A review traces the CETP-inhibitor rationale from CETP-deficient Japanese populations with high HDL to early human trials of torcetrapib and JTT-705 (J Am Coll Cardiol 2006)

Original title: Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease

J Am Coll Cardiol · 18 January 2006 · 5

Barter PJ, Kastelein JJ

This review by leading investigators in the field lays out the case for targeting cholesteryl ester transfer protein (CETP) to raise HDL cholesterol, noting that currently available HDL-raising drugs are relatively ineffective compared with LDL-lowering agents. CETP transfers cholesteryl esters from HDL to very low-density and low-density lipoproteins, and the observation that Japanese populations with CETP deficiency have high HDL cholesterol supported the idea that CETP-targeting drugs could raise HDL and potentially lower cardiovascular risk. This concept was supported in rabbits, where CETP inhibition was markedly antiatherogenic. Two CETP inhibitors, torcetrapib and JTT-705, were then in early clinical development and had substantially increased HDL cholesterol and modestly decreased LDL cholesterol in initial human studies, with larger outcome trials still needed to establish clinical benefit.

Original abstract

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.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.