Effects of Torcetrapib in Patients at High Risk for Coronary Events

TLDR

Inhibition of cholesteryl ester transfer protein (CETP) markedly alters plasma lipoprotein levels. The study examined whether torcetrapib, a potent CETP inhibitor, could reduce major cardiovascular events. In a double‑blind, randomized trial of 15,067 high‑risk patients, participants received torcetrapib plus atorvastatin or atorvastatin alone, with the primary outcome defined as first major cardiovascular event (death from coronary heart disease, non‑fatal MI, stroke, or unstable angina hospitalization) and 12‑month lipid and blood‑pressure changes measured. The trial was terminated early because torcetrapib increased the risk of death and cardiovascular events (hazard ratio 1.25 for events, 1.58 for all‑cause mortality), with post‑hoc analyses implicating potassium and bicarbonate shifts and suggesting an unknown off‑target mechanism.

Abstract

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.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.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.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]. ).