Outcomes trials
Review tallies CETP inhibitor trial results from the 2006 failure of torcetrapib to the early promise of evacetrapib (Curr Opin Lipidol 2012)
Original title: Rationale for cholesteryl ester transfer protein inhibition
This review examines the rationale for cholesteryl ester transfer protein (CETP) inhibition as a way to raise HDL cholesterol (HDL-C) and reduce cardiovascular risk beyond statins. Torcetrapib, the first CETP inhibitor tested in a phase III trial (ILLUMINATE), failed in 2006 due to increased all-cause mortality and cardiovascular events later attributed to nonclass-related off-target effects, particularly increased blood pressure and low potassium linked to aldosterone stimulation. Anacetrapib raised HDL-C by approximately 138% and lowered LDL-C by approximately 40% without the adverse effects of torcetrapib in the DEFINE study, dalcetrapib raised HDL-C by approximately 30% with minimal LDL-C effect and proved safe across nearly 600 patients in the dal-VESSEL and dal-PLAQUE trials, and evacetrapib showed favorable lipid changes in a phase II study. The authors conclude the ongoing dal-OUTCOMES and REVEAL outcome trials will provide more conclusive answers on whether raising HDL-C via CETP inhibition reduces cardiovascular risk.
Original abstract
Purpose Of Review: Raising HDL cholesterol (HDL-C) has become an attractive therapeutic target to lower cardiovascular risk in addition to statins. Inhibition of the cholesteryl ester transfer protein (CETP), which mediates the transfer of cholesteryl esters from HDL to apolipoprotein B-containing particles, leads to a substantial increase in HDL-C levels. Various CETP inhibitors are currently being evaluated in phase II and phase III clinical trials. However, the beneficial effect of CETP inhibition on cardiovascular outcome remains to be established.
Recent Findings: Torcetrapib, the first CETP inhibitor tested in a phase III clinical trial (ILLUMINATE), failed in 2006 because of an increase in all-cause mortality and cardiovascular events that subsequently were attributed to nonclass-related off-target effects (particularly increased blood pressure and low serum potassium) related to the stimulation of aldosterone production. Anacetrapib, another potent CETP inhibitor, raises HDL-C levels by approximately 138% and decreases LDL cholesterol (LDL-C) levels by approximately 40%, without the adverse off-targets effects of torcetrapib (DEFINE study). The CETP modulator dalcetrapib raises HDL-C levels by approximately 30% (with only minimal effect on LDL-C levels) and proved safety in the dal-VESSEL and dal-PLAQUE trials involving a total of nearly 600 patients. Evacetrapib, a relatively new CETP inhibitor, exhibited favorable changes in the lipid profile in a phase II study.
Summary: The two ongoing outcome trials, dal-OUTCOMES (dalcetrapib) and REVEAL (anacetrapib), will provide more conclusive answers for the concept of reducing cardiovascular risk by raising HDL-C with CETP inhibition.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.