Torcetrapib Associated with Higher CV Event Rates in ILLUMINATE
November 4, 2007 By Scott P. Williams 
Orlando, FL: The results of the ILLUMINATE trial suggest that patients with a history of cardiovascular disease (CVD) who are treated with torcetrapib face an increased risk of death and cardiac events. Importantly, the increased risk of adverse events may be mediated by off target toxicity due to a rise in aldosterone and blood pressure in patients treated with torcetrapib. The results were announced today at the American Heart Association’s Scientific Sessions.
The research team hypothesized that torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, would decrease the risk of clinical cardiovascular events by lowering the patients’ LDL cholesterol level and raising their HDL cholesterol levels. To test this hypothesis the researchers conducted a prospective, randomized, multi-center, double-blind clinical trial. Men and women spanning the ages of 45 to 75 years old were eligible to participate in the trial if they displayed symptoms of CVD (MI, stroke, ACS, UA, PVD, cardiac revascularization) 30 days to 5 years prior to enrollment. Diabetic patients without prior CVD were also eligible for the study. Upon the completion of 4 to 10 weeks of lifestyle counseling treatment with atorvastatin (as necessary) to reach an LDL cholesterol level of less than 100 mg per deciliter, patients were randomized to receive either atorvastatin and 60 mg torcetrapib (n=7533) or atorvastatin and placebo (n=7534). The median follow up for both groups of patients was 550 days.
The primary endpoint of ILLUMINATE was the occurrence of a major cardiovascular event, which was defined as any of the following: death from coronary heart disease, nonfatal MI, stroke, and hospitalization for UA. Secondary endpoints were the time to occurrence of each individual component of the primary endpoint, the time to all cause death, and change in HDL and LDL cholesterol levels.
A 72.1% increase in HDL cholesterol and a 24.9% decrease in LDL cholesterol, as compared with baseline, was observed among patients treated with torcetrapib (p<0.001). On the other hand, a 5.4 mm Hg increase in systolic blood pressure, increases in serum bicarbonate, aldosterone, and sodium, and a decrease in serum potassium were all observed among patients treated with torcetrapib (p<0.001).
With respect clinical events, treatment with torcetrapib was associated with an increased risk of major cardiovascular events (6.2% vs. 5.0%, HR 1.25, p = 0.001).
Dr Philip Barter, principal investigator of the study indicated that the HDL formed by the drug appears to be functional, and that the increase in aldosterone levels is most likely responsible for the adverse outcomes. Importantly, other CETP inhibitors do not appear to have the same off target toxicity, and the class of agents may still be of benefit.