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  • 1. Diabetes and Cardiovascular Disease
    • Epidemiology
    • Clinical Trials
    • Management
    Nathan Wong
  • 2. 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.
  • 3. 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)
  • 4. Insulin Resistance and Atherosclerosis: Posited Relationships Accelerated atherosclerosis Clinical diabetes Hyperinsulinemia Impaired glucose tolerance Hypertriglyceridemia Decreased HDL-C Essential hypertension Insulin resistance
  • 5. 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.
  • 6. 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
  • 7. Framingham Heart Study 30-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-64) 10 9 20 11 9 6 38 19 3* 30 0 2 4 6 8 10 Age-adjusted annual rate/1,000 Men Women Total CVD CHD Cardiac failure Intermittent claudication Stroke Risk ratio P <0.001 for all values except * P <0.05.
  • 8. Risk Similar in Patients With Type 2 Diabetes and No Prior MI vs Nondiabetic Subjects With Prior MI 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
  • 9. 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
    National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.
  • 10. 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
    SMC=smooth muscle cell. Adapted from Bierman EL. Arterioscler Thromb . 1992;12:647-656.
  • 11. 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
    Kannel WB. Am Heart J . 1985;110:1100-1107. Abbott RD et al. JAMA . 1988;260:3456-3460.
  • 12. 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.
  • 13. 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
  • 14. Abnormal Lipid Levels in Men With Type 2 Diabetes 14 9 26 11 12 13 9 21* 34* 19* 0 10 20 30 40 50 Men without diabetes Men with diabetes TC  260 TG  235 VLDL-C  40 LDL-C  190 HDL-C  31 Prevalence (%) * P <0.05. LRC approximate 90th percentile age- and sex-matched values, except for HDL-C (10th percentile).
  • 15. Abnormal Lipid Levels in Women With Type 2 Diabetes 21 8 31 16 10 24 38 15 25* 17* 0 10 20 30 40 50 Women without diabetes Women with diabetes TC  275 TG  200 VLDL-C  35 LDL-C  190 HDL-C  41 Prevalence (%) * P <0.05. LRC approximate 90th percentile age- and sex-matched values, except for HDL-C (10th percentile).
  • 16.  
  • 17. 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 HDL 2
    • 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
  • 18. Hypertension in Persons with Diabetes
    • Up to 75% of persons with Type II diabetes have hypertension if defined as > 140 / 90 mmHg
  • 19. 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.
  • 20.  
  • 21.  
  • 22. Primary CHD* Prevention in Patients With Type 2 Diabetes: The Helsinki Heart Study 7.4 3.3 10.5 3.4 0 5 10 15 Type 2 (n=135) Others (n=3,946) Type 2 on placebo (n=76) Type 2 on gemfibrozil (n=59) 5-Yr incidence of CHD (%) *Myocardial infarction or cardiac death. NS=not significant. Koskinen P et al. Diabetes Care. 1992;15:820-825. P <0.02 P =NS
  • 23. Total mortality 232 167 24 15 CHD mortality 172 99 17 12 Major CHD event 578 407 44 24 Any CHD event 871 667 56 41 CABG or PTCA 363 238 20 15 Cerebrovascular event 90 70 12 5 Any atherosclerotic event 961 750 61 46 Nondiabetic Diabetic P S 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 RR with 95% CIs No. patients Simvastatin Placebo with events better better