May 2013 ? מטרה לטיפול תרופתי מהווה HDL האם May 2013 ? מטרה לטיפול תרופתי מהווה HDL האם ההסתדרות הרפואית בישראל – החברה לחקר, מניעה וטיפול בטרשת עורקים Israel Medical Association-Society for Research, Prevention and Treatment of Atherosclerosis

ArterialWall Liver CHOLESTEROL TRANSPORT and ATHEROSCLEROSIS Bile Atherogenic Transport Antiatherogenic Transport LipidCore VLDL, LDL HDL

Slowing and Reversing Atherosclerosis VLDL LDL HDL Inflammation Libby (2001) Circulation 104:365

IVUS Trials: REVERSAL, CAMELOT, ACTIVATE, ASTEROID Nicholls S, et al. JAMA. 2007;297: Lowering LDL-C:HDL-C ratio to approx 1:1 stops atherosclerosis progression PAV percent atheroma volume

BYOND LDL ?

HDL at a crucial crossroad for CVD

Atheroprotective functions of HDL Anti-infectious activity Anti-thrombotic activity Anti-proteolytic activity Reverse cholesterol transport/cellular cholesterol efflux Anti- inflammatory activity Immune system Anti-oxidative activity Anti-apoptotic activity Vasodilatory activity/ endothelial repair

The Emerging Risk Factors Collaboration. JAMA 2009;302: Coronary Heart Disease and HDL-C Hazard Ratio HDL-C (mMol/L) N = 302, Unadjusted Adjusted

Fig.?2 Kaplan?Meier curve for probability of disease-free survival stratified by low (?35?mg/dL) and normal (>35?mg/dL) HDL-C levels. Poh-Shiow Yeh, Chun-Ming Yang, Sheng-Hsiang Lin, Wei-Ming Wang, Po-Sheng Chen, Ting-Hsing Chao, Huey-Juan L... Low levels of high-density lipoprotein cholesterol in patients with atherosclerotic stroke: A prospective cohort study Atherosclerosis null 2013 null

Low HDL-C levels are common worldwide 44.0* 37.0** 48.4* 6.6*** Turkey 1 (n=9000) Korea 2 (n=7300) Mexico 3 (n=2256) China 4 (n=959) Prevalence low HDL-C (%) 1.Mahley RW et al. J Lipid Res 1995;36: Kim SM et al. Circ J 2006;70: Aguilar-Salinas CA et al. J Lipid Res 2001;42: *  35 mg/dL; **<40 mg/dL in men and <50 mg/dL in women; *** <35 mg/dL 35.0 ISRAEL

Will increase in HDL CHD Risk according to HDL-C Levels (FHS): can it be modified? HDL-C (mg/dL) CHD risk ratio Kannel WB. Am J Cardiol. 52:9B–12B;1983. result in CHD risk reduction?

Effect of lifestyle interventions on HDL cholesterol InterventionIncrease in HDL Cholesterol Aerobic exercise5-10% Stopping smoking5-10% Losing weight 0.35mg/dL per kg weight lost Healthy diet (rich in omega-3 fatty acids or monosaturated fatty acids) Up to 5% Moderate alcohol intake5-15% Singh IM et al. JAMA 2007: 298:

Effect of Statins on Apo A1 production Apo A1 production (% of control) * † Drug conc (  M) Drug conc (  M) † † † † ‡ Simvastatin AtorvastatinPitavastatin Hep G2 cells were treated for 48h with various concentrations of statins (1-30 μM and 50 μM). The apo AI in the cultured medium was determined by ELISA kit. *P<.05, † P<.001, ‡ P<.01, Dunnett’s test. Maejima. Biochem Biophys Res Commun 2004;324:835

Therapeutic lifestyle changes Pharmacologic therapy –Statins –Niacin ER on top of statin –CETP Inhibition –Other new targets Management of Low HDL-C

All the effects of Niacin

Pharmacotherapy of low HDL cholesterol LDL-C HDL-C Triglycerides % Change from baseline

The best HDL raiser today is Nicotinic acid

Change in Carotid Wall Area by MRI

Kaplan–Meier Curve AIM HIGH for the Primary End Point. The AIM-HIGH Investigators. N Engl J Med 2011;365:

Merck Announces HPS2-THRIVE Study of TREDAPTIVE™ (Extended-Release Niacin/Laropiprant) Did Not Achieve Primary Endpoint Release Date: Thursday, December 20, :30 am EST Terms: Prescription Medicine NewsPrescription Medicine News [1]. In the study, adding the combination of extended-release niacin and laropiprant to statin therapy did not significantly further reduce the risk of the combination of coronary deaths, non-fatal heart attacks, strokes or revascularizations compared to statin therapy. In addition, there was a statistically significant increase in the incidence of some types of non-fatal serious adverse events in the group that received extended-release niacin/laropiprant. Merck Announces HPS2-THRIVE Study of TREDAPTIVE™ (Extended-Release Niacin/Laropiprant) Did Not Achieve Primary Endpoint Release Date: Thursday, December 20, :30 am EST Terms: Prescription Medicine NewsPrescription Medicine News [1]. In the study, adding the combination of extended-release niacin and laropiprant to statin therapy did not significantly further reduce the risk of the combination of coronary deaths, non-fatal heart attacks, strokes or revascularizations compared to statin therapy. In addition, there was a statistically significant increase in the incidence of some types of non-fatal serious adverse events in the group that received extended-release niacin/laropiprant.

Comparison of the AIM-HIGH and the HPS2-THRIVE trial. Landmesser U Eur Heart J 2013;34: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author For permissions please

Niacin (vitamin B3)—a lipid-modifying agent with a long history. Rise & Fall of Niacin Landmesser U Eur Heart J 2013;34: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author For permissions please

5 y risk of MCVEs (%) (<37)(37-42)(42-47)(47-52)(>52) No of Events No of Patients HR (95% CI) vs Q1 Q ( ) Q ( ) Q ( ) Q ( ) Quintile of HDL-C (mg/dL) Major cardiovascular events in patients with LDL-C < 70 mg/dL in the TNT trial: effect of HDL level Adjusted for: Age and gender, smoking, hypertension, BMI, fasting glucose, presence of diabetes, prior CVD, on treatment triglyceride, baseline level of LDL-C Barter et al, NEJM 2007, 357; 13,

Is there room for NIACIN?

Therapeutic lifestyle changes Pharmacologic therapy –Statins –Niacin ER on top of statin –CETP Inhibition –Other new targets Management of Low HDL-C

Figure. This schematic illustrates how CETP activity could potentially have proatherogenic or atheroprotective effects. Shah P K Circulation 2009;120: Copyright © American Heart Association

CETP LOF mutations Reduce CVD!

Tall, A. R. et al. Arterioscler Thromb Vasc Biol 2007;27: The adverse outcome of the ILLUMINATE study in patients receiving Torcetrapib indicates that potential adverse effects outweighed beneficial effects

May 2013 ? מטרה לטיפול תרופתי מהווה HDL האם ההסתדרות הרפואית בישראל – החברה לחקר, מניעה וטיפול בטרשת עורקים Israel Medical Association-Society for Research, Prevention and Treatment of Atherosclerosis

Lipid effects with dalcetrapib * D 48 weeks vs. placebo Stein EA et al. Eur Heart J 2010;31(4):480-8 %change from baseline *p< *p<0.01 *p=0.002 D Dalcetrapib 900 mg/day

All CETP Inhibitors

Fig 1. DEFINE: Change from baseline lipids (mg/dL) HDL Forum November 2010Cannon CP et al. N Engl J Med 2010: published on-line November 17. HDL-C LDL-C TG Lp(a) 138% vs. placebo % - 6.8% % vs. placebo  60 vs. 6 mg/dL

Anacetrapib - Phase III trial (REVEAL) The REVEAL (Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification) will assess whether there is clinical benefit associated with anacetrapib. REVEAL is currently recruiting 30,000 participants for a randomized, double-blinded, placebo- controlled trial. The study will compare patients with a history of vascular disease (such as heart disease, cerebrovascular disease, and peripheral vascular disease) on 100 mg of anacetrapib daily to those on placebo, to determine if the addition of anacetrapib reduces the risk of major coronary events (such as heart attack, death from heart disease, or requiring a coronary revascularization.) Data will be collected through 2017

Fig. 1 Percent change from baseline in HDL and LDL cholesterol with statin plus evacetrapib 100 mg/day or statin alone. The relative percent change between the two groups is indicated. Jane Stock Controversies in dyslipidaemia management Atherosclerosis Volume 221, Issue Evacetrapibe CETP inhibitor

ACCELERATE Evacetrapibe CETP inhibitor

Strategies of ongoing clinical trials to examine which lipid-targeted therapy should be added to statin treatment in patients with high vascular risk. Landmesser U Eur Heart J 2013;34: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author For permissions please

Don’t give up on HDL, researchers plead At a session on the subject, Dr Alan Tall (Columbia University, New York) summarized the situation: Hughs S, Jun, 2012 "The HDL hypothesis is certainly under attack. And there have been a lot of setbacks. But we mustn't throw the baby out with the bathwater. I think we need a new, modified HDL hypothesis."

Fig. 1 Source: Atherosclerosis (DOI: /j.atherosclerosis )Atherosclerosis Terms and Conditions HDL good or bad?

Instrumental variable analysis using lipid levels corrected for statin use. Shah S et al. Circ Cardiovasc Genet 2013;6:63-72 Copyright © American Heart Association

מתי יש Dysfunctional HDL: 1. Metabolic syndrome, Diabetes mellitus. 2. Atherogenic dyslipidemia. 3. Inflammatory diseases 4. Chronic renal disease. 5. Autoimmune disease 6. Women, increased HDL-C, no other cardiovascular risk factors, evident atherosclerosis.

Assays for HDL function HDL inhibits monocyte chemotaxis induced by LDL using an in vitro reconstituted artery wall model by the coculture of smooth muscle cells and endothelial cells. Cell free antioxidant activity. Inhibition of endothelial cell adhesion molecule expression. Ability of HDL to act as an acceptor of cellular cholesterol. Navab M. J Lipid Res. 2000;41:1495–1508. Ansell BJ,Circulation. 2003;108:2751–2756. Cockerill GW. Arterioscler Thromb Vasc Biol. 1995;15:1987–1994.

HDL Functionality as target?

More Efflux Less CAD risk

61 Efflux Capacity more important than just HDL Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis Amit V. Khera NEJM 364;127, 2011

Effect of recombinant Apo A-I Milano on Coronary Atherosclerosis in Patients With Acute Coronary Syndromes A Randomized Controlled Trial JAMA. 2003;290: Steven E. Nissen, Taro Tsunoda, E. Murat Tuzcu, et al.

Raising HDL or ApoA-I reduced Atheroma

Atheroma Regression in a patient who received High-Dose ETC-216 (45mg/kg) Atheroma Area 8.1 mm 2 Atheroma Area 5.35 mm 2 Nissen S et al. JAMA. 2003; 290: ETC-216 : Apo A-IMilano / Phospholipids

Future directions for HDL