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(Circulation. 2005;111:1847-1854.)
© 2005 American Heart Association, Inc.

Contemporary Reviews in Cardiovascular Medicine

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

An Update for Clinicians

James S. Forrester, MD; Rajenda Makkar, MD; P.K. Shah, MD

From the Cardiology Division, Cedars-Sinai Medical Center, Los Angeles, Calif.

Correspondence to James S. Forrester, MD, Burns and Allen Professor, Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail forrester{at}cshs.org

Received July 9, 2004; revision received August 21, 2004; accepted October 19, 2004.

Reduced HDL cholesterol may be a risk factor comparable in importance to increased LDL cholesterol. Interventions that raise HDL are antiatherosclerotic, presumably through acceleration of reverse cholesterol transport and by antioxidant and antiinflammatory effects. In the hypercholesterolemic rabbit, HDL levels can be increased by >50% by inhibition of cholesteryl ester transfer protein (CETP), a molecule that plays a central role in HDL metabolism. This HDL-raising effect is antiatherosclerotic in moderately severe hyperlipidemia but appears to be ineffective in the presence of severe hypertriglyceridemia. In humans, mutations resulting in CETP inhibition have been associated with both reduced and increased risk of atherosclerosis. Proposed explanations for these apparently disparate observations are that the antiatherosclerotic effect of CETP inhibition varies with either the metabolic milieu or the degree of CETP inhibition. We now have pharmacological inhibitors of CETP that are capable of increasing HDL by as much as 50% to 100% in humans. The importance of this development is that reduced HDL is a risk factor independent of LDL and that these new agents alter HDL by a magnitude comparable to that of statins on LDL. Clinical trials, now beginning, will need to identify the patient subsets in which CETP inhibition may be more or less effective.

Key Words: atherosclerosis • cholesterol • lipids • metabolism • statins

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