The ILLUMINATE trial halts torcetrapib development after finding a 58 percent rise in death from any cause despite a 72 percent HDL cholesterol increase (N Engl J Med 2007)

Original title: Effects of torcetrapib in patients at high risk for coronary events

N Engl J Med · 5 November 2007 · 10

Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH et al.

This randomized, double-blind trial tested whether the CETP inhibitor torcetrapib could reduce major cardiovascular events in 15,067 patients at high cardiovascular risk, randomized to torcetrapib plus atorvastatin or atorvastatin alone, but was terminated prematurely after an increased risk of death and cardiac events emerged in the torcetrapib group. At 12 months, torcetrapib raised HDL cholesterol by 72.1% and lowered LDL cholesterol by 24.9% versus baseline, alongside a 5.4 mmHg rise in systolic blood pressure and increases in sodium, bicarbonate, and aldosterone with a fall in potassium (p < 0.001 for all). Torcetrapib was associated with an increased risk of cardiovascular events (hazard ratio 1.25, p = 0.001) and death from any cause (hazard ratio 1.58, p = 0.006), with post hoc analyses linking greater potassium reduction or bicarbonate increase to higher mortality risk. The trial concluded torcetrapib increased mortality and morbidity through an unknown mechanism, with evidence pointing to an off-target effect but not ruling out harm from CETP inhibition itself.

Original abstract

Background: Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib.

Methods: We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina.

Results: At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P<0.001 for both comparisons), in addition to an increase of 5.4 mm Hg in systolic blood pressure, a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone (P<0.001 for all comparisons). There was also an increased risk of cardiovascular events (hazard ratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P=0.001) and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to 2.19; P=0.006). Post hoc analyses showed an increased risk of death in patients treated with torcetrapib whose reduction in potassium or increase in bicarbonate was greater than the median change.

Conclusions: Torcetrapib therapy resulted in an increased risk of mortality and morbidity of unknown mechanism. Although there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition. (ClinicalTrials.gov number, NCT00134264 [ClinicalTrials.gov].).

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.