The Cardiovascular Institute Mount Sinai School of Medicine, New York

Transcription

1 The Cardiovascular Institute Mount Sinai School of Medicine, New York HDL YES HDL NO Juan Jose Badimon, Ph.D Professor of Medicine Director, Atherothrombosis Research Unit The Mount Sinai School of Medicine New York Dubai May, 2013

2 Atherosclerotic Disease LDL HDL

3 LDL-C vs Events in Statin Trials Badimon J et al. Rev Esp Cardiol 2010;63 (suppl 2) 20-35

4 CV events and HDL despite statins Residual high risk for CV events despite statin therapy among patients with low HDL-C levels

5 Cholesterol, HDL-Cho and CHD Risk MRFIT SIX-YEAR Follow-up

6 HDL, RCT and ATHEROSCLEROSIS 1950 s First epidemiological evidence (Barr DP et al. Am J Med; 1951:11: ) 1975 Miller & Miller (Lancet 1975; 1:16-19) 1980 s: 1990 S: Epidemiological observations suggesting HDL as protective factor against CAD. (Framingham, Tromso, premenopausal women, athletes) First interventional evidences HDL administration ( Badimon JJ) Helsinki Heart Study (Gemfibrozil) Transgenic data ( apo A-I overexpression) Apo A-I Milano (Franceschini, Ameli, Shah, REVERSAL) % of CAD hospitalizations have low HDL levels (<40mg/dl) independently of LDL levels (Fonarow ACC 2007)

7 Why raise HDL Levels? 1970 s Framingham demonstrated low HDL-C levels (<40 mg/dl in M <50mg/dl in F) with increased CV risk. Increases of 1 mg/dl were associated with a 2-3% reduction in CV risk Gordon Am J Med 1977;62:707 PROCAM: HDL-C levels >35 mg/dl associated with 70% reduction of CV risk Assmann G Atherosclerosis 1996;124: S11-20 European study with more than dyslipemic patients showed low HDL in 33% M and 40% F. Bruckert E. Curr Med Res Op 2005; 21:1927

8 HDL and CAD In a large cohort of patients (n=231,986) hospitalized with CAD, almost half had admission levels of LDL<100mg/dl. More than half had HDL levels <40mg/dl, whereas <10% had HDL levels 60mg/dl. These observations support the need for even lower LDL goals and effective ways to raise HDL Sachdeva A et al. Am Heart H 2009;157:111

9 Cholesterol Deposition in the arterial wall

10 Effect of lifestyle on HDL-C levels Therapeutic Intervention Raise in HDL-C levels (%) Mechanism of action Aerobic exercise 5-10 Tobacco cessation 5-10 Weight loss 0.35 mg/dl per kilogram of weight lost Alcohol consumption 5-15 Dietary factors (n-3 PUFAs, n-6 PUFAs, MUFAs) 0-5 pre-β-hdl, RCT, LPL, and atheroprotective subpopulations LCAT, LPL, and RCT Decreases CETP LCAT, LPL, and RCT ABCA1, apo A-I, and paraoxonase Decreases CETP Improves LDL-C:HDL-C ratio atheroprotective subpopulations Singh et al, JAMA 2007; 298: 786

11 Coronary stenosis Frequency regression Frequency progression Meta-analysis of Nicotinic acid on CV events and atherosclerosis Majority of studies are on secondary prevention and done before statins Brucket E et al. Atherosclerosis 2010;210:353 Results on CIMT

12 JACC 2013;61:440 The consensus perspective derived from available clinical data supports that niacin reduces CVD events and further, that this may occur through a mechanism not reflected by changes in HDL-Cho

13 Effects of Fibrates on CV outcomes Meta-analysis of 18 trials Fibrate vs Placebo 45,058 patients 2,870 major CV events 4,552 CHD events 3,880 deaths 10% RRR 13% RRR No effect Jun M et al. Lancet 2010; 375: Rosenson R Expert Rev Cardiovasc Ther 2008;6:1319

14 Human Evidence supporting HDL-raising Coronary Drug project (niacin 25% HDL) Lipid Research Clinical Trial (cholestryramine 3% HDL) Helsinky Heart Trial (gemfibrozil 10% HDL) Veterans HDL Intervention Trial (gemfibrozil 6% HDL) Imaging/Angiographic studies FATS (nicotinic acid) HATS (nicotinic acid) REVERSAL (statin) ASTEROID (statin) Apo A-I Milano (Apo A-I) ERASE (rhdl) Estrogens??? Torcetrapib????

15 Reverse Cholesterol Transport Brewer B, NEJM 2004;350:1491

16 HDL-raising Interventions: YES or NO?? Torcetrapib does NOT work ACCORD-LIPID Fenofibrate does NOT work AIM-HIGH: Niacin does NOT work HPS-2 Thrive Niacin+ Statin does NOT work Dalcetrapib stopped Anacetrapib IS safe Evacetrapib IS safe

17 Vasan et al. Zachariah et al J Hypertens ; 29: 863

18 Increased CV mortality with Reduced CETP The Ludwigshafen Risk and Cardiovascular Health Study 3,256 patients undergoing Coronary angiography F/U 7.75 years Questioning the rationale for the benefits of the pharmacological inhibition of CETP activity. Ristch A et al. Circ 2010; 121:366;

19 CETP Inhibitors Torcetrapib Dalcetrapib Anacetrapib Evacetrapib

20 NEJM 2010;363:2406 DEFINE Phase II, RCT trial 1623 CHD/high risk patients LDL-C: 50 but 100 mg/dl HDL-C:<60mg/dl TGL: 400 mg/dl LDL-C 40% HDL-C 138% TGL 15%

21 The Dis-ACCORD Lipid Study After a follow-up of 4.3 years, fenofibrate+simvastatin had no effect the rate of the primary outcome vs simvastatin monotherapy N Engl J Med 2010;362: Even though there are NO evidence from this trial to routinely add fenofibrate to a statin for treatment of T2DM. Indeed it might even be harmful for women. The ACCORD data together with 3 other fibrate trials suggest that when TGLs>200mg/dl and HDL<35mg/dl After statins reduced LDL-C levels, fibrate treatment should be considered, at least in men. Ginsberg H Diabetes Care 2011 The combination therapy resulted in a 31 % reduction in the rate of primary outcome among the 17% of ACCORD patients with high TGL and low HDL Goldfine et al NEJM 2011;365:481

22 AIM-HIGH Trial stopped by NIH Niaspan in addition to statin F/U 5 years 3500 CVD patients with high TGLs and low HDL. Prematurely terminated because futility. Target LDL-C 40-80mg/dl very low risk subjects End-points: 5.8 vs 5.6% in Niacin & Placebo groups FDA will not change the labeling for Niacin HDL metabolism more complex than initially thought!!

23 Limitations of the AIM-HIGH Trial Control arm allowed changes in Rx to maintain 40-80mg/dl of LDL-C levels. Niacin group received 1.5 and 2.0g/day (50% each) while control arm received mg leading to modest HDL increased (35 to 39 Pbo; 35 to 44 Rx) Short-term follow-up (VA-HIT needed 3 years for curves separation) Subjects selected per Niacin tolerance (20% had pre-rx) and some were on statin for >5 years. Adverse effects: Increase in diabetes (effect of high statin dose?) Stroke rate (low overall stroke rate 1/3 of strokes in Niacin group had stopped Rx > 2 months)