Evacetrapib raises ABCA1-specific cholesterol efflux capacity and pre-beta-1 HDL, effects that statins alone do not share (JACC 2015)

Original title: Cholesterol Efflux Capacity and Pre-Beta-1 HDL Concentrations Are Increased in Dyslipidemic Patients Treated With Evacetrapib

J Am Coll Cardiol · 17 November 2015 · 7

Nicholls SJ, Ruotolo G, Brewer HB, Kane JP, Wang MD, Krueger KA, Adelman SJ, Nissen SE, Rader DJ

Potent CETP inhibitors substantially raise HDL cholesterol and apoA-I, but their effect on macrophage cholesterol efflux capacity, a functional measure of reverse cholesterol transport, was poorly characterized. This phase 2 substudy analyzed 377 subjects with elevated LDL-C or low HDL-C after 12 weeks of placebo, statin monotherapy, evacetrapib monotherapy, or evacetrapib combined with statin (NCT01105975), measuring total, non-ABCA1-, and ABCA1-specific cholesterol efflux capacity and pre-beta-1 HDL. Evacetrapib monotherapy dose-dependently increased total and non-ABCA1-specific efflux capacity by up to 34% and 47% versus placebo, and ABCA1-specific efflux capacity by up to 26%; combined with statins it increased total, non-ABCA1-, and ABCA1-specific efflux capacity by 21%, 27%, and 15% versus statin alone. Rosuvastatin and simvastatin significantly reduced total and ABCA1-specific efflux capacity, while atorvastatin had no significant effect, and evacetrapib alone or with statins significantly raised pre-beta-1 HDL by both immunofixation and 2D gel electrophoresis, a mechanism the authors say requires further study.

Original abstract

Background: Potent cholesteryl ester transfer protein (CETP) inhibitors have been shown to substantially increase high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I levels as monotherapy and combined with statins. However, data on the effects of this class of drugs on macrophage cholesterol efflux capacity (CEC), a functional assay that characterizes a key step in the process of reverse cholesterol transport, are limited.

Objectives: This study assessed the impact of evacetrapib, statins, or combination therapy on CEC.

Methods: We analyzed samples from 377 subjects with elevated low-density lipoprotein cholesterol (LDL-C) or low HDL-C levels who were enrolled in a phase 2 trial of evacetrapib. Percent changes from baseline in CEC (total, non-ABCA1-, and ABCA1-specific) and HDL subpopulations were evaluated after 12 weeks of treatment with placebo, statin monotherapy, evacetrapib monotherapy, or evacetrapib combined with statins. Pre-beta-1 HDL levels were quantified by immunofixation and nondenaturing 2-dimensional gel electrophoresis (2DGE).

Results: Relative to placebo, evacetrapib monotherapy increased dose-dependent total and non-ABCA1-specific CEC up to 34% and 47%, respectively. Evacetrapib monotherapy also increased ABCA1-specific CEC up to 26%. Relative to statin monotherapy, evacetrapib with statins also increased total, non-ABCA1-, and ABCA1-specific CEC by 21%, 27%, and 15%, respectively. In contrast, rosuvastatin and simvastatin significantly reduced total and ABCA1-specific CEC, whereas atorvastatin had no significant effect. Consistent with ABCA1-specific CEC, evacetrapib monotherapy and evacetrapib combined with statins significantly increased pre-beta-1 HDL levels as measured by either method.

Conclusions: Evacetrapib, as monotherapy and combined with statins, not only increased total CEC, but also increased ABCA1-specific CEC and pre-beta-1 HDL. The mechanisms by which potent CETP inhibition increases ABCA1-specific CEC and pre-beta-1 HDL require further study. (A Study of LY2484595 in Patients With High LDL-C or Low HDL-C; NCT01105975).

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.