Cholesterol Efflux Capacity and Pre-Beta-1 HDL Concentrations Are Increased in Dyslipidemic Patients Treated With Evacetrapib
Stephen J Nicholls, Giacomo Ruotolo, H Bryan Brewer, John P Kane, Ming-Dauh Wang, Kathryn A Krueger, Steven J Adelman, Steven E Nissen, Daniel J Rader, Stephen J Nicholls, Giacomo Ruotolo, H Bryan Brewer, John P Kane, Ming-Dauh Wang, Kathryn A Krueger, Steven J Adelman, Steven E Nissen, Daniel J Rader
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).
Keywords: apolipoproteins; cholesterol; lipoproteins.
Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Source: PubMed