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Discussant: Lipid-Modulating Effects of Evacetrapib, a Novel CETP Inhibitor AHA Scientific Sessions November 15, 2011. Daniel J. Rader, MD University of Pennsylvania. Lipoproteins and Atherosclerosis. ?. A-I. TG, CE. B. CE. VLDL, LDL, remnants, Lp(a). HDL. The HDL-C hypothesis.

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Daniel J. Rader, MD University of Pennsylvania


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    1. Discussant:Lipid-Modulating Effects of Evacetrapib, a Novel CETP InhibitorAHA Scientific Sessions November 15, 2011 Daniel J. Rader, MD University of Pennsylvania

    2. Lipoproteins and Atherosclerosis ? A-I TG, CE B CE VLDL, LDL, remnants, Lp(a) HDL

    3. The HDL-C hypothesis Raising plasma HDL-C levels will reduce CV events.

    4. Anti-atherogenic HDL functions HDL Anti-oxidant NO-promoting Anti-inflammatory Anti-thrombotic Cholesterol efflux and reverse cholesterol transport

    5. Reverse Cholesterol Transport Bile ABCG1 A-I A-I FC CE FC LCAT FC CE ABCA1 SR-BI Macrophage Liver

    6. Cholesteryl ester transfer protein (CETP) transfers cholesterol out of HDL Bile ABCG1 A-I A-I FC CE FC LCAT FC CE ABCA1 SR-BI Macrophage Liver CETP LDLR CE B TG VLDL/LDL

    7. CETP Deficiency is Associated with Markedly Increased HDL-C Levels A-I Bile ABCG1 FC A-I FC CE CE LCAT FC ABCA1 SR-BI Macrophage Liver X CETP LDLR CE B TG VLDL/LDL

    8. CETP Inhibition as a Novel Strategy to Raise HDL Cholesterol Bile A-I A-I FC CE FC LCAT FC CE ABCA1 SR-BI Macrophage Liver X CETP LDLR CETP inhibitor CE B TG VLDL/LDL

    9. CETP Inhibitors o o o CETP Evacetrapib Torcetrapib Anacetrapib Dalcetrapib Slide courtesy of Dr Bryan Brewer

    10. Lipid efficacy of CETP inhibitors(% change from baseline) Adapted from Cannon C, JAMA 306:2154; 2011

    11. dal-OUTCOMES Dalcetrapib 600 mg 15,600 patients 4-12 weeks after an index ACS event Statin therapy to optimal LDL-C level Placebo 2.5-year follow-up Primary End Point CHD death, non-fatal MI, atherothrombotic stroke, unstable angina requiring hospitalization or resuscitated cardiac arrest Schwartz et al. Am Heart J. 2009;158:896-901.

    12. 30,000 patients with occlusive arterial disease in North America, Europe and Asia Background LDL-lowering with atorvastatin Randomized to anacetrapib 100 mg vs. placebo Scheduled follow-up: 4 years Primary outcome: coronary death, myocardial infarction or coronary revascularization www.revealtrial.org

    13. CETP inhibitor outcome trials

    14. CETP inhibitor outcome trials