1

Diabetes Mellitus Evidence and Diabetes Mellitus Evidence and GuidelinesGuidelines

Andrew P. DeFilippis, Ty J. Gluckman, James Mudd, Catherine Campbell,

& Roger S. Blumenthal

2

AGE=Advanced glycation end products, CRP=C-reactive protein, CHD=Coronary heart disease HDL=High-density lipoprotein, HTN=Hypertension, IL-6=Interleukin-6, LDL=Low-density lipoprotein, PAI-1=Plasminogen activator inhibitor-1, SAA=Serum amyloid A protein, TF=Tissue factor, TG=Triglycerides, tPA=Tissue plasminogen activator

Subclinical Atherosclerosis

Atherosclerotic Clinical Events

Hyperglycemia

AGE Oxidative

stress

Inflammation

IL-6 CRP SAA

Infection

Defensemechanisms

Pathogen burden

Insulin Resistance

HTN Endothelial dysfunction

Dyslipidemia

LDL TG HDL

Thrombosis

PAI-1 TF tPA

Disease Progression

Biondi-Zoccai GGL et al. JACC 2003;41:1071-1077

Mechanisms by which Diabetes Mellitus leads to CHDMechanisms by which Diabetes Mellitus leads to CHD

3

• Consists of a constellation of major risk factors, life-habit risk factors, and emerging risk factors

• Over-represented among populations with CVD

• Often occurs in individuals with a distinctive body-type including an increased abdominal circumference

The Metabolic SyndromeThe Metabolic Syndrome

4

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497

Risk Factor Defining Level

Waist circumference (abdominal obesity) >40 in (>102 cm) in men

>35 in (>88 cm) in women

Triglyceride level >150 mg/dl

HDL-C level <40 mg/dl in men

<50 mg/dl in women

Blood pressure >130/>85 mmHg

Fasting glucose >100 mg/dl

ATP III Definition of the Metabolic SyndromeATP III Definition of the Metabolic Syndrome

Defined by the presence of >3 risk factors

HDL-C=High-density lipoprotein cholesterol

5

40–49

Ford ES et al. JAMA 2002;287:356-359

Pre

vale

nce,

%

20–70+Age, yrs

20–29 30–39 50–59 60–69 700%

10%

20%

30%

40%

50%

National Health and Nutrition Examination Survey (NHANES)

Metabolic Syndrome: Prevalence in U.S. AdultsMetabolic Syndrome: Prevalence in U.S. Adults

Men

Women

6

CH

D P

reva

lenc

e

No MS/No DM

54%

MS/No DM

29%

DM/No MS

2%

DM/MS

15%

8.7%

13.9%

7.5%

19.2%

0%

5%

10%

15%

20%

25%

Metabolic Syndrome: CHD Prevalence*Metabolic Syndrome: CHD Prevalence*

National Health and Nutrition Examination Survey (NHANES)

% of Population =

Alexander CM et al. Diabetes 2003;52:1210-1214

*Among individual >50 years

CHD=Coronary heart disease, DM=Diabetes mellitus, MS=Metabolic syndrome

7

0

1

2

3

4CVD*

CHD†

0 1 2 3 4 5

Mo

rta

lity

haz

ard

ra

tio

Number of Metabolic Syndrome Criteria

*Adjusted for age, sex, race or ethnicity, education, smoking status, non–HDL-C level, recreational and non-recreational activity, white blood cell count, alcohol use, prevalent heart disease, and stroke †Similar adjustments except for prevalent stroke

Ford ES et al. Atherosclerosis 2004;173:309-314

Metabolic Syndrome: Risk of DeathMetabolic Syndrome: Risk of Death

CHD=Coronary heart disease, CVD=Cardiovascular disease

Risk is Proportional to the Number of ATP III Criteria

8Tuomilehto J et al. NEJM 2001;344:1343-1350

0

0.05

0.1

0.15

0.2

0.25

InterventionControl

11%

23%

% with Diabetes Mellitus

Metabolic Syndrome: Risk of Developing DMMetabolic Syndrome: Risk of Developing DM

Finnish Diabetes Prevention Study

†Defined as a glucose >140 mg/dl 2 hours after an oral glucose challenge

522 overweight (mean BMI=31 kg/m2) patients with impaired fasting glucose† randomized to intervention‡ or usual care for 3 years

Lifestyle modification reduces the risk of developing DM

‡Aimed at reducing weight (>5%), total intake of fat (<30% total calories) and saturated fat (<10% total calories); increasing uptake of fiber (>15 g/1000 cal); and physical activity (moderate at least 30 min/day)

9

Metabolic Syndrome: Risk of Developing DMMetabolic Syndrome: Risk of Developing DM

Diabetes Prevention Program (DPP)

Knowler WC et al. NEJM 2002;346:393-403

0 1 2 3 4

0

10

20

30

40Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )

Percent developing diabetes

All participants

All participants

Years from randomization

Cu

mu

lativ

e in

cid

en

ce (

%)

*Includes 7% weight loss and at least 150 minutes of physical activity per week

Placebo

Metformin

Lifestyle modification

Inci

denc

e of

DM

(%

)

0

20

30

10

40

00 1 42 3

Years

3,234 patients with elevated fasting and post-load glucose levels randomized to placebo, metformin (850 mg bid), or lifestyle modification*

for 3 years

Lifestyle modification reduces the risk of developing DM

10

Metabolic Syndrome: Risk of Developing DMMetabolic Syndrome: Risk of Developing DM

Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) Trial

Gerstein HC et al. Lancet 2006;368:1096-1105

CVD=Cardiovascular disease, DM=Diabetes mellitus, IFG=Impaired fasting glucose, IGT=Impaired glucose tolerance

0.6

0.4

0.2

0.00 1 2 3 4

PlaceboRosiglitazone

Inci

dent

DM

or

Dea

th

Years

60% RRR, P<0.0001

5,269 patients with IFG and/or IGT, but without known CVD randomized to rosiglitazone (8 mg) or placebo for a median of 3 years

Thiazolidinediones reduce the risk of developing DM

11

Diabetes Mellitus: Lifetime RiskDiabetes Mellitus: Lifetime Risk

Narayan et al. JAMA 2003;290:1884-1890

12

19911991 20012001

< 4-6% 7-8% 9-10%No Data < 4% >10%

Mokdad AH et al. JAMA 2003;289:76-79

Diabetes Mellitus: Prevalence in U.S. AdultsDiabetes Mellitus: Prevalence in U.S. Adults

13

109

20

11

9 6 38 19

3*

30

Total CVD CHD Cardiac failure Intermittent claudication

CVA

Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N et al, eds. Oxford; 1992.

P<0.001 for all values except *P<0.05

Ris

k ra

tio

Men Women

0

2

4

10

8

6

Age-adjusted Annual Rate/1000

Diabetes Mellitus: Risk of CVD EventsDiabetes Mellitus: Risk of CVD Events

CHD=Coronary heart disease, CVD=Cardiovascular disease

Framingham Heart Study: 30 year follow-up

14Haffner SM et al. NEJM 1998;339:229–234

Patients with DM but no CHD experience a similar rate of MI as patients without DM but with CHD

Eve

nts

*/1

00

per

son-

yea

rs

Prior CHD

45 DMNo DM

No prior CHD

50

40

30

20

10

0

19 20

3.5

Diabetes Mellitus: Risk of Myocardial InfarctionDiabetes Mellitus: Risk of Myocardial Infarction

*Fatal or non-fatal MI

CHD=Coronary heart disease, DM=Diabetes mellitus, MI=Myocardial infarction

15

0 1 2 3 4 5 6 7 8

20

40

60

80

100

Nondiabetic subjects without prior MI

Diabetic subjects without prior MI

Nondiabetic subjects with prior MI

Diabetic subjects with prior MI

Years

Sur

viva

l (%

)

Diabetes Mellitus: Risk of DeathDiabetes Mellitus: Risk of Death

Haffner SM et al. NEJM 1998;339:229–234

Patients with DM but no CHD experience a similar rate of death as patients without DM but with CHD

CHD=Coronary heart disease, DM=Diabetes mellitus, MI=Myocardial infarction

16

WOMENWOMENMENMEN

Sprafka JM et al. Diabetes Care 1991;14:537-543

100

80

60

40

0

Sur

viva

l (%

)

Months Post-MI

No diabetes

n=228

n=1628

Months Post-MI

0 20 40 60

Diabetes

80 0 20 40 60 80

Diabetes

No diabetes

n=156

n=568

Survival post-MI in Diabetics and Non-diabeticsSurvival post-MI in Diabetics and Non-diabetics

Minnesota Heart Survey

MI=Myocardial infarction

17

-25-21

-16-12

-33

-50

-40

-30

-20

-10

0

Microalbuminuria at 12 years Microvascular complicationsRetinopathy Myocardial infarctionAny DM endpoint

% r

ela

tive

ris

k re

du

ctio

n

P=0.03

P<0.01

P<0.01

P=0.05

P=0.02

UKPDS Group. Lancet 1998;352:837-853

A lower HbA1c is associated with reduced vascular risk in diabetics

Intensity of Glucose Control in DM in UKPDSIntensity of Glucose Control in DM in UKPDS

DM=Diabetes mellitus, HbA1C=Glycosylated hemoglobin

18

*Death from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for PAD

Prim

ary

End

poin

t* (

%)

Months of Follow-Up

20

12 24 36 48 60 72 84 96

Intensity of Risk Factor Control in DMIntensity of Risk Factor Control in DM

STENO-2 Study

40

60

0

Intensive Therapy†

Conventional Therapy

†Aggressive treatment of dyslipidemia, hyperglycemia, hypertension, microalbuminuria, and secondary prevention of CV disease

Gaede P et al. NEJM 2003;348:383-393

CABG=Coronary artery bypass graft surgery, CV=Cardiovascular, DM=Diabetes mellitus MI=Myocardial infarction, PAD=Peripheral artery disease, PCI=Percutaneous coronary intervention

160 patients with type 2 DM randomized to targeted intensive multifactorial intervention† or conventional treatment of CV risk factors for 8 years

Lifestyle modification reduces the risk of developing DM

HR=0.47, P=0.008

19

Goals Recommendations

Diabetes Mellitus GuidelinesDiabetes Mellitus Guidelines

Goal HbA1C <7% Intensive lifestyle modification to prevent the development of DM (especially in those with the metabolic syndrome)

Aggressive management of CV risk factors

Hypoglycemic Rx to achieve a normal to near normal fasting plasma glucose as defined by the HbA1C

• Weight reduction and exercise• Oral hypoglycemic agents• Insulin therapy

Coordination of diabetic care with the patient’s primary physician and/or endocrinologist

CV=Cardiovascular, DM=Diabetes mellitus, HbA1C=Glycosylated hemoglobin, Rx=Treatment

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII