The ILLUMINATE trial was designed to investigate the effects of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib on major coronary events in 15,067 high-risk patients treated with atorvastatin. The combination of torcetrapib plus atorvastatin substantially increased HDL cholesterol levels (72.1%) and reduced LDL cholesterol and triglyceride levels by 24.9% and 9%, respectively. However, systolic blood pressure increased by 5.4 mmHg in the torcetrapib group. Because of increased mortality rates (93 vs. 59 patients, in the torcetrapib plus atorvastatin and the atorvastatin alone groups, respectively), the trial was ended prematurely. Although increases in serum sodium, bicarbonate, and aldosterone suggest a potential off-target effect of torcetrapib, the adverse effects of CETP inhibition per se cannot be ruled out. This paper was accompanied by an editorial by Daniel Rader who stressed that the interruption of the clinical research program with torcetrapib does not mean the “death” of CETP inhibition as an HDL raising modality. In this regard, Rader raised fundamental research questions that will need to be answered in the quest for a safe and effective CETP inhibitor: 1) was the increase in adverse events and mortality caused by CETP inhibition, off-target effects, or both? and 2) might a “clean” CETP inhibitor reduce cardiovascular events without increasing noncardiovascular adverse events? This editorial also presents several mechanisms by which torcetrapib might have caused harm and, more importantly, discusses the effects of CETP inhibition on HDL metabolism.
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