Agents to Raise HDL (Do We Have the Right Biomarker of HDL Function?) Khalid Al-Rasadi, BSc, MD, FRCPC Head of Biochemistry Department, SQU Head of Lipid and LDL-Apheresis Unit, SQUH President of Oman society of Lipid & Atherosclerosis (OSLA) Disclosures • Honoraria for Speakers Bureau (Pharma) AstraZeneca, Sanofi, Pfizer • Advisory Boards: Sanofi, Aegerion, AstraZeneca • Research Funding: Pfizer Coronary heart Disease anD HDL 3.5 N = 302,430 3.0 Emerging Risk Factors ADjusteD for age anD genDer Collabration) 2.5 ADjusteD for multiple factors long trem, prospective, population based study, 2.0 association between CVD outcomes and 1.5 circulating lipids and inflammatory markers HazarDRatio 1.0 0.8 30 40 50 60 70 80 HDL-C (mg/DL) The Emerging Risk Factors Collaboration. JAMA 2009;302:1993-2000. Low HDL-C Predicts Residual CVD Risk After Optimal Statin Rx: TNT Study LDL-C ≤70 mg/dL on Statina,b (Treating to New Targets (TNT) Study) 10 Case: HDL-C 32; LDL-C 67 on statin 8 6 4 2 Year Risk of Major CVD Events, % - 5 0 HDL-C Quintiles,a Q1 Q2 Q3 Q4 Q5 mg/dL <37<38 3837 toto <42 <43 4342 toto <47<48 4847 to to <55 >=55≥55 Hazard Ratio Versus Q1* 0.85 0.57 0.55 0.61 aOn-treatment level (3 months statin therapy); n = 2661 bMean LDL-C, 58 mg/dL; mean TG, 126 mg/dL *P=.03 for differences among quintiles of HDL-C Barter P et al. New Engl J Med. 2007;357:1301-1310. HDL-C Risk Factor vs Risk Marker? • Low HDL-C predicts high CVD Risk • High HDL-C predicts anti-atherogenic effects: – Anti-inflammatory – Antioxidant – Antithrombotic – Pro-endothelial • But clinical trials have not yet proven that: – HDL is a causal factor vs biomarker of risk, or – Raising HDL-C reduces CVD risk HDL Subpopulations Particle Shape Apolipoprotein Content Discoidal Spherical A-I HDL A-I/A-II HDL Globular +other apos: A-IV, C, D, E, etc. +non-apo proteins: inflam, thromb, etc. HDL Particle Size/Electrophoretic Mobility Lipid-poor apoA-I Globular Discoidal HDL2b HDL2a HDL3a HDL3b HDL3c --------------------------Alpha-migrating------------------------- --Pre-beta-migrating-- Adapted from Barter PJ. Atheroscler Suppl. 2002;3:39-47. Potential Antiatherogenic Actions of HDL HDL inhibits expression of endothelial cell adhesion molecules and MCP-1 Monocyte Vessel Lumen LDL MCP-1 Endothelium Adhesion LDL molecule HDL inhibits oxidation of LDL-C Cytokines Oxidized LDL Intima Foam Macrophage cell HDL promotes efflux of cholesterol from foam cells MCP-1 = monocyte chemoattractant protein-1 Adapted from Barter PJ et al. Circ Res. 2004;95:764-772. Should High-density Lipoprotein Be a Target of Therapy ? • ATP III Guidelines on HDL-C: “Current documentation of risk reduction through controlled clinical trials is not sufficient to warrant setting a specific goal value for raising HDL-C” (Grundy SM et al. Circulation. 2004;110:227-239) • Failure of ACCORD, FIELD, AIM-HIGH and the experience with torcetrapib have increased doubts as to the value of raising HDL-C • Recent clinical trial data from next generation investigational CETP inhibitors has refueled hope that this approach may increase HDL-C and improve clinical outcomes Lifestyle Modifications to Raise HDL-C Levels • Smoking Cessation − HDL-C levels are 7-20% lower in smokers, but return to normal 1-2 months after smoking cessation • Whole Food Plant Based Diet • Weight Reduction − For every 3 kg (7 lb) of weight loss, HDL-C levels increase about 1 mg/dL (~2-4% increase) • Exercise − Aerobic exercise (40 min, 3-4 times weekly) increases HDL-C by about 2.5 mg/dL (~5-10% increase) Rössner S et al. Atherosclerosis. 1987;64:125-130. Cullen P et al. Eur Heart J. 1998;19:1632-1641. Wood PD et al. N Engl J Med. 1988;319:1173-1179. Kokkinos PF et al. Arch Intern Med. 1995;155:415-420. Ornish D et al. JAMA. 1998;280:2001-2007. Kodama S et al. Arch Intern Med. 2007;167:999-1008. Available Agents for HDL-C Raising Agent HDL-C ↑ Primary Use Nicotinic acid 15-35% HDL ↑ Fibrates 5-20% TG ↓ Statins 5-15% LDL ↓ Prescription Om-3* 2-10% TG ↓ Bile-acid resins* 2-5% LDL ↓ Ezetimibe* 1-3% LDL ↓ Pioglitazone* 5-20% Glucose ↓ Estrogens* 10-25% Hot flashes a-blockers* 10-20% BPH Alcohol* 5-15% Social, etc. *Lacking FDA-approved indication for HDL-raising. Belalcazar LM, Ballantyne CM. Prog Cardiovasc Dis. 1998;41:151-174. Insull W et al. Mayo Clin Proc. 2001;76:971-982. McKenney JM et al. Pharmacother. 2007;27:715-728. Rationale for using niacin • Niacin increases the level of HDL-C by up to 25% • It also reDuces the level of LDL-C by about 15% • Given as monotherapy, niacin reDuces CV events • Given in combination with a statin, niacin promotes regression of atherosclerosis as assesseD by measuring carotiD intima-media thickness Schachter M. Br J Cardiol 2003;10:462-8. CDP Research Group. JAMA 1975;231:360-81. Taylor et al. NEJM 2009; 361:2113-2122 Meta-Analysis: Effects of Nicotinic Acid Major Coronary Events, Pre-AIM-HIGH Trials Treatment Control Peto OR Peto OR Study n/N n/N 95% Cl 95% Cl ARBITER-6-HALTS 2/187 9/176 0.25 (0.08, 0.84) Guyton JR et al 1/676 1/272 0.35 (0.02, 7.56) AFREGS 0/71 1/72 0.14 (0.00, 6.92) ARBITER-2 2/87 2/80 0.92 (0.13, 6.65) HATS 1/38 5/38 0.24 (0.05, 1.26) UCSF_SCOR 0/48 1/49 0.14 (0.00, 6.96) STOCKHOLM 72/279 100/276 0.61 (0.43, 0.88) CLAS 1/94 5/94 0.25 (0.05, 1.29) CDP 287/1119 839/2789 0.81 (0.69, 0.94) Total Test for heterogeneity: P = 0.24, I2 = 23.0% 0.75 (0.65, 0.86) Test for overall effect: P < 0.0001 Subtotal excluding CDP 0.53 (0.38, 0.73) 0.1 0.2 0.5 1 2 5 10 Log scale Many of these trials were tests of drug combinations that included niacin Bruckert E et al. Atherosclerosis. 2010;210:353-361. Meta-Analysis: Effects of Nicotinic Acid Carotid Intima Media Thickness Treatment Control WMD (fixed) WMD (fixed) Study N N Mean (SD) Mean SD 95% Cl 95% Cl ARBITER-6-HALTS 97 -12 (36) 111 -1 (31) -12 (-21, -2) Thoenes M et al 30 -5 (11) 15 9 (12) -14 (-21, -7) ARBITER-2 78 14 (104) 71 44 (100) -30 (-63, -3) CLAS 39 -12 (20) 39 12 (20) -25 (-34, -16) Total -17 (-22, -12) Test for heterogeneity: P = 0.13, I2 = 47.4% Test for overall effect: P < 0.0001 -100 -50 0 50 100 Annual change, µm/y E. Bruckert et al, Atherosclerosis 210 (2010) 353-361 Niacin Reduces CVD Events Coronary Drug Project Event Rate (%) • Subjects: men with prior MI 35 –14 • Treatment arms, 5 lipid meds: 30 Placebo Niacin – IR Niacin, 1 g TID (n=1119) 25 estrogen (2 arms), 20 dextrothyroxine, clofibrate –27 15 –26 – Niacin lipid effects: TC ¯ 10%, TG ¯ 27% (HDL-C not meas.) 10 –47 • Results (6 yrs, end-study): benefit 5 only seen in Niacin arm (¯ MI 27%, no ¯ 1o endpoint=total mortality) 0 Nonfatal Nonfatal Stroke/ CV • Post-study f/u 15 yrs: 4% absolute ¯ MI/CHD Death MI TIA Surgery total mortality (NNT = 25) Coronary Drug Project. JAMA. 1975;231:360-381. Canner PL et al. J Am Coll Cardiol. 1986;8:1245-1255. Niacin promotes regression of atherosclerosis ARBITER-6 HALTS This trial in statin treateD patients compareD the effects of ezetimibe (aDDeD to the statin to achieve further lowering of LDL-C) with those of niacin (aDDeD to the statin to achieve not only aDDitional lowering of LDL-C but also raising of HDL-C) Taylor et al. NEJM 2009; 361:2113-2122 ARBITER-6 HALTS HDL-Cholesterol LDL-Cholesterol 0 Niacin 20 -10 Niacin 10 P<0.001 -20 P<0.01 0 Ezetimibe %Change from Baseline from %Change Baseline from %Change Ezetimibe -10 -30 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Months Months Taylor et al. NEJM 2009; 361:2113-2122 Change from Baseline in Mean cIMT 0.06 Ezetimibe 0.00 P=0.003 Niacin -0.01 Mean(mm) CarotiD IMT Change from Baseline inChange from -0.02 0 8 14 Months Taylor et al. NEJM 2009; 361:2113-2122 AIM HIGH: Atherothrombosis Intervention in Metabolic SynDrome With Low HDL/High Triglycerides anD Impact on Global Health Outcomes Simvastatin ³40 mg + ER niacin 2 g 3300 patients § Men anD women Simvastatin ³40 mg § AgeD ³45 years § EstablisheD vascular Disease anD atherogenic DyslipiDemia (low HDL-C anD high triglyceriDes) 4-year follow-up Primary EnD Point Key SeconDary EnD Points § Composite of CHD Death, nonfatal MI, § Composite of CHD Death, nonfatal MI, ischemic stroke, or hospitalization for or ischemic stroke high-risk ACS with objective eviDence of ischemia clinicaltrials.gov/ct/show/NCT00120289 AIM-HIGH—Results Primary Outcome 1o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579. AIM-HIGH Early Termination • Lipids – Baseline: LDL-C 71 mg/dL w/ prior stain Rx (94% of subjects) – On Rx: HDL-C ↑ 25% ERN vs ↑ 10% “placebo” (<2/3 of projected) • Data, Safety and Monitoring Board chose early termination – Due to futility (likely lack of efficacy) - 1° Endpoint HR 1.05 – Early concern about possible increased stroke rate signal • Potential explanations for lack of observed efficacy: – “Placebo” arm received IR niacin, ↑ statin dose & ↑ ezetimibe (poor test of HDL hypothesis w/ just 15% net ↑ HDL-C) – Early study termination (VA HIT also negative at 3 y) – Sl lower than expected event rate (but still >5%/yr) – High prior statin use (94%, 40%>5y), prior niacin use (20%) Press conference transcript; May 26, 2011.