CETP inhibitors, challenges and perspectives: off-target failure for torcetrapib, futility for dalcetrapib and evacetrapib, early promise for anacetrapib and TA-8995 (Expert Rev Cardiovasc Ther 2016)

Original title: Cholesteryl ester transfer protein inhibitors: challenges and perspectives

Expert Rev Cardiovasc Ther · 28 May 2016 · 5

Filippatos TD, Klouras E, Barkas F, Elisaf M

A review of CETP inhibitor cardiovascular effects and safety at a formative point in the history of the class. Torcetrapib was discontinued for off-target adverse effects, raised aldosterone and blood pressure; dalcetrapib and evacetrapib, which did not raise blood pressure, were terminated for futility on cardiovascular outcomes. The authors note shared characteristics across the inhibitors that raise the possibility some adverse effects are class-specific rather than compound-specific, despite the failure of torcetrapib usually being attributed to distinct off-target effects. The newer agents anacetrapib and TA-8995 (obicetrapib) showed promising lipid and lipoprotein effects, including raised HDL-C and reduced LDL-C and Lp(a), but their cardiovascular effects and safety had not yet been confirmed in large outcomes trials at the time of writing.

Original 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.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.