The Off-Target Effects of Torcetrapib

Cholesterol ester transfer protein (CETP) is responsible for the transfer of lipid from high-density lipoprotein (HDL; so-called good cholesterol) to low-density lipoprotein (LDL; so-called bad cholesterol). From a number of epidemiological studies, there is wide assent that subjects with high HDL are relatively protected in terms of cardiovascular risk, whereas a high LDL is a recognized risk factor. Inhibition of CETP thus presented an attractive therapeutic target, and the CETP inhibitor torcetrapib was shown in preliminary human studies to elevate HDL levels by 60–100%, and to lower LDL by up to 25%. On this basis, a number of large-scale trials were launched in which ultrasonography and other imaging techniques were used; in these trials, however, torcetrapib was found to have no significant effect on coronary atheroma burden or on carotid intima-media thickness (1, 2, 3). At the same time, a very large outcome trial [the Investigation of Lipid Level Management to Understand Its Impact on Atherosclerotic Events (ILLUMINATE)] began, comparing torcetrapib plus atorvastatin with atorvastatin alone, in more than 15,000 high-risk subjects (4). On December 4, 2006, the trial was terminated on the advice of the Data Safety Monitoring Board, reflecting higher all-cases mortality and major cardiovascular events in the torcetrapib arm.