1. Lipid Disorders The Science and Art of Treatment in 2004 Alan Jansujwicz, M.D. DHMC Cardiology Update Symposium 2004

2. Session Outline Background Review of Data to Support Current Lipid Treatment Paradigms Current Recommendations for Treatment Time for Questions (Hopefully)

3. Introduction CHD remains the no. 1 killer in the U.S. –Eradicate CAD – life expectancy up to 84 –Eradicate Cancer – life expectancy up to 80 Dyslipidemia plays a major role in CHD Safe and effective treatments available Less than ½ of eligible patients treated Many who are initially treated, stop Rx

4. Lipid Lowering Drugs and the Data HMG Co-A Reductase Inhibitors Niacin Fibrates Ezetimibe Others

5. HMG Co-A Reductase Inhibitors “ Statins ” Drugs structurally similar to HMG-CoA –precursor of cholesterol Competitive inhibitors of HMG-CoA reductase –last step in cholesterol synthesis Lower serum LDL concentrations by: –Upregulating LDL receptor activity –Reducing LDL entry into the circulation Most effective agents for lowering LDL Impressive body of evidence for CHD treatment

6. LDL Reduction by Individual Statins 5 mg10 mg20 mg40 mg80 mg Atorvastatin39%43%50%60% Fluvastatin21%24% Lovastatin21%24%30%40% Pravastatin22%32%34% Rosuvastatin45%52%58%69% Simvastatin22%30%35%41%47% In general, doubling dose = additional 6% reduction in LDL Source: Gau G, Mayo Clinic Cardiovascular Review

7. Chronic Statin Therapy Initial Major Secondary Prevention Studies Scandinavian Simvastatin Survival Study (4S) – Lancet ‘94 – 4444 patients with remote MI or Angina –Total Cholesterol 213-309 mg/dL –Simvastatin 20/40 mg vs placebo for 5.4 years Cholesterol and Recurrent Events Trial (CARE) – NEJM ‘96 –4159 patients with remote MI –Total Cholesterol < 240 mg/dL, LDL 115-174 mg/dL –Pravachol 40 mg vs placebo for 5 years Long-Term Intervention with Pravastatin (LIPID) – NEJM ‘98 –9014 patients with remote MI or Angina –Total Cholesterol 155 to 271 mg/dL –Pravachol 40 mg vs placebo for 6.1 years

8. LDL Lowering in 4S, CARE, and LIPID -35% -29% -25%

9. Risk Reduction in 4S, CARE, and LIPID

10. LIPID Trial – Risk of CHD Death The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group, N Engl J Med 1998;339:1349-1357 Time Delay to Benefit…

11. CARE Trial – CHD Events Sacks, F. M. et al. N Engl J Med 1996;335:1001-1009 Investigators postulated that there might be a “benefit floor” Possible Lower Limit to Benefit…

12. Chronic Statin Therapy The Heart Protection Study 20K patients ages 40-80 years in the UK Inclusion criteria of –Known CAD –Known PVD –Diabetes –Males > 65 with HTN (also a high risk group, but only 1%) No upper or lower limit of serum cholesterol Assigned to simvastatin 40 mg vs placebo Direct LDL measured from nonfasting samples Followed for average of 5 years HPS Collaborative Group. Lancet 2002;360: 7-22.

13. The Heart Protection Study Lipid Levels Baseline Lipid Panel –Total Chol228 mg/dL –dLDL131 mg/dL (15% less than calculated LDL) –HDL41 mg/dL –Trig81 mg/dL Average dLDL levels during 5 years of follow-up –Simvastatin89 mg/dL (85% avg compliance) –Placebo128 mg/dL(17% avg crossover) HPS Collaborative Group. Lancet 2002;360: 7-22. **Below previously suggested floor to benefit**

14. The Heart Protection Study Major Outcomes RRR = 13%RRR = 18%RRR = 25%RRR = 24% All risk reductions statistically significant

15. The Heart Protection Study Safety Measures p = ns

16. Chronic Statin Therapy Primary Prevention WOSCOPS – NEJM ’95 –6595 men, age 45 to 64, with no documented CAD –Total cholesterol at least 252 mg/dL –Pravachol 40 mg vs placebo for 4.9 years –Primary Endpoint – Nonfatal MI or Death from CHD AFCAPS/TexCAPS – JAMA ’98 –997 women (age 55-73) and 5608 men (age 45-73) –No documented CAD or PVD –Total cholesterol 180 to 264 mg/dL –Lovastatin 20/40 mg vs placebo for 5.2 years –Primary Endpoint – MI, USA, or Sudden Cardiac Death

17. Primary Prevention Trials Lipid Lowering Results WOS – RRR 31%, due to reduction in nonfatal MI and CHD death AFCAPS – RRR 37%, due to difference in nonfatal events 26% 25%

18. Acute Statin Therapy MIRACL – JAMA 2001 –3086 patients undergoing noninvasive ACS treatment –Total cholesterol less than 270 mg/dL; no lower limit –Atorvastatin 80 mg vs placebo for 16 weeks PROVE-IT – NEJM 2004 –4162 patients undergoing mostly invasive ACS treatment –Total cholesterol less than 240 mg/dL (naïve), 200 mg/dL (Rx) –Atorvastatin 80 mg vs Pravastatin 40 mg for 2 years A to Z – JAMA 2004 –4497 patients with acute NSTEMI or STEMI (complicated trial) –Total cholesterol less than 250 mg/dL; no lower limit –Simva 40(1mo)/80 mg vs Placebo(4mo)/Simva 20 mg for 2 years

19. MIRACL Trial Results RRR = 16% in Treatment Group at 16 weeks (p=0.048) Higher baseline LDL not predictive of increased event rate No significant association between % change in LDL and event rate

20. PROVE-IT and AtoZ Results Similar Reductions in LDL achieved in both trials RRR = 16% in PROVE-IT met significance RRR = 11% in A to Z did not meet significance Limitations in A to Z design likely responsible for lack of significant outcome

21. LDL Levels and CHD Risk Lower is Better! 4S-PL 4S-Rx LIPID-PL CARE-PL LIPID-Rx CARE-Rx HPS-PL HPS-RxWOS-PL AF-PL WOS-Rx AF-Rx PROV-Rx PROV-PL AtoZ-PL AtoZ-Rx

22. Niacin Cholesterol-lowering effect 1 st reported in 1955 Reduces LDL (5-25%) by decreasing peripheral mobilization of FFAs from adipose tissue Most effective drug available clinically for raising HDL (15-35%) Also effective for reducing triglycerides (25-50%) Reduces Lp(a) by 30% Converts small, dense LDL to large, buoyant LDL

23. Niacin Pitfalls with niacin therapy –Cutaneous flushing, pruritis, nausea, abd pain –Hepatotoxicity –Glucose intolerance –Increase risk of myositis if used with statin –Minimal hard endpoint outcome data

24. Niacin Outcome Data Trials Coronary Drug Project – JACC 1986 –8,000+ men, post-MI, Rx with 1 of 5 drugs or placebo –Patients treated for 6 years (some arms stopped early) –Patients subsequently followed for 9+ years post-Rx HDL Atherosclerosis Treatment Study – NEJM 2001 –160 patients with established CAD –Low HDL (31 mg/dL), “normal” LDL (125 mg/dL) –Four Rx regimens: Placebo, N+S, AV, N+S+AV –Followed for 3 years for clinical or angiographic events –All but 14 patients underwent an end of trial angiogram

25. Niacin Placebo P = 0.0012 100 90 80 70 60 50 40 30 20 10 0 2 4 6 8 12 14 16 Years of follow-up Survival (%) Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255 Coronary Drug Project Long-Term Mortality Benefit of Niacin source = www.lipidsonline.org

26. HDL-Atherosclerosis Treatment Study (HATS) Niacin and Statin Outcome Trial RRR = 89% p < 0.05 LDL 116 HDL 34 LDL 75 HDL 40 LDL 112 HDL 33 LDL 79 HDL 36

27. Fibrates Class of drugs which resemble short chain fatty acids Increase oxidation of fatty acids in muscle and liver Most effective class of drugs for lowering triglycerides Increase size of LDL particles and enhance removal May increase HDL-mediated reverse cholesterol transport Reduce levels of plasminogen activator inhibitor type I Currently available drugs in U.S. –Gemfibrozil –Fenofibrate (less risk of myopathy when used with a statin) ADRs: GI, ED, myopathy (CRF)

28. Major Fibrate Therapy Trials Helsinki Heart Study – NEJM 1987 –Primary prevention trial –4,081 dyslipidemic (non-HDL > 200 mg/dL) men, age 40 to 55 –Gemfibrozil 600 mg bid vs Placebo for 5 years –Primary endpoint – CHD death or nonfatal MI VA-HIT – NEJM 1999 –Secondary prevention trial –2,531 men with documented CAD in the VA system –HDL < 40 mg/dL and LDL < 140 mg/dL –Gemfibrozil 600 mg bid vs Placebo for 5.1 years –Primary endpoint – CHD death or nonfatal MI

29. Major Fibrate Trials Outcome Data RRR = 34%RRR = 66%RRR = 22% * HHS-Post Hoc: Subgroup with TG > 200 mg/dL and HDL < 42 mg/dL ** All results met statistical significance

30. Ezetimibe 1 st in new class of cholesterol absorption inhibitors Likely works by binding to and blocking the sterol transporter on the intestinal brush border Results in increased LDL-R activity and LDL clearance Drug and its metabolites circulate enterohepatically with little systemic penetration Potential toxicities essentially limited to liver Does not induce or inhibit cytochrome P450 system Single dosing option of 10 mg once daily

31. Lipid Lowering with Ezetimibe Ballantyne CM. Circulation 2003; 107: 2409-2415.

32. Lipid Risk Assessment NCEP ATP III + Recent Update Obtain a fasting lipoprotein profile on all adults aged 20 years or older (repeat every 5 years) Assess for CHD, CHD risk equivalents, and risk factors for developing CHD Framingham Risk Assessment for intermediate risk patients Assess for the metabolic syndrome Consider emerging risk factors (i.e. hs-CRP) NCEP. JAMA 2001; 285(19): 2486-97.

33. Lipoprotein Profile Classification LDL Cholesterol –< 70Optimal in HRP –< 100Optimal –100-129Near Optimal –130-159Borderline High –160-189High –190+Very High HDL Cholesterol –< 40Low –60+High Total Cholesterol –< 200Desirable –200-239Borderline High –240+High Triglycerides –< 150normal –150-199Borderline High –200-499High –500+Very High

34. CHD and CHD Risk Equivalents CHD CHD Risk Equivalents –Peripheral Vascular Disease –Abdominal Aortic Aneurysm –Symptomatic Carotid Arterial Disease –Diabetes –Framingham 10-year risk 20+%

35. Major Risk Factors ATP III Cigarette Smoking Hypertension (140+/90+ or on meds) Low HDL Cholesterol (< 40 mg/dL) FH of Premature CAD –Male 1 st degree relative < 55 –Female 1 st degree relative < 65 Personal Age –Male 45+ –Female 55+

36. Framingham Risk Assessment For Intermediate Risk Patients Gender Specific Calculates risk based on –Age –Total Cholesterol (age stratified) –Current Smoking Status (age stratified) –HDL Cholesterol –Systolic Blood Pressure (Rx or no Rx) Overall point score allows for calculation of 10 year risk of a CHD event Framingham Risk stratifies patients into –CHD equivalent10-year risk > 20% –Moderately high risk10-year risk 10-20% –Intermediate Risk10-year risk < 10%

37. The Metabolic Syndrome Any 3 of the following Abdominal Obesity (waist circumference) –Men> 40 inches –Women> 35 inches Triglycerides 150+ mg/dL HDL –Men< 40 mg/dL –Women< 50 mg/dL Blood Pressure 130+/85+ mm Hg Fasting Glucose 110+ mg/dL

38. Risk Stratification Update to ATP III Very High Risk –CHD + multiple risk factors (diabetes) –CHD + poorly controlled risk factor (smoking) –CHD + metabolic syndrome –CHD + ACS High Risk –CHD –CHD Equivalents Moderately High Risk –2+ Risk Factors + Framingham Risk of 10-20% Intermediate Risk –2+ Risk Factors + Framingham Risk of < 10% Low Risk –0-1 Risk Factor

39. LDL Treatment Based on Risk Stratification Very High Risk Patient –Optional LDL goal of < 70 mg/dL –Standard LDL goal of < 100 mg/dL –For LDL ≥ 100 mg/dL, initiate both lifestyle changes and drug treatment –For LDL < 100 mg/dL, lifestyle changes are indicated, drug Rx is therapeutic option

40. High Risk Patient (CHD / CHD Equivalent) –LDL goal of < 100 mg/dL –For LDL ≥ 100 mg/dL, initiate both lifestyle changes and drug treatment –For high TG / low HDL, consider adding niacin or fibrate to statin LDL Treatment Based on Risk Stratification

41. Moderately High Risk Patients –2+ RFs and 10-year risk 10-20% –Optional LDL goal of < 100 mg/dL –Standard LDL goal of < 130 mg/dL –For LDL ≥ 130 mg/dL, initiate both lifestyle changes and drug treatment –For LDL 100 to 129 mg/dL, lifestyle changes are indicated, drug Rx is therapeutic option LDL Treatment Based on Risk Stratification

42. Intermediate Risk Patients –2+ RFs and 10-year risk < 10% –LDL goal < 130 mg/dL –For LDL ≥ 130 mg/dL, initiate lifestyle changes –For LDL ≥ 160 mg/dL, initiate both lifestyle changes and drug Rx LDL Treatment Based on Risk Stratification

43. Low Risk Patients –0 to 1 risk factor –LDL goal < 160 mg/dL –For LDL ≥ 160 mg/dL, initiate lifestyle changes, drug Rx optional –For LDL ≥ 190 mg/dL, initiate both lifestyle changes and drug Rx LDL Treatment Based on Risk Stratification

44. Secondary Goal – Non HDL Cholesterol Elevated triglycerides are an independent risk factor for CHD (meta-analyses) Non HDL cholesterol captures risk of both LDL and triglycerides Non HDL goals are set 30 mg/dL higher than LDL goals –High risknon HDL goal < 130 mg/dL –Int risknon HDL goal < 160 mg/dL –Low risknon HDL goal < 190 mg/dL

45. hs-CRP Large body of evidence now supports CRP as in independent predictor of CHD risk However, the data all comes from post hoc analysis of lipid-lowering trials and observational trials Probably most useful in identifying moderately high risk patients who may be at greater risk than predicted by traditional risk assessment

46. hs-CRP hs-CRP measurement is now a Class IIa recommendation in two subgroups of patients –Moderately high risk Framingham patients (10- 20% risk) –Patients with known CAD for risk assessment of future events

47. Measuring and Using hs-CRP Measure twice, two weeks apart, in metabolically stable patients Tertiles of risk –Low risk< 1 mg/dL –Intermediate risk1-3 mg/dL –High risk> 3 mg/dL High risk CRP results in moderately high risk patients and in those with CHD should result in intensification of treatment hs-CRP values > 10 mg/dL indicate an ongoing inflammatory or infectious process and should not be used

48. When to Stop Treatment Statins and Ezetimibe –Myopathy - Muscle aches with CK > 10x ULN –Abnormal LFTs – 3x ULN –Pregnancy and Breast Feeding Niacin –Abnormal LFTs (3x ULN) or chronic liver disease –Gout –Poorly controlled diabetes –Pregnancy Fibrates –Chronic liver dysfunction or renal failure –Abnormal LFTs or myopathy –Pregnancy

49. Summary Recent clinical trials have confirmed the log-linear relationship between CHD risk and LDL cholesterol at lower levels This relationship means that risk reduction is independent of initial cholesterol levels and is dependent only on absolute reduction in levels This has led to more aggressive lipid lowering benchmarks, especially in certain high risk groups Additionally, novel risk factors such as hs-CRP have become available which allow us to further stratify certain risk populations The charge remains to identify and effectively treat our dyslipidemic patients over the long-term