4 S Total Mortality Reduction in a Subgroup

4 S: Total Mortality Reduction in a Subgroup of Patients With Diabetes 1. 00 29% 0. 90 Proportion alive 0. 80 0. 70 0. 60 43% Diabetic, simvastatin - P=0. 08 Diabetic, placebo Nondiabetic, simvastatin - P=0. 001 Nondiabetic, placebo Yr since randomization TM © 1999 Professional Postgraduate Services ®

4 S: Major CHD Event Reduction in a Subgroup of Patients With Diabetes Proportion without major CHD event 32% Diabetic, simvastatin Diabetic, placebo - P=0. 002 Nondiabetic, simvastatin Nondiabetic, placebo 55% - P=0. 0001 Yr since randomization TM © 1999 Professional Postgraduate Services ®

4 S: Treatment Benefit in Subgroup With Impaired Fasting Glucose (FG 110 -125 mg/d. L) Total mortality Coronary mortality Major coronary events Revascularizations in events (%) P=0. 001 P=0. 010 TM P=0. 005 © 1999 Professional Postgraduate Services ®

CARE: Reduction of Coronary Events in Patients With Diabetes 40 35 27% 30 % with event 25 22% 20 15 Diabetic, pravastatin - P=0. 001 Diabetic, placebo 10 Nondiabetic, pravastatin 5 Nondiabetic, placebo 0 0 1 2 3 Yr 4 N=4, 159 males and females; 976 diabetics. 5 - P=0. 012 6 TM © 1999 Professional Postgraduate Services ®

CARE: Major Coronary Events in the Diabetic Subgroup Number of patients Number (%) of patients with event Diabetes: Placebo Pravastatin Placebo Risk reduction Pravastatin (95% CI) Present 304 282 112 (37) 81 (29) Absent 1774 1799 437 (25) 349 (19) 25 (0 to 43) P value 0. 05 23 (11 to 33) <0. 001 TM Sacks FM et al. N Engl J Med. 1996; 335: 1001 -1009. © 1999 Professional Postgraduate Services ®

Post-CABG: Effect of Aggressive Lipid Lowering on a Subgroup of Patients With Diabetes Therapy No Diabetes Therapy RR Aggressive Moderate (99% CI) Aggressive Substantial progression Per patient % of grafts Number of grafts Occlusion Per patient % of grafts Number of grafts 27. 0 43. 3 122 104 11. 5 19. 2 122 104 0. 49 (0. 20 -1. 19) 0. 54 (0. 15 -2. 02) RR Moderate (99% CI) 27. 8 39. 0 1, 238 1, 214 10. 4 16. 0 1, 238 1, 214 0. 60 (0. 46 -0. 79) 0. 61 (0. 41 -0. 92) TM Hoogwerf BJ et al. Diabetes. 1999; 48: 1289 -1294. © 1999 Professional Postgraduate Services ®

Effects of Lipid-Lowering Therapy in Patients With Type 2 Diabetes 10 5 0 -5 Mean % from baseline -10 -15 at 4 wk -20 (N=17) -25 -30 -35 -40 -45 *P<0. 01 8 TC LDL-C 8 TG HDL-C -18 -24 -30* -30 -42* -27 Atorvastatin 10 mg Simvastatin 10 mg TM © 1999 Professional Postgraduate Services ®

WOSCOPS: Development of Type 2 Diabetes 6 Placebo Pravastatin 40 mg/d 5 % diabetic 4 3 2 1 0 0 0. 5 1 1. 5 2 2. 5 3 3. 5 Years in study 4 Kaplan-Meier plots of time to development of type 2 diabetes according to treatment assignment. 4. 5 5 5. 5 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 (JNCVI), goal <130/80 (ADA) • Lipid management - Goal LDL-C <100 mg/dl (NCEP III), consider medication when LDL-C >130 mg/dl • Glucose control - weight reduction and exercise are first steps, furtherapy involve oral hypoglycemic agents and insulin 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 <102 cm in men and <88 cm in women • Estrogen replacement therapy - no current recommendations given recent clinical trials 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) TM © 1999 Professional Postgraduate Services ®

ADA-Suggested Standards for Biochemical Indices of Metabolic Control Biochemical index Fasting plasma glucose (mg/d. L) Postprandial (2 hr) plasma glucose (mg/d. L) Hemoglobin A 1 c (%)† (Goal: <7%) Fasting plasma TC (mg/d. L) Fasting plasma TG (mg/d. L) Fasting plasma LDL-C (mg/d. L) Fasting plasma HDL-C (mg/d. L) Acceptable Borderline* High <115 126 >200 >7 200 -239 200 -399 100 -129 >235 >10 240 400 130 35 -45 <35 <140 <6 <200 <100 ( 100 if CAD) >45 * Current ADA recommendations call for therapeutic action for values above “borderline. ” † Adjust for normal lab values. TM © 1999 Professional Postgraduate Services ®

Glycemic Control for People With Diabetes Biochemical index Diabetic Action Nondiabetic goal suggested Preprandial glucose (mg/d. L) <115 80 -120 Bedtime glucose (mg/d. L) <120 100 -140 Hemoglobin A 1 c (%) <6 <7 <80 >126 <100 >160 >8 These values are for nonpregnant individuals. “Action suggested” depends on individual patient circumstances. Hemoglobin A 1 c is referenced to a nondiabetic range of 4. 0 -6. 0% (mean 5. 0%, standard deviation 0. 5%). TM ADA. Diabetes Care. 1996; 19(suppl 1): S 8 -S 15. © 1999 Professional Postgraduate Services ®

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

1999 ADA Risk Stratification Based on Lipoprotein Levels in Adults With Diabetes* Risk LDL-C HDL-C TG High 130 <35 400 35 -45 200 -399 >45 <200 Borderline 100 -129 Low <100 *Values represent mg/d. L. For women, HDL-C should be increased by 10 mg/d. L. TM ADA. Diabetes Care. 1999; 22: S 56 -S 59. © 1999 Professional Postgraduate Services ®

1999 ADA Recommendations Based on LDL -C Levels in Adults With Diabetes* Medical nutrition tx Drug tx Initiation level LDL-C goal With CHD, PVD or CVD >100 Without CHD, PVD, and CVD >100 130† 100 Status *Values represent mg/d. L. †Some authorities recommend drug initiation between 100 and 130 mg/d. L. TM ADA. Diabetes Care. 1999; 22: S 56 -S 59. © 1999 Professional Postgraduate Services ®

Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults • LDL-C lowering – first choice: HMG-Co. A 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: S 56 -S 59. 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) TM ADA. Diabetes Care. 1999; 22: S 56 -S 59. © 1999 Professional Postgraduate Services ®

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

Hypolipidemic Drug Therapy: HMG-Co. A Reductase Inhibitors Lipid effects (% )* Drug at starting dose TC LDL-C HDL-C TG 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 TM * Values reported in Package Inserts. © 1999 Professional Postgraduate Services ®

Hypolipidemic Drug Therapy Range of lipid effects (% ) Drug TG Fibric acid derivatives 35 -50 Bile acid sequestrants * Nicotinic acid 25 -30 HDL-C LDL-C 10 -25 10 -15 15 -30 10 -30 10 -25 * May increase in patients with pre-existing hypertriglyceridemia. TM © 1999 Professional Postgraduate Services ®