The Target is LDL, HDL not so much

The Target is LDL, HDL not so much HDL: A riddle wrapped in a mystery inside an enigma Jacques Genest MD Cardiovascular Research Laboratories McGill University Health Center

Disclosure J. Genest MD 2013 Advisory Board, Speaker s Bureau, Consultant, Grants, Clinical Trials Merck * Pfizer Novartis AMGEN * Roche * AstraZeneca Stock ownership: none; Off label use: none * Scientific Advisory Sanofi/Regeneron Lilly Valeant Biotech: Danone Acasti Nutrasource Relevant disclosure: JUPITER, IMPROVE-IT, CANTOS, CAPREE steering Committees; REVEAL, ACCELERATE, AMG145 Clinical Trials.

The Case for HDL Epidemiology and Mendelian randomization What does HDL actually do? The Future

Figure 45-2

Hazard Ratios for Coronary Heart Disease or Ischemic Stroke Across Quantiles HDL-C JAMA 2009;302:1993-2000

PTTH*-1 Association does NOT imply Causality * Points To Take Home

Human Serum Lipoproteins Blaha MJ et al., J Clin Lipidol 2008;2:267-273

Figure 3. Hazard Ratios for Coronary Heart Disease Across Fifths of Usual Lipids or Apolipoproteins JAMA 2009;302:1993-2000 Copyright restrictions may apply.

HDL and the CVD: Animal Models Mouse apo AI transgenic Rabbit apo AI transgenic Genetically modified animals with increased apo AI production have less atherosclerosis and less aortic stenosis (Fuster V 2010) Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Plump AS, Scott CJ, Breslow JL. PNAS 1994;91:9607-1 Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. Pászty C, Maeda N, Verstuyft J, Rubin EM. J Clin Invest. 1994;94:899-903.

Frikke-Schmidt R et al. Lancet 2008;299(21):2524-2532 Voight BF et al. Lancet 2012;May 17 e-pub

Incidence Rate / 100 person years HDL as a Predictor of Residual Risk in JUPITER 2.0 1.8 1.6 Placebo Rosuvastatin 20mg 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 Q1 Q2 Q3 Q4 Quartile of On-Treatment HDLC Ridker PM et al. JUPITER 2010

Clinical study DATA Fibrates: FIELD; Accord Niacin: AIM-HIGH; HPS2-THRIVE Torcetrapib, Dalcetrapib The rest is Surrogate End Points FATS, HATS Apo AI Milano, rhdl 12

Effects of Combination Lipid Therapy on Cardiovascular Events in Type 2 Diabetes Mellitus: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial Henry C. Ginsberg, MD College of Physicians & Surgeons, Columbia University, New York For The ACCORD Study Group Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus The ACCORD Study Group Published at www.nejm.org March 14, 2010 (10.1056/NEJMoa1001282)

ACCORD Study www.nejm.org March 14, 2010 (10.1056/NEJMoa1001282)

Meta-Analysis of Fibrate trials Jun M, Lancet 2010;375:1875

Comparison of ACCORD subgroup results with those from prior fibrate studies Trial (Drug) Primary Endpoint: Entire Cohort (P-value) Lipid Subgroup Criterion Primary Endpoint: Subgroup HHS (Gemfibrozil) -34% (0.02) TG > 200 mg/dl LDL-C/HDL-C > 5.0-71% BIP (Bezafibrate) -7.3% (0.24) TG > 200 mg/dl -39.5% FIELD (Fenofibrate) -11% (0.16) TG > 204 mg/dl HDL-C < 42 mg/dl -27% ACCORD (Fenofibrate) -8% (0.32) TG > 204 mg/dl HDL-C < 34 mg/dl -31% ACCORD Study www.nejm.org March 14, 2010 (10.1056/NEJMoa1001282)

HDL Clinical trials: Niacin AIM-HIGH: Niacin Plus Statin to Prevent Vascular Events Age: >45 years, CAD + Dyslipidemia Simvastatin 40mg daily Randomized to: Niacin 2 g/day n=3,300 2005 2011 Sponsor: NHLBI

HDL Clinical trials: Niacin AIM-HIGH: Niacin Plus Statin to Prevent Vascular Events Age: >45 years, CAD + Dyslipidemia Simvastatin 40mg daily Randomized to: Niacin 2 g/day n=3,300 2005 2011 Sponsor: NHLBI

Pourcentage cumulé de patients avec des résultats primaires AIM-HIGH : Results 50 40 30 20 10 P=0.79 by log-rank best Niacine plus statine Placebo plus statine 0 0 1 2 3 4 Années No. à risque Placebo plus statine 1695 1581 1381 910 436 Niacin plus statine 1718 1606 1366 903 428

HPS-2 THRIVE: Major Findings ER niacin/laropiprant to simvastatin (or ezetimibe/simvastatin) did not reduce the risk of MI, strokes and revascularizations This result were consistent across study sites ER niacin/laropiprant did cause side-effects. (skin irritation, strokes and gastrointestinal bleeding; increase diabetes risk). Increased risk of myopathy (among patients in China). There was no effect on cancer nor risk of death These results are important because they tell us more about Niacin. This is disappointing but still matters. 22

Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome Schawartz GG. N Engl J Med. 2012 Nov 5. [Epub ahead of print]

DALcetrapib Outcomes

PTTH-2 The epidemiological association between HDL-C and CVD is strong and coherent. Animal data is unequivocal: HDL protect against atherosclerosis Strong biological plausibility for HDL as a therapeutic target

PTTH-2 The epidemiological association between HDL-C and CVD is strong and coherent. Animal data is unequivocal: HDL protect against atherosclerosis Mendelian Randomization does not support HDL- Cholesterol as a causal risk factor HDL-C looses its predictive value if LDL-C is low Strong biological plausibility for HDL as a therapeutic target The Clinical trial data is neutral

HDL Protects the Vascular System HDL mediate reverse cholesterol transport Potent antioxidant effects Potent anti-inflammatory effects Improves vascular endothelial function ( NO) Promotes vascular endothelial progenitor cells Anti-apoptosis Anti-thrombotic effects Anti trypasonomial activity (apo L1 and haptoglobin)

ABCA1 Mediated Cellular Cholesterol Efflux LxR/RxR

HDL- Vascular endothelial Cell Interaction Campbell S, Genest J, 2012

HDL and Endothelial Progenitor Cells Sorrentino SA et al. Circulation 2010;121;110-122

Points to Take Home -3 HDL particles are complex Genes involved in HDL biogenesis may make better therapeutic targets than genes involved in HDL remodeling (Lipases, CETP) New Gene, new pathways

LDL-C (mg/dl) (SE) HDL-C (mg/dl) (SE) Anacetrapib: Effects on LDL-C and HDL-C 100 LDL-C 120 HDL-C 80 100 60 40-39.8% (p<0.001) 80 +138.1% (p<0.001) 60 40 20 Anacetrapib Placebo 20 Anacetrapib Placebo 0 Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 0 Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 Anacetrapib n = 804 771 716 687 646 604 568 540 Placebo n = 803 759 741 743 735 711 691 666 Study Week Anacetrapib n = 776 757 718 687 647 607 572 543 Placebo n = 766 761 741 744 736 711 691 666 Study Week

Conclusions Modulation of HDL function for the prevention and treatment of CVD shows great promise Biomarkers of HDL function (and not solely HDL-C mass) are required in pre- and early clinical trials Outcome-driven clinical trials are absolutely required

The Case for LDL Clinical Data Clinical Data Clinical Data Some science stuff

It s the LDL, Stupid LDL-C <2.0 mmol/l in highrisk patients No HDL-C targets, yet Pres. T. Anderson 2013 Guidelines

On Going Trials of Statin Add-on Landmesser U. Eur Heart J 2013 Feb 26

Medications Statins Ezetimibe Fibrates Niacin BAR CETP inh MTP inh ApoB irna PCSK9 mab

Absolute effect of statin therapy on MAJOR VASCULAR EVENTS Five year risk of a major vascular event, % 0 5 10 15 20 More statin Statin Control 21% relative risk reduction per mmol/l 15% relative risk reduction per 0.5 mmol/l Combined evidence: ~33% relative risk reduction per 1.5 mmol/l (0.79 x 0.85 = 0.67) 0 1 2 3 4 5 LDL cholesterol, mmol/l

Proportional effects on MAJOR VASCULAR EVENTS per mmol/l reduction in LDL cholesterol No. of events (% pa) Statin/ Contr ol/ More statin Less statin Relative risk (CI) Nonfatal MI CHD death Any major coronary event 3485 (1.0) 1887 (0.5) 5105 (1.4) 4593 (1.3) 2281 (0.6) 6512 (1.9) 0.73 (0.69-0.78) 0.80 (0.74-0.87) 0.76 (0.73-0.78) CABG PTCA Unspecified Any coronary revascularisation 1453 (0.4) 1767 (0.5) 2133 (0.6) 5353 (1.5) 1857 (0.5) 2283 (0.7) 2667 (0.8) 6807 (2.0) 0.75 (0.69-0.82) 0.72 (0.65-0.80) 0.76 (0.70-0.82) 0.75 (0.72-0.78) Ischaemic stroke Haemorrhagic stroke Unknown stroke Any stroke 1427 (0.4) 257 (0.1) 618 (0.2) 2302 (0.6) 1751 (0.5) 220 (0.1) 709 (0.2) 2680 (0.8) 0.79 (0.72-0.87) 1.12 (0.88-1.43) 0.88 (0.76-1.01) 0.84 (0.79-0.89) Any major vascular event 10973 (3.2) 13350 (4.0) 0.78 (0.76-0.80) 99% or 95% CI 0.4 0.6 0.8 1 1.2 1.4 Statin/more statin better Control/less statin better

LDL-C (mg/dl) (SE) HDL-C (mg/dl) (SE) Anacetrapib: Effects on LDL-C and HDL-C 100 LDL-C 120 HDL-C 80 100 60 40-39.8% (p<0.001) 80 +138.1% (p<0.001) 60 40 20 Anacetrapib Placebo 20 Anacetrapib Placebo 0 Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 0 Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 Anacetrapib n = 804 771 716 687 646 604 568 540 Placebo n = 803 759 741 743 735 711 691 666 Study Week Anacetrapib n = 776 757 718 687 647 607 572 543 Placebo n = 766 761 741 744 736 711 691 666 Study Week

Medications Statins Ezetimibe Fibrates Niacin BAR CETP inh MTP inh ApoB irna PCSK9 mab

Q4W Dosing Q2W Dosing Mean Percent Change From Baseline in Calculated LDL-C* Mean Percent Change From Baseline in Calculated LDL-C* Effects of AMG 145 on LDL-C Over 12 Weeks 10-10 -30-50 -70-90 10-10 -30-50 -70-90 BL 2 4 6 8 10 12 Weeks BL 2 4 6 8 10 12 Weeks Placebo Ezetimibe 70 mg AMG 145 105 mg AMG 145 140 mg AMG 145 Placebo Ezetimibe 280 mg AMG 145 350 mg AMG 145 420 mg AMG 145 *Data show mean observed values without imputation for missing data BL = baseline Koren M, et al. Lancet. Epub 2012Nov 6

Mean Percent Change from Baseline in Low-Density Lipoprotein (LDL) Cholesterol Levels, According to Treatment Group. Roth EM et al. N Engl J Med 2012;367:1891-1900.

Conclusions Novel therapeutic avenues targeted at LDL-C lowering. Little data presently supporting HDL-C increase pharmacologically On-going clinical trials of CETP inhibitors and PCSK9 inhibitors will alter the therapeutic landscape