CETP inhibition first emerged as a therapeutic concept on the back of observations in the Framingham heart study—and in other population-based studies—of an apparent inverse association between high levels of HDL-c and risk of death from cardiovascular disease (Arteriosclerosis 8, 737–741, 1988). Animal data appeared to support the concept as well—mice and rats are naturally deficient in CETP and do not develop atherosclerosis, whereas rabbits, which have high levels of CETP, appeared to benefit from inhibition. But, following failures in large-scale outcomes trials, drug developers have lost faith in the idea that raising HDL-c is beneficial.
“The goalposts have moved now,” says Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital, in Boston. “I think there is some suggestive evidence, at least, from human genetics that the LDL-lowering properties of CETP might be protective,” he says. “That part of the hypothesis is still in play.” Merck, of Kenilworth, New Jersey, is banking on this aspect of the mechanism in a mammoth outcomes trial, dubbed REVEAL (Randomized Evaluation of the Effects of Anacetrapib Through Lipid-modification), which is recruiting 30,000 patients. “They've powered their study entirely for the LDL-lowering effect,” says Kathiresan. The scale of the trial is huge—in contrast, Lilly's trial of evacetrapib, called ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes), recruited 12,000 patients. Not only will it improve sensitivity for weaker efficacy signals, but it has a longer follow-up period, of four years versus 2.75 years for evacetrapib. The Merck study also excluded patients with acute coronary syndrome—heart attack or unstable angina—whereas Lilly's ACCELERATE study did not.
This is a preview of subscription content, access via your institution