Defining the Safety of Anacetrapib, a CETP Inhibitor, in Patients at High Risk for Coronary Heart Disease: the DEFINE study

Abstract

In 2004, the Third Report of the National Cholesterol Education Panel Adult Treatment Panel (ATP) III Guidelines were updated based on recent trials available at that time to expand the scope and intensity of low-density lipoprotein cholesterol (LDL-C) lowering therapy [1]. That report also recommended consideration of combination therapy for high-risk patients with high triglycerides and low high-density lipoprotein cholesterol (HDL-C). One pharmacologic approach to such a regimen is the use of cholesterol ester transfer protein (CETP) inhibitors, which raise HDL-C and may decrease LDL-C. The Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial attempted to test the hypothesis that CETP inhibition with torcetrapib would decrease clinical cardiovascular events, but despite substantial increases in HDL-C, the trial was terminated early due to excess adverse events, including increased mortality in the group that received torcetrapib plus atorvastatin compared to the group that received atorvastatin alone [2]. Hypotheses for the increased mortality, both due to cardiovascular and noncardiovascular causes, included an off-target effect of the drug unrelated to CETP inhibition, or an adverse effect of CETP inhibition itself, including possibly the generation of dysfunctional or even proatherogenic HDL-C. The ILLUMINATE trial did find a known off-target effect of torcetrapib (an increase in blood pressure) but could not definitively rule in or out either of the two potential explanations. Other effects of torcetrapib included increased sodium and bicarbonate levels, decreased potassium levels, and apparent increases in aldosterone levels. Other CETP inhibitors, including anacetrapib [3], have not shown increases in blood pressure and appear to be better candidates for further study.