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European Heart Journal Advance Access published online on October 12, 2009
European Heart Journal, doi:10.1093/eurheartj/ehp399
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org
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Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors

M. John Chapman*, Wilfried Le Goff, Maryse Guerin and Anatol Kontush

INSERM, UMR S939, Dyslipidemia, Inflammation and Atherosclerosis Research Unit, University Pierre and Marie Curie-Paris 6, Pavillon Benjamin Delessert, Hôpital de la Pitié, 83, Boulevard de l'Hôpital, F-75013 Paris Cedex 13, France

Received 5 March 2009; revised 6 July 2009; accepted 27 August 2009 * Corresponding author. Tel: +33 1 42 17 78 78, Fax: +33 1 45 82 81 98, Email: john.chapman{at}upmc.fr

Subnormal plasma levels of high-density lipoprotein cholesterol (HDL-C) constitute a major cardiovascular risk factor; raising low HDL-C levels may therefore reduce the residual cardiovascular risk that frequently presents in dyslipidaemic subjects despite statin therapy. Cholesteryl ester transfer protein (CETP), a key modulator not only of the intravascular metabolism of HDL and apolipoprotein (apo) A-I but also of triglyceride (TG)-rich particles and low-density lipoprotein (LDL), mediates the transfer of cholesteryl esters from HDL to pro-atherogenic apoB-lipoproteins, with heterotransfer of TG mainly from very low-density lipoprotein to HDL. Cholesteryl ester transfer protein activity is elevated in the dyslipidaemias of metabolic disease involving insulin resistance and moderate to marked hypertriglyceridaemia, and is intimately associated with premature atherosclerosis and high cardiovascular risk. Cholesteryl ester transfer protein inhibition therefore presents a preferential target for elevation of HDL-C and reduction in atherosclerosis. This review appraises recent evidence for a central role of CETP in the action of current lipid-modulating agents with HDL-raising potential, i.e. statins, fibrates, and niacin, and compares their mechanisms of action with those of pharmacological agents under development which directly inhibit CETP. New CETP inhibitors, such as dalcetrapib and anacetrapib, are targeted to normalize HDL/apoA-I levels and anti-atherogenic activities of HDL particles. Further studies of these CETP inhibitors, in particular in long-term, large-scale outcome trials, will provide essential information on their safety and efficacy in reducing residual cardiovascular risk.

Key Words: HDL • Atherosclerosis • Cholesteryl ester transfer protein • Cholesteryl ester transfer protein inhibitor • Triglycerides • Reverse cholesterol transport


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