Lessons Learned from the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) Trial

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.