through the use of

thiazolidinediones, has been found to be partially related to insulin sensitization and thus antidiabetic effects.

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Abdominal obesity and increased risk of cardiovascular events

Dagenais GR et al, 2005

Ad

just

ed r

elat

ive

risk

1 1 1

1.17 1.16 1.14

1.29 1.27

1.35

0.8

1

1.2

1.4

CVD death MI All-cause deaths

Tertile 1

Tertile 2Tertile 3

Men Women<95

95–103>103

<87

87–98>98

Waistcircumference (cm):

The HOPE study

Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-cholesterol, total-C; CVD: cardiovascular disease; MI: myocardial infarction; BMI: body mass index; DM: diabetes mellitus; HDL: high-density lipoprotein cholesterol

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Abdominal obesity increases the risk of developing type 2 diabetes

<71 71–75.9 76–81 81.1–86 86.1–91 91.1–96.3 >96.3

24

20

16

12

8

4

0

Rel

ativ

e ri

sk

Waist circumference (cm)

Carey VJ et al, 1997

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Abdominal obesity is linked to an increased risk of coronary heart disease

Waist circumference has been shown to be independently associated with increased age-adjusted risk of CHD, even after

adjusting for BMI and other cardiovascular risk factors

0.0

0.5

1.0

1.5

2.0

2.5

3.0

<69.8 69.8<74.2 74.2<79.2 79.2<86.3 86.3<139.7

1.27

2.06 2.31

2.44p for trend = 0.007

Rel

ativ

e ri

sk

Quintiles of waist circumference (cm)

Rexrode KM et al, 1998

CHD: coronary heart disease; BMI: body mass index

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QUALITY IMPROVEMENT & ASSURANCE

CONSENSUS GUIDELINES EVIDENCE BASED MEDICINE PERSONALIZED MEDICINE

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MS Excel Program for Risk AssessmentFrom The Framingham Heart Study Enter Values HereCHD(MI and Coronary Death) Risk Prediction National Cholesterol Education Program Adult Treatment Panel III

Risk Factor Units

(Type Over Placeholder Values in

Each Cell) NotesGender male (m) or female (f) M Age years 52 Total Cholesterol mg/dL 220 HDL mg/dL 45 Systolic Blood Pressure mmHg 146 Treatment for Hypertension {Only if SBP>120} yes (y) or no (n) N Current Smoker yes (y) or no (n) Y

Time Frame for Risk Estimate 10 years 10

Your Risk (The risk score shown is derived on the basis of an equation. Other NCEP materials, such as ATP III print products, use a point-based system

to calculate a risk score that approximates the equation-based one.)0.17 17%

Tables for Graph

If value is < the minimum for the field, enter the minimum value. If value is > the maximum for the field, enter the maximum value.

These functions and programs were prepared by Ralph B. D'Agostino, Sr., Ph.D. and Lisa M. Sullivan, Ph.D., Boston University and The Framingham Heart Study and Daniel Levy, M.D., Framingham Heart Study, National Heart, Lung and Blood Institute.

0.17

0.04

0.02

0.00 0.05 0.10 0.15 0.20 0.25 0.30

Your Risk Estimate, Comparative Risks for Lowest = Total Chol<160, HDL>60, Optimal SBP (<120), No Trt for Htn, Non-Smoker Same Age and Gender Low = Total Chol 160-199, HDL 50-59, Normal SBP (<130), No Trt for Htn, Non-Smoker

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TargetingTargeting

Cardiometabolic RiskCardiometabolic Risk

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Six Aims for Improvement

Safe – avoiding injuries to patients from the care that is intended to help them.

Effective – providing services based on scientific knowledge to all who could benefit and refraining from providing services to those not likely to benefit (avoiding underuse and overuse)

Patient-centered – providing care that is respectful of and responsive to individual patient preferences, needs and values and ensuring that patients values guide all clinical decisions.

Timely – reducing waits and sometimes harmful delays for both those who receive and those who give care.

Efficient – avoiding waste, including waste of equipment, supplies, ideas and energy.

Equitable – providing care that does not vary in quality because of personal characteristics such as gender, ethnicity, geographic location, and socio-economic status.

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Global cardiometabolic risk*

Gelfand EV et al, 2006; Vasudevan AR et al, 2005* working definition

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Intensive therapyIntensive therapyAggressive Aggressive

TTOTTOMaximum TherapMaximum Therap

dosedose

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Public Health Public Health ApprachApprach

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Diabetes prevention

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Public Education Screening for at risk individuals:

Blood Sugar/ HbA1cLipidsBlood pressureTobacco useBody habitusFamily history

Screening/Public Health ApproachScreening/Public Health Approach

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Prevention of type 2 diabetesBefore people develop type 2 diabetes, they almost always have "pre-diabetes" -- blood glucose levels that are higher than normal but not yet high enough to be diagnosed as

diabetes

Take our diabetes risk test to see if you are at risk for developing diabetes. Diabetes is more common in African Americans, Latinos, Native Americans, Asian Americans and Pacific Islanders.

is a powerful new risk assessment tool. It can be used to explore the effects of a wide variety of health care interventions, including losing weight, stopping smoking, and taking certain medications.

Diabetes Prevention Program study conclusively showed that people with pre-diabetes can prevent the development of type 2 diabetes by making changes in their diet and increasing their

level of physical activity.

Keeping an eye on these risk factors -- keeping them "in check" -- can help you prevent diabetes and heart disease.Keeping an eye on these risk factors -- keeping them "in check" -- can help you prevent diabetes and heart disease.

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PREVENTION AND MANAGEMENT OFDIABETES COMPLICATIONS

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Lifestyle modification

Diet Exercise Weight loss Smoking

cessation

If a 1% reduction in HbA1c is achieved, you could expect a

reduction in risk of:• 21% for any diabetes-related

endpoint• 37% for microvascular

complications• 14% for myocardial infarction

However, compliance is poor and most patients will require oral pharmacotherapy within a few years of diagnosis

Stratton IM et al. BMJ 2000; 321: 405–412.

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WEIGHT LOSSWEIGHT LOSS = =⇩⇩ INSULININSULIN--RESISTANCERESISTANCE

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WEIGHT LOSS: HOW?WEIGHT LOSS: HOW?

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Weight loss may be obtained Weight loss may be obtained through:through:

• Therapeutic lifestyle changeTherapeutic lifestyle change

• Drug therapyDrug therapy (if Therapeutic lifestyle change is not sufficient)(if Therapeutic lifestyle change is not sufficient)

• Bariatric surgery Bariatric surgery (in selected cases; to estimate the risk/benefit ratio)(in selected cases; to estimate the risk/benefit ratio)

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glycemia ed insulinaemiaglycemia ed insulinaemia

HbAHbA1C1C

VLDL and triglycerides VLDL and triglycerides

HDL-cholesterolHDL-cholesterol

blood pressureblood pressure

microalbuminuriamicroalbuminuria..

EFFECTIVE LONG TERM WEIGHT LOSS:EFFECTIVE LONG TERM WEIGHT LOSS:ACHIEVABLE OBJECTIVES and HEALTH BENEFITS ACHIEVABLE OBJECTIVES and HEALTH BENEFITS

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STANDARDS OF MEDICAL CARESTANDARDS OF MEDICAL CAREIN DIABETES ADAIN DIABETES ADA

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ADA Evidence Grading System for Clinical ADA Evidence Grading System for Clinical RecommendationsRecommendations

Level of Level of EvidenceEvidence DescriptionDescription

A Clear or supportive evidence from adequately powered well-conducted, generalizable, randomized controlled trials

Compelling nonexperimental evidence 

B Supportive evidence from well-conducted cohort studies or case-control study

C Supportive evidence from poorly controlled or uncontrolled studies 

Conflicting evidence with the weight of evidence supporting the recommendation

E Expert consensus or clinical experience

ADA. Diabetes Care 2011;34(suppl 1):S12. Table 1.

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Recommendations: Glycemic, Blood Pressure, Recommendations: Glycemic, Blood Pressure, Lipid Control in AdultsLipid Control in Adults

A1C <7.0%* 6.5

Blood pressure <130/80 mmHg†

LipidsLDL cholesterol <100 mg/dl (<2.6

mmol/l)‡

*More or less stringent glycemic goals may be appropriate for individual patients. Goals should be individualized based on: duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular complications, hypoglycemia unawareness, and individual patient considerations.

†Based on patient characteristics and response to therapy, higher or lower systolic blood pressure targets may be appropriate.

‡In individuals with overt CVD, a lower LDL cholesterol goal of <70 mg/dl (1.8 mmol/l), using a high dose of statin, is an option.

ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S31. Table 12.

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J Am Coll Cardiol. 2012;60(14):1231-1238. doi:10.1016/j.jacc.2012.05.019

Clinical Research | October 2012 Statins, Risk of Diabetes, and Implications on Outcomes in

the General Population Kang-Ling Wang, MD; Chia-Je 

Conclusions  Risk of diabetes was increased after statins, but outcomes were favorable.

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Diabetes. 2012 Feb;61(2):463-73.

Silence of TRIB3 suppresses atherosclerosis and stabilizes plaques in diabetic ApoE-/-/LDL receptor-/- mice.

Toll-like receptor (TLR)4TLR4 antagonist inhibited vascular inflammation and atherogenesis in diabetic apoE-/- mice and lowered serum cholesterol and triglyceride levels in non-diabetic apoE-/- mice.

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A Critical Look at the A Critical Look at the Metabolic Syndrome Metabolic Syndrome

Is it a Syndrome?*Is it a Syndrome?* “…too much clinically important information is

missing to warrant its designations as a syndrome.”

Unclear pathogenesis, Insulin resistance is not a consistent finding in some definitions.

CVD risks has not shown to be greater than the sum of it’s individual components.

*ADA

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A Critical Look at the A Critical Look at the Metabolic SyndromeMetabolic Syndrome

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