1. Modern Management of Cholesterol in the High-Risk Patient

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

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

6. SECONDARY PREVENTION

7. Consequences of CHD 50 % of all MI’s in patients with previous MI 70 % of all fatal MI’s in patients with previous MI 4 -7 x increased risk of MI compared to people without CHD

8. Mortality in Hypercholesterolemic Men With CHD LDL cholesterol level 5 10 15 20 Deaths per 1000 person-years 25 X 12 X CHD >160 mg/dl (4.1 mmol/l) 19.15 CHD <130 mg/dl (3.4 mmol/l) 1.64 No CHD <130 mg/dl (3.4 mmol/l) 0.77 TikkanenJ. et al. N Engl J Med 1990:322(24):1700 - 1707

9. 168-191 (4.3-4.9) 180 (4.6) 192-217 (4.9-5.5) 204 (5.2) >218 (5.6) 245 (6.3) <167 (4.2) 149 (3.7) Serum cholesterol mg/dl (mmol/l) RangeMean Cumulative incidence of AMI per 100,000 screened subjects in 3 yr. 100 0 400 200 300 500 MenWomen Cholesterol/AMI Link in Low TC Population Wakugami K., et al. Jpn Cir J. 1998;52:7-14

10. PRIMARY PREVENTION

11. Diabetes Mellitus type 2

12. ‘With an excess of fat diabetes begins and from an excess of fat diabetics die…’ Elliott P. Joslin MD 1927

13. National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995. Atherosclerosis in Diabetes ~80% of all diabetic mortality ~80% of all diabetic mortality –75% from coronary atherosclerosis –25% from cerebral or peripheral vascular disease >75% of all hospitalizations for diabetic complications >75% of all hospitalizations for diabetic complications >50% of patients with newly diagnosed type 2 diabetes have CHD >50% of patients with newly diagnosed type 2 diabetes have CHD

14. 1816 14 12 10 8 6 4 2 0 menwomen Framingham study: DM type 2 and cardiovascular mortality Annual cardiovascular mortality per 1000 persons DM+ Kannel et al, JAMA 241: 2035 - 38 1979 DM -

15. MRFIT: DM type 2 and CVD mortality Stamler J et al. Diabetes Care 16(2): 434 - 444, 1993 0 20 40 60 80 100 120 140160 < 4.7 4.7-5.15.2-5.75.8-6.26.3-6.76.8-7.2  7.3 mmol/l CV mortality per 10.000 person years Diabetes No diabetes total cholesterol

16. UKPDS BMJ 1998 Impact of CHD Risk Factors in Patients with DM type 2 % risk increase % risk increase HbA 1C per 1 %+11 Systolic blood pressure per 10 mm Hg.+15 HDL-cholesterol per 0.1 mmol/l -15 LDL-cholesterol per 1 mmol/l+57

17. 8 year CV mortality in Finnish DM (n=1059) and non-DM (n=1378) subjects following MI non DM DM MI +MI - MI + MI - non DM DM MI +MI - MI + MI - CV events (%)18.83.54520.2 Strokes (%)7.21.919.510.3 Haffner et. al. NEJM July 23 1998 (Vol 339: 229-334)

19. Kannel WB. Am Heart J. 1985;110:1100-1107. Abbott RD et al. JAMA. 1988;260:3456-3460. Women, Diabetes, and CHD Diabetic women are at high risk for CHD Diabetic women are at high risk for CHD Diabetes eliminates relative cardioprotective effect of being premenopausal 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 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

20. Diabetes Mellitus and Reduction of CHD in the US 1971 9639 individuals (670 DM+) Age: 35 – 74 years 9 year follow-up 1982 8463 individuals (637 DM+) Age: 35 – 74 years 8 year follow-up K. Gu, et al. JAMA 1999; 281:1291

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

22. 22.6 15.9/13.2 7.9 2.8 Placebo MI rate per 100 subjects per 5 years WOS : NEJM 1995; 333 : 1301-1307 CARE : NEJM 1996; 335 : 1001-1009 LIPID : NEJM 1998; 339: 1349-1357 4S : Lancet 1994; 344 : 1383-1389 TexCAPS: JAMA 1998; 279: 1615-1622 Major HMG-CoA Trials CAREn=4,159 TC 5.4 mmol/l LIPIDn=9,014 TC 5.6 mmol/l WOS n=6,595 TC 7.0 mmol/l 4Sn=4,444 TC 6.8 mmol/l With CHD + high cholesterol With CHD + normal cholesterol Without CHD + high cholesterol TexCAPS n=6,605 TC 5.7 mmol/l Without CHD + low HDL

23. ‘Numbers Needed to Treat’ Major Coronary Events (MACE) LDL cholesterol Low High 4-S nnt 13 LIPID nnt 26 CARE nnt 33 AFCAPS nnt 59 WOS nnt 43

24. *p=0.048 vs an adjusted significance level of p=0.045 atorvastatin vs angioplasty/UC. % of patients with an ischemic event 13% 21% -36% difference * (p = 0.048) Ischemic Events n = 22 of 164n = 37 of 177 Pitt B et al. N Engl J Med. 1999;341:70-76.

25. 0 5 10 15 20 0-6 months>6-18 months % of patients with an ischemic event Atorvastatin 7% 6% Angioplasty/UC 10% 11% Pitt B et al. N Engl J Med. 1999;341:70-76. 46% difference 24% difference AVERT: Incidence of First Ischemic Event by Time

26. p=0.027 Cumulative incidence (%) Time since randomization (months) Time to First Ischemic Event Data on file. Parke-Davis, Morris Plains, NJ, Study 981-068. Atorvastatin (n=164) Angioplasty/UC (n=177)

27. Acute coronary event WOSCOPSAFCAPS Primary preventionSecondary prevention 03 m6 m9 m1 y2 y3 y4 y 03 m6 m9 m1 y2 y3 y4 y 4 S CARE LIPID MIRACL : unstable a.p. and non-Q infarct FLORIDA: AMI ( ischemie) A-Z: standard vs. aggressive care Start of Statin Therapy in Secondary Prevention

28. Ischaemic Stroke placebotreated reduction Primary prevention Woscop514610% Secondary prevention CARE785431% 4S987030% Hebert et al JAMA 1997; 278: 313 - 21 Ischaemic Stroke Reduction in Statin Trials

29. Crouse JR et al. Arch Intern Med. 1997;157:1305-1310. *P=0.001. † 95% confidence interval of percentage of relative reduction. Effects of Statins on Stroke Events: A Meta-analysis of Primary- and Secondary-Prevention Trials Relative reduction in rates (%) 1° Prevention (-42 to -27) † 2° Prevention (13-45) † Combined (11-40) †

30. 0 1 Cholesterol Reduction and Stroke Pre Statin Trials (1965 - 1992) Intervention Cholestyramine Niacin Diet Gemfibrozil Clofibrate and Niacin Clofibrate Multiple Summary Odds ratio (N) Fatal Stroke - Clofibrate (3) Fatal Stroke - Other (11) Fatal Stroke - All (13) Total Stroke All Odds Ratio of Stroke Cholesterol Reduction and the Risk for Stroke in Men. David Atkins et al. Ann. Intern. Med. 1993;119:136-145