1. TM © 1999 Professional Postgraduate Services ® 0.60 0.70 0.80 0.90 1.00 4S: Total Mortality Reduction in a Subgroup of Patients With Diabetes Proportion alive Yr since randomization - P=0.08 - P=0.001 Diabetic, simvastatin Diabetic, placebo Nondiabetic, simvastatin Nondiabetic, placebo 29% 43%

2. TM © 1999 Professional Postgraduate Services ® 4S:Major CHD Event Reduction in a Subgroup of Patients With Diabetes Proportion without major CHD event Yr since randomization - P=0.002 - P=0.0001 Diabetic, simvastatin Diabetic, placebo Nondiabetic, simvastatin Nondiabetic, placebo 32% 55%

3. TM © 1999 Professional Postgraduate Services ® 4S: Treatment Benefit in Subgroup With Impaired Fasting Glucose (FG 110-125 mg/dL) Total mortality Coronary mortality Major coronary events Revas- culari- zations  in events (%) P=0.005 P=0.001 P=0.010

4. TM © 1999 Professional Postgraduate Services ® CARE: Reduction of Coronary Events in Patients With Diabetes N=4,159 males and females; 976 diabetics. 0 5 10 15 20 25 30 35 40 012345 % with event Yr 27% 22% - P=0.001 Diabetic, pravastatin Diabetic, placebo Nondiabetic, pravastatin Nondiabetic, placebo - P=0.012 6

5. TM © 1999 Professional Postgraduate Services ® Risk reductionP Diabetes:PlaceboPravastatinPlaceboPravastatin(95% CI)value Present 304 282112 (37) 81 (29)25 (0 to 43) 0.05 Absent17741799437 (25)349 (19)23 (11 to 33)<0.001 Number (%) of Number of patientspatients with event Sacks FM et al. N Engl J Med. 1996;335:1001-1009. CARE: Major Coronary Events in the Diabetic Subgroup

6. TM © 1999 Professional Postgraduate Services ® Post-CABG: Effect of Aggressive Lipid Lowering on a Subgroup of Patients With Diabetes Substantial progression Per patient % of grafts27.043.30.4927.839.00.60 (0.20-1.19) (0.46-0.79) Number of grafts1221041,2381,214 Occlusion Per patient % of grafts11.519.20.5410.416.00.61 (0.15-2.02) (0.41-0.92) Number of grafts1221041,2381,214 Therapy Diabetes No Diabetes Hoogwerf BJ et al. Diabetes. 1999;48:1289-1294. RR RR AggressiveModerate (99% CI) AggressiveModerate (99% CI)

7. TM © 1999 Professional Postgraduate Services ® -27 8 -24 -30 -18 8 -30* -42* -45 -40 -35 -30 -25 -20 -15 -10 -5 0 5 10 Atorvastatin 10 mg Simvastatin 10 mg Mean %  from baseline at 4 wk (N=17) *P<0.01 TCLDL-CTG HDL-C Effects of Lipid-Lowering Therapy in Patients With Type 2 Diabetes

8. TM © 1999 Professional Postgraduate Services ® WOSCOPS: Development of Type 2 Diabetes Kaplan-Meier plots of time to development of type 2 diabetes according to treatment assignment. % diabetic Years in study 00.511.522.533.544.555.5 65432106543210 Placebo Pravastatin 40 mg/d

9. TM © 1999 Professional Postgraduate Services ® AHA Primary Prevention Guidelines for CVD in Patients with Diabetes Smoking: provide counseling to patient and family -- goal is complete cessation Blood pressure control: Measure BP at each visit, consider medication above 130/85 (JNC- VI), goal <130/80 (ADA) Lipid management - Goal LDL-C 130 mg/dl Glucose control - weight reduction and exercise are first steps, further therapy involve oral hypoglycemic agents and insulin

10. TM © 1999 Professional Postgraduate Services ® AHA Primary Prevention Guidelines for Diabetics (continued) Antiplatelet agents - Aspirin 80-325 mg/day recommended in high risk pts (e.g., 1+ risk factors in addition to diabetes- ADA) Physical activity - 30 minutes moderate intensity exercise 3-4 times/week in daily life habits Weight management - Desirable BMI 21-25, desirable waist circumference <102cm in men and <88cm in women Estrogen replacement therapy - no current recommendations given recent clinical trials

11. TM © 1999 Professional Postgraduate Services ® Considerations for Prevention in Type I Diabetes Duration of disease is the predominant risk factor in Type I diabetics Smoking, hypertension, renal disease (macroalbuminuria and renal insufficiency), and dyslipidemia remain important and should be treated as indicated for Type II diabetic patients Depending on age, use of certain lipid-lowering medications (e.g., statins) may be contraindicated, although goal LDL<100 mg/dl is still appropriate. Ongoing Epidemiology of Diabetes Interventions and Complications (EDIC) study will examine impact of intensive glucose control on future risk factor status and presence of subclinical disease (carotid atherosclerosis and coronary calcium)

12. 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)<200200-239  240 Fasting plasma TG (mg/dL)<200200-399  400 Fasting plasma LDL-C (mg/dL)<100100-129  130 (  100 if CAD) Fasting plasma HDL-C (mg/dL) >4535-45<35 * Current ADA recommendations call for therapeutic action for values above “borderline.” † Adjust for normal lab values.

13. 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 4.0-6.0% (mean 5.0%, standard deviation 0.5%). ADA. Diabetes Care. 1996;19(suppl 1):S8-S15.

14. TM © 1999 Professional Postgraduate Services ® Weight Management and Physical Activity in Persons with Diabetes

15. 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 Borderline100-12935-45200-399 Low 45<200 *Values represent mg/dL. For women, HDL-C should be increased by 10 mg/dL.

16. 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

17. 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.

18. 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.

19. 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 Click for larger picture

20. 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

21. TM © 1999 Professional Postgraduate Services ® DrugTGHDL-CLDL-C Fibric acid derivatives  35-50  10-25  10-15 Bile acid sequestrants  *    15-30 Nicotinic acid  25-30  10-30  10-25 * May increase in patients with pre-existing hypertriglyceridemia. Range of lipid effects (%  ) Hypolipidemic Drug Therapy 