CETP inhibition improves the lipid profile but has no effect on clinical cardiovascular outcomes in high-risk patients.

Commentary on: Lincoff AM, Nicholls SJ, Riesmeyer JS, et al . Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med 2017;376:1933–42. High-density lipoprotein (HDL) cholesterol (HDL-C) is a robust predictor of cardiovascular disease (CVD) events; however, research into both rare monogenic HDL disorders and Mendelian randomisation studies of dysfunctional traits associated with HDL-C demonstrate that this biomarker is not involved in the causal pathway for atherosclerosis.1 Small-effect variants in the gene encoding cholesteryl ester transfer protein (CETP) associate with higher HDL-C and lower myocardial infarction rates, whereas large-effect variants associate with reduced survival. CETP loss-of-function variants also associate with low levels of low-density lipoprotein (LDL) cholesterol (LDL-C), which confounds the attribution of the atheroprotective effect of CETP-mediated HDL changes. Small molecules that inhibit CETP activity have been previously investigated in two randomised clinical trials of CVD outcomes.2 3 Treatment with torcetrapib, in combination with atorvastatin increased HDL-C …