tm © 1999 professional postgraduate services ® diabetes and cardiovascular disease epidemiology...

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© 1999 Professional Postgraduate Services®

Diabetes and Cardiovascular Disease

• Epidemiology

• Clinical Trials

• Management

Nathan Wong

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Diabetes: Scope of Problem• At least 10.3 million Americans have been

diagnosed with diabetes mellitus, and another 5.4 million are estimated to have undiagnosed diabetes. Onset often precedes diagnosis by several years.

• About 90% of diabetic patients have Type II diabetes

• Hispanics, blacks, Native Americans, and Asians (especially South Asians) are especially susceptible to diabetes.

• Diabetes in women essentially cancels out any hormonal protection.

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Diabetes: Type II Diabetes and Insulin Resistance

• Type II diabetes is most common form, occurring later in life, and involving combination of impaired insulin-mediated glucose disposal (insulin resistance) and defective secretion of insulin by pancreatic beta cells

• Insulin resistance develops from obesity and physical inactivity and insulin secretion declines with advancing age (and accelerated by genetic factors)

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Accelerated atherosclerosis

Clinical diabetes

Hyperinsulinemia Impairedglucose

tolerance

HypertriglyceridemiaDecreased HDL-C

Essentialhypertension

Insulin resistance

Insulin Resistance and Atherosclerosis: Posited Relationships

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Diabetes and the Dysmetabolic Syndrome

• Insulin resistance often precedes type II diabetes and is often accompanied by other risk factors-- dyslipidemia, hypertension, and prothrombotic factors, the “dysmetabolic syndrome”

• Impaired fasting glucose (110-125 mg/dl) often accompanies the dysmetabolic syndrome.

• The threshold for fasting plasma glucose for diagnosis of diabetes has been lowered from 140 mg/dl to 126 mg/dl.

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Diabetes: Complications• Cardiovascular diseases (CVD) account for about 65%

of all deaths in diabetics; those with CVD have a worse prognosis than CVD patients without diabetes.

• Complications include CHD, stroke, peripheral arterial disease, nephropathy, retinopathy, and possibly neuropathy and cardiomyopathy.

• Stroke mortality 3-fold in diabetics vs. nondiabetics. Carotid atherosclerosis and likelihood of irreverisible brain damage from stroke more common in diabetics.

• Renal impairment is a severe complication of diabetes; about 35% of pts with Type I diabetes have some renal impairment. End stage renal disease (ESRD) carries a high mortality (20%/year in dialysis pts) and is more common in Hispanics, blacks, and Native Americans

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Framingham Heart Study 30-Year Follow-Up:CVD Events in Patients With Diabetes (Ages 35-64)

109

20

11

9 63819

3*

30

0

2

4

6

8

10

Age-adjusted annual rate/1,000

Men Women

Total CVD

CHD Cardiac failure

Intermittent claudication

Stroke

Riskratio

P<0.001 for all values except *P<0.05.

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© 1999 Professional Postgraduate Services®Haffner SM et al. N Engl J Med. 1998;339:229-234.

0 1 2 3 4 5 6 7 8

0

20

40

60

80

100

Nondiabetic subjects without prior MI (n=1,304)Diabetic subjects without prior MI (n=890)Nondiabetic subjects with prior MI (n=69)Diabetic subjects with prior MI (n=169)

Survival(%)

Year

Risk Similar in Patients With Type 2 Diabetes and No Prior MI vs Nondiabetic Subjects With Prior MI

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National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.

Atherosclerosis in Diabetes

• ~80% of all diabetic mortality

– 75% from coronary atherosclerosis

– 25% from cerebral or peripheral vascular disease

• >75% of all hospitalizations for diabetic complications

• >50% of patients with newly diagnosed type 2 diabetes have CHD

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SMC=smooth muscle cell.

Adapted from Bierman EL. Arterioscler Thromb. 1992;12:647-656.

Potential Mechanisms of Atherogenesis in Diabetes• Abnormalities in apoprotein and lipoprotein particle

distribution

• Glycosylation and advanced glycation of proteins in plasma and arterial wall

• “Glycoxidation” and oxidation

• Procoagulant state

• Insulin resistance and hyperinsulinemia

• Hormone-, growth-factor–, and cytokine-enhanced SMC proliferation and foam cell formation

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Kannel WB. Am Heart J. 1985;110:1100-1107.Abbott RD et al. JAMA. 1988;260:3456-3460.

Women, Diabetes, and CHD

• Diabetic women are at high risk for CHD

• Diabetes eliminates relative cardioprotective effect of being premenopausal

– risk of recurrent MI in diabetic women is three times that of nondiabetic women

• Age-adjusted mean time to recurrent MI or fatal CHD event is 5.1 yr for diabetic women vs 8.1 yr for nondiabetic women

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Diabetes in California

• Diabetes has increased more than 28% since 1987, corresponding with a more than 50% increase in the prevalence of overweight / obesity during the same time period

• 12.9% of Hispanics, 14.5% of Blacks, compared to 4.3% in Whites report diabetes in California.

• 4.6% of Men and 6.3% of Women report diabetes in California.

• Prevalence of diabetes increases with age and is inversely related to educational attainment.

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Evaluation of Risk Factors Affecting Diabetes and CVD

• Body weight and fat distribution - assess history, BMI (obesity >=30 Obesity) and waist circumference (abdominal obesity >40 in. in men and >36 in. in women)

• Physical activity - assess past and current levels

• Family history of CVD (<65 female,<55 male relative)

• Dyslipidemia (esp. low HDL-C and high TG)

• Hypertension (treshold for treatment 130/80 mmHg)

• Cigarette Smoking - current, past habits, and intensity

• Albuminuria - measure serum creatinine and test urine with dipstick for protein (do alb/creat if neg)

• Glycemic status - age of onset of hyperglycemia, family history of diabetes, complications, measure fasting plasma glucose, periodic measures of HgbA1c

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149

26

11 12139

21*

34*

19*

0

10

20

30

40

50 Men without diabetes

Men with diabetes

TC260

TG235

VLDL-C40

LDL-C190

HDL-C31

Prevalence(%)

*P<0.05.LRC approximate 90th percentile age- and sex-matched values, except for HDL-C (10th percentile).

Abnormal Lipid Levels in Men With Type 2 Diabetes

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21

8

31

16

10

24

38

15

25*

17*

0

10

20

30

40

50 Women without diabetesWomen with diabetes

TC275

TG200

VLDL-C35

LDL-C190

HDL-C41

Prevalence(%)

*P<0.05.LRC approximate 90th percentile age- and sex-matched values, except for HDL-C (10th percentile).

Abnormal Lipid Levels in Women With Type 2 Diabetes

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T M

© 1 9 9 9 P ro fe s s io n a l P o s tg ra d u a te S e rv ic e s ®

T h e S tro n g H e a rt S tu d y : D iffe re n c e s in C V D R is kF a c to rs b y D ia b e tic S ta tu s in M e n a n d W o m e n *

*A d ju s te d fo r a g e a n d c e n te r.

A d a p te d fro m H o w a rd B V e t a l. D ia b e te s C a re . 1 9 9 8 ;2 1 :1 2 5 8 -1 2 6 5 .

-4.4

-3.7

-7.5

-5.3

-8

-7

-6

-5

-4

-3

-2

-1

0

Men

Women

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Significance of Small, Dense LDL

• Low cholesterol content of LDL particles particle number for given LDL-C level

• Associated with levels of TG and LDL-C, and levels of HDL2

• Marker for common genetic trait associated with risk of coronary disease (LDL subclass pattern B)

• Possible mechanisms of atherogenicity– greater arterial uptake uptake by macrophages oxidation susceptibility

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Hypertension in Persons with Diabetes

• Up to 75% of persons with Type II diabetes have hypertension if defined as >140 / 90 mmHg

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Treatment of Hypertension in Diabetics

• The JNC-VI recommends pharmacologic treatment concurrently with lifestyle management for hypertension in diabetics with a systolic blood pressure of 130mmHg or higher, or a diastolic blood pressure of 85 mmHg or higher.

• An angiotensin converting enzyme (ACE)-inhibitor is recommended as first line therapy also because of renal-protective effects in preventing progression of microalbuminuria / proteinuria.

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UKPDS: Intensive Blood-Glucose vs ConventionalTreatment in Patients With Type 2 Diabetes

RR=relative risk.PVD=peripheral vascular disease.

UKPDS Group. Lancet. 1998;352:837-853.

Any diabetes-related end point 0.88 (0.79–0.99) 0.029

Diabetes-related deaths 0.90 (0.73–1.11) 0.34

All-cause mortality 0.94 (0.80–1.10) 0.44

MI 0.84 (0.71–1.00) 0.052

Stroke 1.11 (0.81–1.51) 0.52

Amputation or death from PVD 0.65 (0.36–1.18) 0.15

Microvascular disease 0.75 (0.60–0.93) 0.0099

Favors Favors Log-rank RR (95% CI) intensive conventional P value

Clinical End Point0.1 1 10

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Any diabetes-related end point 0.76 (0.62–0.92) 0.0046

Diabetes-related deaths 0.68 (0.49–0.94) 0.019

All-cause mortality 0.82 (0.63–1.08) 0.17

MI 0.79 (0.59–1.07) 0.13

Stroke 0.56 (0.35–0.89) 0.013

Peripheral vascular disease 0.51 (0.19–1.37) 0.17

Microvascular disease 0.63 (0.44–0.89) 0.0092

UKPDS: Tight Blood Pressure Control vs LessTight Control in Patients With Type 2 Diabetes

RR=relative risk.

UKPDS Group. BMJ. 1998;317:703-713.

RR for Favors Favors tight control tight less tight P

(95% CI) control control value

Clinical End Point10.1 10

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7.4

3.3

10.5

3.4

0

5

10

15Type 2 (n=135)

Others (n=3,946)

Type 2 on placebo (n=76)

Type 2 on gemfibrozil (n=59)

5-Yr incidenceof CHD (%)

*Myocardial infarction or cardiac death.NS=not significant.

Koskinen P et al. Diabetes Care. 1992;15:820-825.

P<0.02

P=NS

Primary CHD* Prevention in Patients With Type 2 Diabetes: The Helsinki Heart Study

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Total mortality 232167

2415

CHD mortality 172991712

Major CHD event 578407

4424

Any CHD event 871667

5641

CABG or PTCA 363238

2015

Cerebrovascular event 907012

5

Any atherosclerotic event 961750

6146

NondiabeticDiabetic

P S

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4RR with 95% CIs

No. patients Simvastatin Placebowith events better better

tm © 1999 professional postgraduate services ® diabetes and cardiovascular disease epidemiology...

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