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Review dissects biochemical pathways beyond HDL-C by which CETP inhibition might protect against atherosclerosis (Arterioscler Thromb Vasc Biol 2006)
Original title: Cholesteryl ester transfer protein (CETP) inhibition beyond raising high-density lipoprotein cholesterol levels: pathways by which modulation of CETP activity may alter atherogenesis
This review surveys the mechanistic pathways proposed to underlie CETP inhibitors' atheroprotective potential beyond simply raising HDL-C, noting that CETP inhibition had already been shown to reduce atherosclerosis in rabbits while human atheroma-burden data remained pending. Beyond raising HDL-C and lowering LDL-C, with putative beneficial increases in both HDL and LDL particle size, the review discusses unresolved questions about whether CETP inhibition affects the initial step of cholesterol efflux from peripheral tissues to HDL and the role of scavenger receptor BI in human reverse cholesterol transport. It also covers a second pathway, CETP inhibition's reported increase in HDL-associated antioxidant enzymes linked to reduced LDL oxidation, concluding that human atheroprotection remained anticipated rather than confirmed at the time of writing.
Original abstract
Raising high-density lipoprotein cholesterol (HDL-C) is a promising strategy in the struggle to prevent cardiovascular disease, and cholesteryl ester transfer protein (CETP) inhibitors have been developed to accomplish this. The first results are encouraging, and, in fact, in rabbits, inhibition of CETP reduces atherosclerosis. Because human data regarding the reduction of atheroma burden require more time, the biochemical mechanisms underlying the putative atheroprotection of CETP inhibitors are currently dissected, and several pathways have emerged. First, CETP inhibition increases HDL-C and reduces low-density lipoprotein cholesterol (LDL-C) levels consistent with CETP lipid transfer activity and its role in reverse cholesterol transport (RCT). This coincides with putative beneficial increases in both HDL and LDL size. However, many aspects regarding the impact of CETP inhibition on the RCT pathway remain elusive, in particular whether the first step concerning cholesterol efflux from peripheral tissues to HDL is influenced. Moreover, the relevance of scavenger receptor BI and consequently the central role of HDL in human RCT is still unclear. Second, CETP inhibition was shown recently to increase antioxidant enzymes associated with HDL, in turn associated with decreased oxidation of LDL. Atheroprotection in man is currently anticipated based on the improvement of these biochemical parameters known to influence atherosclerosis, but final confirmation regarding the impact of CETP inhibition on cardiovascular outcome will have to come from trials evaluating clinical end points.
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Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.