Torcetrapib
Barter reflects on ILLUMINATE: the harm caused by torcetrapib likely reflects off-target effects, not CETP inhibition itself (Am J Cardiol 2009)
Original title: Lessons learned from the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial
In this commentary, the lead investigator of the ILLUMINATE trial reviews lessons from the study of torcetrapib, a CETP inhibitor that raises HDL cholesterol and lowers LDL cholesterol and had been shown to inhibit atherosclerosis in rabbits. Imaging trials of torcetrapib in humans failed to show an effect on carotid or coronary atheroma, and when tested in a large clinical outcome trial, torcetrapib was associated with increased cardiovascular events and total mortality, leading to termination of its development. The author notes the precise cause of the adverse effects of torcetrapib remains uncertain, but emerging evidence points to off-target pharmacologic activity unrelated to CETP inhibition. The author concludes the potential of CETP inhibition to reduce cardiovascular risk will be determined by ongoing trials of CETP inhibitors that do not share the off-target effects of torcetrapib.
Original abstract
Inhibition of the cholesteryl ester transfer protein (CETP), a plasma protein that normally transfers cholesterol from the protective high-density lipoprotein (HDL) fraction to the atherogenic low-density lipoprotein (LDL) fraction, results in an increase in the concentration of HDL cholesterol and a decrease in the concentration of LDL cholesterol and has been shown in rabbits to inhibit the development of atherosclerosis. The CETP inhibitor torcetrapib was investigated in humans in imaging trials that failed to demonstrate an effect on atheroma in either the carotid or coronary arteries. When tested in a large clinical outcome trial, treatment with torcetrapib was associated with an increase in cardiovascular events and an increase in total mortality. As a result, the development of torcetrapib was terminated. The reason for the adverse effects of torcetrapib is still not known with certainty, but evidence is emerging that these effects may have been the consequence of off-target pharmacologic activity of torcetrapib unrelated to the inhibition of CETP. The potential of CETP inhibition to reduce cardiovascular risk will be determined by the outcome of ongoing clinical trials with CETP inhibitors that do not share the off-target effects of torcetrapib.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.