Where are we with high-density lipoprotein raising and inhibition of cholesteryl ester transfer for heart disease risk reduction?

Abstract

To review recent research in the area of high-density lipoprotein raising and coronary heart disease risk reduction. A decreased high-density lipoprotein-cholesterol is an important coronary heart disease risk factor and raising high-density lipoprotein-cholesterol has been associated with coronary heart disease risk reduction. A relative new strategy for raising high-density lipoprotein-cholesterol, i.e. inhibition of cholesteryl ester transfer protein, is markedly effective. Cholesteryl ester transfer protein inhibitors prevent the transfer of cholesteryl ester from high-density lipoprotein to triglyceride-rich lipoproteins in exchange for triglyceride. One inhibitor, torcetrapib, binds to cholesteryl ester transfer protein on high-density lipoprotein, markedly raises high-density lipoprotein-cholesteryl ester and has no effect on fecal cholesterol excretion, but can raise blood pressure. A large clinical trial in coronary heart disease patients on atorvastatin was recently stopped prematurely because of excess mortality in those receiving torcetrapib vs. placebo and two other trials reported no benefit of torcetrapib on coronary atherosclerosis or carotid artery intimal medial thickness as compared with subjects on atorvastatin alone. The adverse effects of torcetrapib may be compound-specific and, since the crystal structure of cholesteryl ester transfer protein is now known, it should be possible to develop more optimal cholesteryl ester transfer protein inhibitors that do not form a nonproductive complex with cholesteryl ester transfer protein on the high-density lipoprotein particle, as has been reported for torcetrapib. The alternative for high-density lipoprotein raising is to develop more effective and better tolerated niacin preparations.