1. Clinical Trials of Lipid Therapy in Diabetic Subjects (subgroup analysis) Haffner Diabetes Care; 1: 1998 StudyjournalNLDL-CBaselineCHD loweringLDL-Creduction Primary prevention Helsinki HSDiabetes135-6 %4,9 mmol/l-60 % (ns) Care 1992191 mg/dl AFCAPS/TEXCAPSJAMA 1998264-25%3.9 mmol/l-43 % (ns) 150 mg/dl Secondary prevention CARENEJM 1996586-28 %3,5 mmol/l-25 % (p=0.05) 137 mg/dl 4SDiabetes202-36 %4,8 mmol/l-55 % (p=0.002) Care 1997186 mg/dl

2. Risk Reduction by Simvastatin Estimated CHD reduction after treating 100 CHD patients for 6 years Expected fatal and non fatal Ml’s Number of prevened Fatal and non fatal MI’s patients with diabetes patients without diabetes 49 29 24 9 Pyörälä K et al. Diabetes Care 20(4): 614 - 620, 1997

3. Overview Presentation Who are at risk –Secondary prevention –Primary prevention - Diabetes Mellitus type 2 Lowering Cholesterol –Secondary prevention –Primary prevention Beyond cholesterol lowering How low should we go Guidelines

4. Atherosclerosis “The Overall Picture”

5. Relationship Between Endothelial Function and HMG-CoA reductase Inhibitors Restoration of endothelium- dependent vasomotion is on of the earliest recognizable benefits after treatment with HMG-CoA reductase inhibitors. Treasure et al. N Engl J Med 332:481-487, 1995 Anderson et al. N Engl J Med 332:488-493,1995 O’Driscoll et al. Circulation 95:1128-1131, 1997

6. Myocardial ischemia 0 5 15 20 10 Baseline6 months Andrews et al.; Circulation 1997 Placebo (N=20) Episodes of ischemia 0 5 15 20 10 Baseline6 months Lovastatin (N=20)

7. Study Design 43 non-diabetic patients –Normal CAG –Positive exercise test –43 –61 yrs –Serum total cholesterol > 7.75 mmol/l ( > 300 mg/dl) Step 1 diet – 12 weeks Randomized for diet (n=20) or statins (n=23) – 16 weeks Statins withdrawn –Lipid profile –Exercise test Repeat after 20 weeks –Lipid profile –Exercise test A.P. Mansur, et al. Heart 1999;82:689

8. Results At week 28: Statin group: significant reductions in plasma lipids Positive exercise test 23 > 3 Diet group:no significant changes in plasma lipids Positive exercise test 20 > 15 At week 48: Statin group: plasma lipids returned to base line levels 17 patients on statins; positive exercise test in 15 Diet group:Positive exercise test in 14 out of 15 patients A.P. Mansur, et al. Heart 1999;82:689

9. Overview Presentation Who are at risk Secondary prevention Primary prevention - Diabetes Mellitus type 2 Lowering Cholesterol Secondary prevention Primary prevention Beyond cholesterol lowering How low should we go? Guidelines

10. Atherogenic Lipoproteins

11. Aggressive Tx (93-96)* Moderate Tx (134-136)* Post-CABG Study: Aggressive vs Moderate Treatment Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162. * Mean achieved. Follow-up (mo) 12243648 6 80 90 100 110 120 130 140 150 160 0 LDL-C (mg/dL)

12. Is Lower Better? Aggressive Lipid Lowering is Associated with More Favorable Outcomes *P  0.001 vs moderate therapy group. Mean lovastatin dose 76 mg in aggressive group and 4 mg in moderate group. After 1 year, mean LDL-C level was 93 mg/dL (2.4 mmol/L) in the aggressive group and 136 mg/dL (3.5 mmol/L) in the moderate group. The Post CABG Trial Investigators. N Engl J Med 1997;336:153–162. Grafts with occlusion or death Grafts with new lesions Grafts with progression or death * * *

13. On-Treatment LDL Levels and Correlation with Major Coronary Events in 4S Circulation 1997;96:I-717 Absolute difference in event rate: 2.3% 5.6%

14. Study Hypothesis: Lower Is Better With CHD event (%) 50 0 5 10 15 20 25 7090110130150170190210 LDL-C (mg/dL) Secondary prevention Primary prevention LIPID-Rx CARE-PBOCARE-Rx 4S-Rx LIPID-PBO 4S-PBO AFCAPS-Rx WOS-Rx WOS-PBO AFCAPS-PBO ?

15. Is Lower Better? TNT/ IDEAL Study Hypotheses With CHD event (%) 0 5 10 15 20 25 507090110130150170190210 LDL-C mg/dL Secondary prevention Primary prevention TNT 80 mg TNT 10 mg TNT Entry IDEAL-sim IDEAL-Entry IDEAL-ator

16. “Normal” Plasma Cholesterol 700 (18.0) 300 (7.7) 200 (5.2) 150 (3.9) 100 (2.6) 50 (1.3) 0 Plasma cholesterol level mg/dl (mmol/l) Physiologic level for plasma LDL-Cholesterol as predicted from receptor studies 25 mg/dl (0.65mmol/l) FH Homozygotes FH Heterozygotes Normal Adults Newborns Guinea pigCowRabbit RatSheepCamel Pig

17. Overview Presentation Who are at risk Secondary prevention Primary prevention - Diabetes Mellitus type 2 Lowering Cholesterol Secondary prevention Primary prevention Beyond cholesterol lowering How low should we go Guidelines

18. National Institute of Health, USA Adult Treatment Panel II Patient categoryLDL-initiation LevelLDL goal Dietary therapy CHD risk factors 150 mg/dl< 150 mg/dl CHD risk factors > 2> 125 mg/dl< 125 mg/dl With CHD> 100 mg/dl < 100 mg/dl Drug treatment CHD risk factors 200 mg/dl < 150 mg/dl CHD risk factors > 2> 150 mg/dl < 125 mg/dl With CHD> 100 mg/dl < 100 mg/dl Circulation 1994:89:1329

19. Current consensus (U.S.): NCEP LDL-C Goals Risk ProfileLDL-C-goal Diagnosed CHD< 100 mg/dl (2.6 mmol/l) > 2 risk factors<130 mg/dl (3.4 mmol/l) < 2 risk factors<160 mg/dl (4.2 mmol/l)

20. Therapeutic groupConservativeDrugs (based on measures (weightLDL-cholesterol) loss, lipid-lowering, diet Cholesterol 200–250 mg/dleffective in majorityOnly in CHD or very LDL cholesterol 135–175 mg/dl high risk and un- responsive to diet Cholesterol 250–300 mg/dl Need close dietaryCHD or high risk if LDL LDL cholesterol 175–200 mg/dl compliance> 125 mg/dl and Most respond unresponsive to diet adequately Cholesterol > 300 mg/dl Need close dietary Justified even in ab- LDL-cholesterol > 200 mmol/lcompliancesense of other risk Three month trialfactors in genetic dyslipidemias European Atherosclerosis Guidelines: management of hypercholesterolemia Nutrition Metabolism and Cardiovascular Disease 1998:2:113

22. Current consensus (Europe): ESC/EAS LDL-C Goals Risk ProfileLDL-C-goals Diagnosed CHD115 - 135 mg/dl (3.0 - 3.5 mmol/l) Moderate risk135 - 155 mg/dl (3.5 - 4.0 mmol/l) No heart disease55 - 175 mg/dl (4.0 - 4.5 mmol/l)

23. Second Joint Task Force Guidelines Lipoprotein markerGoal of therapy LDL-C goal <3.0 mmol/L (115 mg/dL) Total-C goal<5.0 mmol/L (190 mg/dL)

24. CHD events per year 4.5%3.0%2.0%1.5% NNT for 5 years*13203040 Cost per life year gained#£ 5100£ 8200£ 10 700 £ 12 500 Cumulative proportion of 5.1%8.2%15.8%24.7% proportion of adults in UK above CHD risk treshold Annual cost of treatment £ 549 m £ 885 m £ 1 712 m £ 2 673 m if implemented fully in UK *Number needed to treat for 5 years to prevent one major coronary event # For Simvastatin treatment at 27.4 mg daily Statin Treatment at Four CHD Risk Levels Pickin et al. Heart 1999; 82:325

25. Archie Cochrane’s Plea: “All effective treatments be made available” Appears unsustainable at current level of funding and health level service resources Pickin et al. Heart 1999; 82:325

26. Practical Guidelines

27. Guidelines treatment goals? Total cholesterol< 5.0 mmol/l (200 mg/dl) LDL-cholesterol< 3.0 mmol/l (115 mg/dl) triglycerides< 2.0 mmol/l (80 mg/dl) HDL-cholesterol> 1.0 mmol/l (40 mg/dl) 5,3,2,1 rule

28. Guidelines lifestyle Stop smoking Prevent obesity exercise : 3 - 5 x week 30 min Diet: –Fruit, vegetables, whole grain cereals –low fat dairy products –2 x per week fish and 1 x per week vegetarian –avoid snacks and sweets –fish - pasta - olive oil - red wine (Mediterranean-diet)

29. Guidelines Drugs Step 1: LDL-reduction Step 2: HDL-cholesterol increase and triglyceride decrease Start statins when –LDL-cholesterol > 3.0 mmol/l –HDL-cholesterol < 0.9 mmol/l en TG < 2.0 mmol/l –TG < 4.5 mmol/l

30. Priorities for Lipid lowering Secondary prevention Patients with diabetes mellitus type 2 Patients with genetic dyslipidemia's Patients with multiple risk factors

31. Summary Who are at risk –Secondary prevention –Primary prevention - Diabetes Mellitus type 2 Lowering Cholesterol –Secondary prevention –Primary prevention Beyond cholesterol lowering How low should we go Guidelines