Dalcetrapib, a cholesteryl ester transfer protein modulator

Abstract

Introduction: Cholesteryl ester transfer protein (CETP) plays an important role in reverse cholesterol transport by transferring cholesteryl esters from high-density lipoprotein (HDL) to the apolipoprotein B-containing lipoproteins. Inhibition of CETP is a target to increase HDL-cholesterol and potentially reduce atherosclerosis. Dalcetrapib is an orally administered CETP inhibitor developed for the treatment of primary hypercholesterolaemia and mixed hyperlipidaemia.

Areas covered: Areas covered are: mode of action, preclinical development and clinical trials of dalcetrapib, a CETP modulator. The article provides an understanding of the pharmacokinetic and pharmacodynamic characteristics of dalcetrapib and insight into its clinical efficacy and safety. In clinical trials, dalcetrapib produced significant elevations in HDL-cholesterol when taken alone or in combination with statin with no effect on blood pressure or expression of genes involved in the renin–angiotensin–aldosterone system.

Expert opinion: Although dalcetrapib is the least potent CETP inhibitor, it does not impair the formation of CETP-induced pre-β HDL, which might be needed to increase reverse cholesterol transport. While dalcetrapib is well-tolerated and does not show major side effects, the recent interim results of the Phase III dal-OUTCOMES trial have shown the lack of a clinically meaningful benefit, and further testing of the drug has been halted.

Keywords::

• apolipoprotein A-I
• atherosclerosis
• CETP inhibitor
• cholesteryl ester transfer protein (CETP)
• coronary heart disease
• dalcetrapib
• HDL-cholesterol
• lipoproteins
• metabolism