Diabetes and Cardiovascular Disease. Part I

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 ® Insulin Resistance and Atherosclerosis: Posited Relationships Insulin resistance Hyperinsulinemia Impaired glucose tolerance Hypertriglyceridemia Decreased HDL-C Essential hypertension Clinical diabetes Accelerated atherosclerosis 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 (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. 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) 10 8 Men Women 10 9 Risk ratio 6 4 2 0 11 30 38 19 20 9 6 3* Total CVD CHD Cardiac failure Intermittent Stroke claudication Age-adjusted annual rate/1,000 TM P<0.001 for all values except *P<0.05. © 1999 Professional Postgraduate Services ® Risk Similar in Patients With Type 2 Diabetes and No Prior MI vs Nondiabetic Subjects With Prior MI 100 80 60 Survival (%) 40 20 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) 0 1 2 3 4 5 6 7 8 TM 0 Year Haffner SM et al. N Engl J Med. 1998;339:229-234. © 1999 Professional Postgraduate Services ® 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 National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995. © 1999 Professional Postgraduate Services ® 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 SMC=smooth muscle cell. Adapted from Bierman EL. Arterioscler Thromb. 1992;12:647-656. © 1999 Professional Postgraduate Services ® 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 Kannel WB. Am Heart J. 1985;110:1100-1107. Abbott RD et al. JAMA. 1988;260:3456-3460. © 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 ® Abnormal Lipid Levels in Men With Type 2 Diabetes 50 40 30 Men without diabetes Men with diabetes 34* 26 Prevalence (%) 20 10 0 19* 14 13 9 21* 11 9 12 TC 260 TG 235 VLDL-C 40 LDL-C 190 HDL-C 31 *P<0.05. LRC approximate 90th percentile age- and sex-matched values, except for HDL-C (10th percentile). TM © 1999 Professional Postgraduate Services ® Abnormal Lipid Levels in Women With Type 2 Diabetes 50 40 30 Women without diabetes Women with diabetes 38 31 25* 17* 8 16 15 10 Prevalence (%) 20 10 0 21 24 TC 275 TG 200 VLDL-C 35 LDL-C 190 HDL-C 41 TM *P<0.05. LRC approximate 90th percentile age- and sex-matched values, except for HDL-C (10th percentile). © 1999 Professional Postgraduate Services ® The Strong Heart Study: Differences in CVD Risk Factors by Diabetic Status in Men and Women* HDL-C (mg/dL) 0 -1 -2 LDL Size (Å) Difference -3 between subjects -4 with and without -5 diabetes -6 -7 -8 M en -3 .7 -4.4 -5.3 W o m en -7 .5 TM TM *Adjusted for age and center. © 1999 Professional Postgraduate Services ® Adapted from Howard BV et al. Diabetes Care. 1998;21:1258-1265. © 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 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 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 ® UKPDS: Intensive Blood-Glucose vs Conventional Treatment in Patients With Type 2 Diabetes RR (95% CI) Clinical End Point Any diabetes-related end point Diabetes-related deaths All-cause mortality MI Stroke Amputation or death from PVD Microvascular disease 0.88 (0.79–0.99) 0.90 (0.73–1.11) 0.94 (0.80–1.10) 0.84 (0.71–1.00) 1.11 (0.81–1.51) 0.65 (0.36–1.18) 0.75 (0.60–0.93) Favors Favors Log-rank intensive conventional P value 0.1 1 10 0.029 0.34 0.44 0.052 0.52 0.15 0.0099 RR=relative risk. PVD=peripheral vascular disease. UKPDS Group. Lancet. 1998;352:837-853. TM TM © 1999 Professional Postgraduate Services ® © 1999 Professional Postgraduate Services ® UKPDS: Tight Blood Pressure Control vs Less Tight Control in Patients With Type 2 Diabetes RR for tight control (95% CI) Clinical End Point Any diabetes-related end point Diabetes-related deaths All-cause mortality MI Stroke Peripheral vascular disease Microvascular disease 0.76 (0.62–0.92) 0.68 (0.49–0.94) 0.82 (0.63–1.08) 0.79 (0.59–1.07) 0.56 (0.35–0.89) 0.51 (0.19–1.37) 0.63 (0.44–0.89) Favors tight control 0.1 1 Favors less tight control 10 P value 0.0046 0.019 0.17 0.13 0.013 0.17 0.0092 TM RR=relative risk. UKPDS Group. BMJ. 1998;317:703-713. © 1999 Professional Postgraduate Services ® Professional Postgraduate Primary CHD* Prevention in Patients With Type 2 Diabetes: The Helsinki Heart Study 15 P=NS P<0.02 10.5 10 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 (%) 5 7.4 3.3 3.4 0 *Myocardial infarction or cardiac death. NS=not significant. Koskinen P et al. Diabetes Care. 1992;15:820-825. TM © 1999 Professional Postgraduate Services ® No. patients with events P S Simvastatin better Placebo better Total mortality CHD mortality 232 24 172 17 167 15 99 12 Major CHD event Any CHD event CABG or PTCA 578 44 871 56 363 20 407 24 667 41 238 15 70 5 Cerebrovascular event 90 12 Any atherosclerotic event961 750 61 46 Nondiabetic Diabetic 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 TM RR with 95% CIs © 1999 Professional Postgraduate Services ®