TM © 1999 Professional Postgraduate Services ® Diabetes and Cardiovascular Disease Epidemiology Clinical Trials Management Nathan Wong

TM © 1999 Professional Postgraduate Services ® 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.

TM © 1999 Professional Postgraduate Services ® 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)

TM © 1999 Professional Postgraduate Services ® Accelerated atherosclerosis Clinical diabetes HyperinsulinemiaImpaired glucose tolerance Hypertriglyceridemia Decreased HDL-C Essential hypertension Insulin resistance Insulin Resistance and Atherosclerosis: Posited Relationships

TM © 1999 Professional Postgraduate Services ® 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 ( 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.

TM © 1999 Professional Postgraduate Services ® 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

TM © 1999 Professional Postgraduate Services ® Framingham Heart Study 30-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-64) * Age-adjusted annual rate/1,000 MenWomen Total CVD CHDCardiac failure Intermittent claudication Stroke Risk ratio P<0.001 for all values except *P<0.05.

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

TM © 1999 Professional Postgraduate Services ® 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

TM © 1999 Professional Postgraduate Services ® SMC=smooth muscle cell. Adapted from Bierman EL. Arterioscler Thromb. 1992;12: 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

TM © 1999 Professional Postgraduate Services ® Kannel WB. Am Heart J. 1985;110: Abbott RD et al. JAMA. 1988;260: 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

TM © 1999 Professional Postgraduate Services ® 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.

TM © 1999 Professional Postgraduate Services ® 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

TM © 1999 Professional Postgraduate Services ® * 34* 19* 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). Abnormal Lipid Levels in Men With Type 2 Diabetes

TM © 1999 Professional Postgraduate Services ® * 17* 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). Abnormal Lipid Levels in Women With Type 2 Diabetes

TM © 1999 Professional Postgraduate Services ®

TM © 1999 Professional Postgraduate Services ® 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

TM © 1999 Professional Postgraduate Services ® Hypertension in Persons with Diabetes Up to 75% of persons with Type II diabetes have hypertension if defined as >140 / 90 mmHg

TM © 1999 Professional Postgraduate Services ® 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.

TM © 1999 Professional Postgraduate Services ®

TM © 1999 Professional Postgraduate Services ®

TM © 1999 Professional Postgraduate Services ® 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: P<0.02 P=NS Primary CHD* Prevention in Patients With Type 2 Diabetes: The Helsinki Heart Study

TM © 1999 Professional Postgraduate Services ® Total mortality CHD mortality Major CHD event Any CHD event CABG or PTCA Cerebrovascular event Any atherosclerotic event Nondiabetic Diabetic PSPS RR with 95% CIs No. patientsSimvastatinPlacebo with eventsbetterbetter