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Cholesterol ester transfer protein (CETP) inhibitors have failed to improve outcomes despite their marked effects on reducing LDL cholesterol and raising HDL cholesterol. In the ACCELERATE trial, researchers have tested yet another CETP inhibitor, evacetrapib, against placebo among patients with high-risk vascular disease who were receiving standard therapy.
This industry-sponsored, international trial randomized 12,092 patients, one third of whom had an acute coronary syndrome 6 months before randomization. Almost all patients were receiving statins at randomization.
The study was stopped early because of futility, at a median follow-up of 28 months. Mean LDL cholesterol levels were significantly different between groups, with a decrease of 31% with evacetrapib and an increase of 6% with placebo. The mean HDL cholesterol level increased significantly more in the evacetrapib group than in the placebo group (133% vs. 2%). However, the groups had similar results on the primary composite endpoint — death from cardiovascular causes, myocardial infarction, coronary revascularization, stroke, or hospitalization for unstable angina — 12.9% with evacetrapib and 12.8% with placebo.
Lincoff AM et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med 2017 May 18; 376:1933. (http://dx.doi.org/10.1056/NEJMoa1609581)
Comment
We can add this CETP inhibitor to the list of drug failures. People may focus on the failure of raising HDL cholesterol, but what I find remarkable is that a drug that lowers LDL cholesterol by 31% does not budge cardiovascular risk. The reason that lowering LDL cholesterol in this case does not reduce risk is unknown. We await the trial results of yet another CETP, anacetrapib. Meanwhile, the lesson here is that not all drugs producing favorable changes in lab results also improve outcomes; you need to do the study to be sure.