title: Cholesterol Efflux Capacity and Pre-Beta-1 HDL Concentrations Are Increased in Dyslipidemic Patients Treated With Evacetrapib.
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.
  
  
  OBJECTIVE
  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).
authors.affiliation: South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Nicholls
authors.affiliation: Cardiovascular Unit, Eli Lilly and Company, Indianapolis, Indianapolis.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Ruotolo
authors.affiliation: MedStar Heart & Vascular Institute, MedStar Health, Washington, DC.
authors.forename: H Bryan
authors.initials: HB
authors.lastname: Brewer
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, California.
authors.forename: John P
authors.initials: JP
authors.lastname: Kane
authors.affiliation: Cardiovascular Unit, Eli Lilly and Company, Indianapolis, Indianapolis.
authors.forename: Ming-Dauh
authors.initials: MD
authors.lastname: Wang
authors.affiliation: Cardiovascular Unit, Eli Lilly and Company, Indianapolis, Indianapolis.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Krueger
authors.affiliation: Vascular Strategies, LLC, Plymouth Meeting, Pennsylvania.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Adelman
authors.affiliation: Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Nissen
authors.affiliation: Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: rader@mail.med.upenn.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy*; D005260:Female; D053442:High-Density Lipoproteins, Pre-beta / Q000097:blood*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000924:Anticholesteremic Agents; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D053442:High-Density Lipoproteins, Pre-beta; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D001569:Benzodiazepines; C568301:evacetrapib; D002784:Cholesterol
keywords: apolipoproteins; cholesterol; lipoproteins