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Effects of cholesteryl ester transfer protein inhibitors on human lipoprotein metabolism: why have they failed in lowering coronary heart disease risk?

Schaefer, Ernst J.

Current Opinion in Lipidology: June 2013 - Volume 24 - Issue 3 - p 259–264
doi: 10.1097/MOL.0b013e3283612454
LIPID METABOLISM: Edited by Ernst J. Schaefer

Purpose of review: To examine the recent advances in our knowledge of cholesteryl ester transfer protein (CETP) inhibitors, heart disease risk reduction, and human lipoprotein metabolism.

Recent findings: CETP inhibitors block the transfer of cholesteryl ester from HDLs to triglyceride-rich lipoproteins (TRLs), thereby raising HDL cholesterol and lowering TRL cholesterol, and in some cases LDL cholesterol. Two CETP inhibitors, dalcetrapib and torcetrapib, have been tested in large clinical trials in statin-treated coronary heart disease patients and have shown no clinical benefit compared to placebo. Anacetrapib and evacetrapib, two potent CETP inhibitors, are now being tested in large clinical trials. Torcetrapib has been shown to decrease the fractional catabolic rate (FCR) of HDL apolipoproteins (apo) A-I and A-II, enhance the FCR of TRL apoB-100 and apoE, and decrease TRL apoB-48 production, but has no significant effects on fecal cholesterol excretion in humans. Anacetrapib also delays the FCR of HDL apoA-I.

Summary: CETP inhibitors form a complex between themselves, CETP, and HDL particles, which may interfere with the many physiologic functions of HDL, including reverse cholesterol transport. Available data would suggest that CETP inhibitors will fail as lipid-altering medications to reduce coronary heart disease risk because of interference with normal human HDL metabolism.

Lipid Metabolism Laboratory, Tufts University, Boston, Massachusetts, USA

Correspondence to Ernst J. Schaefer, MD, Lipid Metabolism Laboratory, Tufts University, 711 Washington Street, Boston, MA 02111, USA. Tel: +1 617 556 3100; fax: +1 617 556 3103; e-mail:

© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins