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STATE-OF-THE-ART PAPER

Targeting Cholesteryl Ester Transfer Protein for the Prevention and Management of Cardiovascular Disease

Philip J. Barter, MBBS, PhD, FRACP^_*,_* and John J.P. Kastelein, MD, PhD

^_* The Heart Research Institute, Sydney, Australia
Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands

Manuscript received June 24, 2005; revised manuscript received August 26, 2005, accepted September 8, 2005.

^_* Reprint requests and correspondence: Dr. Philip J. Barter, The Heart Research Institute, 145 Missenden Road, Camperdown, Sydney 2050, Australia. (Email: p.barter{at}hri.org.au).

Epidemiologic studies have shown that the concentration of high-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk. This identifies HDL-C as a potential therapeutic target. Compared with low-density lipoprotein cholesterol (LDL-C)-lowering agents, however, currently available HDL-raising drugs are relatively ineffective. Consequently, recent years have seen considerable efforts expended on identifying new drugs that can raise HDL-C. Cholesteryl ester transfer protein (CETP) plays an important role in cholesterol metabolism, being responsible for the transfer of cholesteryl esters from HDL to very low-density lipoproteins and LDLs. The observation that Japanese populations with CETP deficiency exhibited high levels of HDL-C has led to the concept that drugs targeting CETP activity may elevate HDL-C levels and potentially decrease cardiovascular risk. Support of this proposition has been obtained in rabbits where inhibition of CETP activity is markedly antiatherogenic. Two CETP inhibitors—torcetrapib and JTT-705—are currently in the preliminary stages of clinical development. Initial studies with these drugs in humans show that they substantially increase HDL-C levels and modestly decrease LDL-C levels. Larger, long-term, randomized, clinical end point trials are required to determine whether the beneficial effects of CETP inhibitors on lipoprotein metabolism can translate into reductions in cardiovascular events.

Abbreviations and Acronyms   ABCA1 = ATP-binding cassette A1   apo = apolipoprotein   CE = cholesteryl ester   CETP = cholesteryl ester transfer protein   CHD = coronary heart disease   CVD = cardiovascular disease   FH = familial hypercholesterolemia   HDL = high-density lipoprotein   HDL-C = high-density lipoprotein cholesterol   HHS = Helsinki Heart study   LDL = low-density lipoprotein   LDL-C = low-density lipoprotein cholesterol   SR-B1 = scavenger receptor-B1   VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention trial   VLDL = very low-density lipoprotein

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