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Diabetic Dyslipidemia and Atherosclerosis Henry Ginsberg, MD Interrelation Between Atherosclerosis and Insulin Resistance Hypertension Obesity Hyperinsulinemia Insulin Resistance Diabetes Hypertriglyceridemia Small, dense LDL Low HDL Hypercoagulability Atherosclerosis Insulin Resistance and Hyperinsulinemia: Clinical Clues Abdominal obesity TG + HDL-C Glucose intolerance Hypertension Atherosclerosis Ethnicity Dyslipidemia in the Insulin Resistance Syndrome Elevated total TG Reduced HDL-C Small, dense LDL-C Dyslipidemias in Adults with Diabetes Framingham Heart Study MEN WOMEN Normal DM Normal DM Increased cholesterol 14% 13% 21% 24% Increased LDL 11% 9% 16% 15% Decreased HDL 12% 21% 10% 25% 9% 19% 8% 17% Increased triglycerides Garg A et al. Diabetes Care 1990;13:153-169. Mean Plasma Lipids at Diagnosis of Type 2 Diabetes - UKPDS MEN Type 2 WOMEN Control Type 2 Control 2139 52 1574 143 TC (mg/dl) 213 205 224 217 LDL-C (mg/dl) 139 132 151* 135 43 43* 55 103 159* 95 Number of Pts HDL-C (mg/dl) TG (mg/dl) 39** 159* * P<0.001, ** P<0.02 comparing type 2 vs. controll UKPDS Group. Diabetes Care 1997;20:1683-1687. Relation Between Insulin Resistance and Hypertriglyceridemia Plasma TG (mg/dL) 625 500 r = 0.73 P < 0.0001 400 300 200 100 100 200 300 400 500 600 Insulin Response to Oral Glucose* * Total area under 3-hour response curve (mean of 2 tests). Olefsky JM et al. Am J Med. 1974;57:551-560. Association Between Hyperinsulinemia and Low HDL-C HDL-C (mg/dL) 60 50 Hyperinsulinemic P<0.005 Normoinsulinemic P<0.005 40 30 20 Nonobese Reaven GM. In: LeRoith D et al., eds. Diabetes Mellitus. Philadelphia: Lippincott-Raven,1996:509-519. Obese Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells FFA IR X Insulin Liver Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Liver FFA IR X Insulin TG Apo B VLDL VLDL Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Liver FFA IR X Insulin TG Apo B VLDL CE VLDL (CETP) HDL TG (hepatic lipase) Apo A-1 Kidney Mechanisms Relating Insulin Resistance and Dyslipidemia Fat Cells Liver FFA IR X CE TG Apo B VLDL VLDL (CETP) HDL TG (hepatic lipase) Apo A-1 CE (CETP) TG Kidney Insulin LDL SD LDL (lipoprotein or hepatic lipase) Dyslipidemia in Diabetes Increased Decreased Triglycerides HDL VLDL Apo A-I LDL and small dense LDL Apo B LDL Subclass Phenotypes in Diabetes Mellitus LDL Subclass n A Int B 51 24 36 6 Men* Diabetic Nondiabetic 29 87 28 47 Percent 21 29 Women** Diabetic Nondiabetic 54 543 34 85 30 9 * Feingold KR et al. Arterioscler Thromb 1992; 12:1496-1502. ** Selby JV et al. Circulation 1993; 88:381-387. Small Dense LDL and CHD: Potential Atherogenic Mechanisms Increased susceptibility to oxidation Increased vascular permeability Conformational change in apo B Decreased affinity for LDL receptor Association with insulin resistance syndrome Association with high TG and low HDL Austin MA et al. Curr Opin Lipidol 1996;7:167-171. Hypertriglyceridemia and CHD Risk: Associated Abnormalities Accumulation of chylomicron remnants Accumulation of VLDL remnants Generation of small, dense LDL-C Association with low HDL-C Increased coagulability - plasminogen activator inhibitor (PAI-1) - factor VIIc - Activation of prothrombin to thrombin TG Metabolism in CHD: Studies in the Postprandial State Corrected for Fasting Uncorrected TG (mg/dL) 400 CHD Cases 300 300 TG Level* 200 CHD Cases 200 Controls 100 0 100 Controls 0 2 4 0 6 8 0 2 Hours after Test Meal Error bars = SEM Patsch JR et al. Arterioscler Thromb 1992;12:1336-1345. 4 6 8 Factors Promoting Thromboembolic Disease in Diabetes Increased plasma fibrinogen Increased plasminogen activator inhibitor 1 Increased platelet aggregability Thompson SG et al. N Engl J Med 1995;332:635-641. Adverse Effects on Balance Between Thrombosis and Fibrinolysis in Subjects with Diabetes Predisposition to thrombosis - Platelet hyperaggregability - Elevated concentrations of procoagulants - Decreased concentration and activity of antithrombotic factors Predisposition to attenuation of fibrinolysis - Decreased t-PA activity - Increased PAI-1 - Decreased concentrations of 2-antiplasmin Sobel BE. Circulation 1996;93:1613-1615. PAI-1 Activity in Blood in Patients with Type 2 Diabetes PAI-1 Activity (AU/mL) 20 15 No Diabetes Diabetes 10 5 0 Lean PAI-1 = plasminogen activator inhibitor type 1 McGill JB et al. Diabetes. 1994;43:104-109. Obese Elevation of PAI-1 Induced by Hyperinsulinemia, Hyperglycemia, and Increased FFA in Blood of Normal Subjects PAI-I (mg/mL) 21 18 Infusion of glucose and intralipid 15 12 * 9 6 3 0 0 Values are mean + SD 2 4 6 Time (h) *P<0.05 vs saline infusions in same subjects Calles-Escandon J et al. Diabetes. 1998;47:290-293. 8 10 12 Pharmacologic Agents for Treatment of Dyslipidemia Effect on lipoprotein LDL HDL Triglyceride First-line agents HMG CoA reductase inhibitor Fibric acid derivative Second-line agents Bile acid binding resins Nicotinic acid In diabetic patients, nicotinic acid should be restricted to <2g/day. Short-acting nicotinic acid is preferred. American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60. Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults* LDL cholesterol lowering* - First choice: HMG CoA reductase inhibitor (statin) - Second choice: Bile acid binding resin or fenofibrate HDL cholesterol raising - Behavior interventions such as weight loss, increased physical activity and smoking cessation - Glycemic control - Difficult except with nicotinic acid, which is relatively contraindicated, or fibrates Triglyceride lowering - Glycemic control first priority - Fibric acid derivative (gemfibrozil, fenofibrate) - Statins are moderately effective at high dose in hypertriglyceridemic subjects who also have high LDL cholesterol * Decision for treatment of high LDL before elevated triglyceride is based on clinical trial data indicating safety as well as efficacy of the available agents. Adapted from American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.