The class
Hegele argues the pressor effect of torcetrapib, not CETP inhibition itself, doomed the drug and asks if the class deserves another chance (Curr Opin Cardiol 2009)
Original title: The end of the road for CETP inhibitors after torcetrapib?
The unexpected failure of torcetrapib to reduce cardiovascular disease despite raising HDL cholesterol raised broader doubts about both HDL-raising strategies and CETP inhibition as a mechanism. This review discusses the complexity of HDL metabolism, caveats of CETP inhibition, and possible explanations for the torcetrapib failure, concluding it likely stemmed from off-target effects since other CETP inhibitors, such as dalcetrapib and anacetrapib, do not raise blood pressure, a CETP-independent pressor effect specific to torcetrapib. In small, short-duration human trials, anacetrapib and dalcetrapib appeared to improve the lipoprotein profile without obvious adverse effects so far. The authors conclude there is sufficient evidence to justify cautious continued evaluation of dalcetrapib and anacetrapib, since it remains unclear whether the excess cardiovascular risk seen with torcetrapib reflected an agent-specific problem or a more general hazard of CETP inhibition.
Original abstract
Purpose Of Review: Because high-density lipoprotein cholesterol (HDL-C) levels are inversely related to cardiovascular disease (CVD), raising HDL-C levels would seem intuitively valuable. However, the recent failure of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib to decrease CVD has raised doubts regarding HDL-C raising in general and CETP inhibition in particular for CVD prevention. We briefly discuss the complexity of HDL metabolism, caveats of CETP inhibition, possible mechanisms for torcetrapib's failure, and the potential utility of other CETP inhibitors.
Recent Findings: Torcetrapib likely failed because of off-target effects, since other CETP inhibitors, such as dalcetrapib (JTT-705/R1658) or anacetrapib (MK-0859), do not increase blood pressure, a specific pressor effect of tocetrapib that appears to be CETP-independent. In small human trials of short duration, anacetrapib and dalcetrapib appear to improve the lipoprotein profile without obvious adverse effects, so far.
Summary: The relationship between HDL metabolism, pharmacologic CETP inhibition, and atherosclerosis requires further elucidation. There seems to be sufficient evidence that evaluation of CETP inhibitors such as dalcetrapib and anacetrapib should proceed, if cautiously, since it remains uncertain whether the increased CVD risk with torcetrapib was related to agent-specific off-target effects or more generally to CETP inhibition as a mechanism to raise HDL.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.