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J Am Coll Cardiol. 2015 Nov 17;66(20):2201-2210. doi: 10.1016/j.jacc.2015.09.013.

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

Author information

1
South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.
2
Cardiovascular Unit, Eli Lilly and Company, Indianapolis, Indianapolis.
3
MedStar Heart & Vascular Institute, MedStar Health, Washington, DC.
4
Cardiovascular Research Institute, University of California, San Francisco, California.
5
Vascular Strategies, LLC, Plymouth Meeting, Pennsylvania.
6
Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.
7
Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: rader@mail.med.upenn.edu.

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

PMID:
26564598
DOI:
10.1016/j.jacc.2015.09.013
[Indexed for MEDLINE]
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