TM © 1999 Professional Postgraduate Services ® Diabetic Dyslipidemia

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 ® Framingham Heart Study 30-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-64) * Age-adjusted annual rate/1,000 MenWomen Total CVDCHDCardiac failure Intermittent claudication Stroke Risk ratio P<0.001 for all values except *P<0.05. Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N et al, eds. Oxford; 1992.

TM © 1999 Professional Postgraduate Services ®

TM © 1999 Professional Postgraduate Services ®

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 ® 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 ® 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 ® * 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). Adapted from Garg A, Grundy SM. Diabetes Care. 1990;13: 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). Adapted from Garg A, Grundy SM. Diabetes Care. 1990;13: Abnormal Lipid Levels in Women With Type 2 Diabetes

TM © 1999 Professional Postgraduate Services ® Feingold KR et al. Arterioscler Thromb. 1992;12: Lamarche B et al. Circulation. 1997;95: 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 ® 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 ® ADA-Suggested Standards for Biochemical Indices of Metabolic Control Biochemical indexAcceptableBorderline*High Fasting plasma glucose (mg/dL) 200 Postprandial (2 hr) plasma glucose (mg/dL) 235 Hemoglobin A 1c (%) † (Goal: 7>10 Fasting plasma TC (mg/dL)<  240 Fasting plasma TG (mg/dL)<  400 Fasting plasma LDL-C (mg/dL)<  130 (  100 if CAD) Fasting plasma HDL-C (mg/dL) > <35 * Current ADA recommendations call for therapeutic action for values above “borderline.” † Adjust for normal lab values. Adapted from Garber AJ et al. Diabetes Care. 1992;15: ; ADA. Diabetes Care. 1993;16: ; and ADA. Diabetes Care. 1998;21(suppl 1):S36-S39.

TM © 1999 Professional Postgraduate Services ® Glycemic Control for People With Diabetes DiabeticAction Biochemical indexNondiabeticgoalsuggested Preprandial glucose (mg/dL) 126 Bedtime glucose (mg/dL) 160 Hemoglobin A 1c (%) 8 These values are for nonpregnant individuals. “Action suggested” depends on individual patient circumstances. Hemoglobin A 1c is referenced to a nondiabetic range of % (mean 5.0%, standard deviation 0.5%). ADA. Diabetes Care. 1996;19(suppl 1):S8-S15.

TM © 1999 Professional Postgraduate Services ® 1999 ADA Risk Stratification Based on Lipoprotein Levels in Adults With Diabetes* ADA. Diabetes Care. 1999;22:S56-S59. RiskLDL-CHDL-CTG High  130<35  400 Borderline Low 45<200 *Values represent mg/dL. For women, HDL-C should be increased by 10 mg/dL.

TM © 1999 Professional Postgraduate Services ® 1999 ADA Recommendations Based on LDL-C Levels in Adults With Diabetes* ADA. Diabetes Care. 1999;22:S56-S59. InitiationLDL-CInitiationLDL-C Statuslevelgoallevelgoal With CHD, PVD or CVD>100  100>100  100 Without CHD, PVD, and CVD>100  100  130 †  100 *Values represent mg/dL. † Some authorities recommend drug initiation between 100 and 130 mg/dL. Medical nutrition txDrug tx

TM © 1999 Professional Postgraduate Services ® Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults LDL-C lowering –first choice: HMG-CoA reductase inhibitors (statins) –second choice: bile acid binding resin or fenofibrate HDL-C raising –behavioral interventions (weight loss,  physical activity, smoking cessation) –glycemic control –difficult (except with niacin, which is relatively contraindicated, or fibrates) TG lowering –glycemic control first priority –fibric acid derivative (gemfibrozil, fenofibrate) –statins (moderately effective at high dose in patients with  TG and  LDL-C) ADA. Diabetes Care. 1999;22:S56-S59.

TM © 1999 Professional Postgraduate Services ® Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults Combined hyperlipidemia –first choice: improved glycemic control plus high-dose statin –second choice: improved glycemic control plus statin plus fibric acid derivative (gemfibrozil or fenofibrate) –third choice: improved glycemic control plus resin plus fibric acid derivative or improved glycemic control plus statin plus niacin (glycemic control must be monitored carefully) ADA. Diabetes Care. 1999;22:S56-S59.

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 ® DrugTGHDL-CLDL-C Fibric acid derivatives    Bile acid sequestrants  *    Nicotinic acid    * May increase in patients with pre-existing hypertriglyceridemia. Range of lipid effects (%  ) Hypolipidemic Drug Therapy 

TM © 1999 Professional Postgraduate Services ® Lovastatin 20 mg  19  27  6  9 Pravastatin 20 mg  24  32  2  11 Simvastatin 20 mg  25  33  11  9 Atorvastatin 10 mg  29  39  6  19 Cerivastatin 0.3 mg  19  28  10  13 * Values reported in Package Inserts. Lipid effects (%  )* Hypolipidemic Drug Therapy: HMG-CoA Reductase Inhibitors Drug at starting doseTCLDL-CHDL-CTG

TM © 1999 Professional Postgraduate Services ® * -42* Atorvastatin 10 mg Simvastatin 10 mg Mean %  from baseline at 4 wk (N=17) *P<0.01 Best JD. Atherosclerosis. 1994;109:312. Abstract. Data on file. Parke-Davis, Morris Plains, NJ. TCLDL-CTG HDL-C Effects of Lipid-Lowering Therapy in Patients With Type 2 Diabetes

TM © 1999 Professional Postgraduate Services ® *Without vascular disease. † With vascular disease. Approach to Patients With Diabetes and Hyperlipidemia Acceptable LDL-C <100 TG <200 Monitor annually Improvement Hypercholesterolemia Goal LDL-C <130* LDL-C <100 † HMG-CoA Resin Hypertriglyceridemia Goal TG <400* TG <200 † Fibrate HMG-CoA if LDL  Mixed Dyslipidemia Goal TG <400 LDL-C <130* TG <200LDL-C <100 † HDL-C >35 HMG-CoA Fibrate + resin Hyperchylomicronemia TG  1000 Fibrate and fat restriction (<10% of calories) Measure (fasting): TC, TG, HDL-C, LDL-C (calculated), glucose, HbA 1c Higher risk: LDL-C  130, TG  400, HDL-C <35 Lower risk: LDL-C 45 Regulate diabetes: weight loss, exercise, restrict dietary saturated fat and cholesterol No improvement

TM © 1999 Professional Postgraduate Services ®

TM © 1999 Professional Postgraduate Services ®