Cholesteryl ester transfer protein inhibitors: challenges and perspectives

ABSTRACT

Introduction: Cholesteryl ester transfer protein (CETP) inhibitors substantially increase the concentration of high-density lipoprotein cholesterol (HDL-C), which may have a possible beneficial effect for cardiovascular disease risk reduction.

Areas covered: Current data regarding the effects of CETP inhibitors on cardiovascular disease risk and possible mechanisms for their effects and safety are presented in this review.

Expert commentary: The first CETP inhibitor, torcetrapib, was discontinued because of increased off-target adverse effects (increased serum aldosterone and blood pressure levels). The development program of dalcetrapib and evacetrapib, which were not associated with increased blood pressure, was terminated due to futility (insufficient efficacy) concerning cardiovascular outcomes. Although the failure of torcetrapib has been attributed to specific off-target effects, there are some common characteristics between CETP inhibitors pointing to the possibility that certain adverse effects may be class-specific. The newer CETP inhibitors anacetrapib and TA-8995 have promising effects on lipid profile and metabolism (increase of HDL-C and reduction of both low-density lipoprotein cholesterol and lipoprotein (a) levels), but their cardiovascular effects and safety profile have not yet been confirmed in large outcome trials.

KEYWORDS:

• Cholesteryl ester transfer protein inhibitors
• cardiovascular disease
• torcetrapib
• dalcetrapib
• evacetrapib
• anacetrapib
• TA-8995

Declaration of interest

TD Filippatos, E Klouras and F Barkas have given talks and attended conferences sponsored by various pharmaceutical companies including Bristol-Myers Squibb, Pfizer, Eli-Lilly, Abbott, Amgen, AstraZeneca, Novartis, Vianex, TEVA and MSD. M Elisaf has received speakers’ honoraria, consulting fees and research funding from AstraZeneca, Schering Plough, Merck, Pfizer, Solvay, Abbott, Boehringer-Ingelheim, and Fournier. He has also participated in clinical trials with AstraZeneca, Merck, Sanofi-Synthelabo, Solvay, GlaxoSmithKline, Novartis, Pfizer and Fournier. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.