Cholesteryl Ester Transfer Protein and Coronary Artery Disease

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Abstract
Lasma levels of high-density lipoprotein cholesterol (HDL-C) are strongly inversely associated with risk of atherosclerotic cardiovascular disease (ASCVD). It has been estimated that for every 1-mg increase in HDL-C, there is a 2% to 3% decrease in cardiovascular risk,1 which suggests that therapy to increase HDL-C levels could be effective in reducing cardiovascular risk. HDL metabolism is therefore a major emerging target for drug discovery.2 The finding more than a decade ago that genetic deficiency of the cholesteryl ester transfer protein (CETP) in humans is asso- ciated with markedly elevated plasma HDL-C levels led to the concept that CETP inhibition could be a therapeutic strategy for raising HDL.3 Indeed, 2 small-molecule inhibi- tors of CETP have been shown to raise HDL-C levels in humans, 4-6 and this finding has generated substantial enthu- siasm for CETP inhibition as a therapeutic strategy. See p 1418 Important questions remain about whether CETP inhibi- tion, despite its positive effects on HDL-C levels, will reduce ASCVD. One theoretical concern is that CETP inhibition could slow the rate of reverse cholesterol transport (RCT), the process by which macrophage cholesterol in the vessel wall is returned to the liver for excretion. In studies in humans, radiolabeled cholesteryl esters that originated in HDL ulti- mately appeared in the bile primarily after their transfer (presumably mediated by CETP) to apolipoprotein B- con- taining lipoproteins, 7 which suggests that CETP might play an important physiological role in RCT. Ultimately, random- ized controlled trials of CETP inhibitors will definitively address their effect on atherosclerosis and cardiovascular events. In the meantime, observational studies in humans have the potential to provide important insights into this critical question. Such observational studies include careful assessment of cardiovascular risk in CETP-deficient subjects (both homozygous and heterozygous), as well as studies of the association of CETP polymorphisms and plasma CETP levels with cardiovascular outcomes.

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