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Effect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: Results of a phase IIb dose-ranging study.
MedLine Citation:
PMID:  22424025     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
BACKGROUND: Cholesteryl ester transfer protein (CETP) is involved in high-density lipoprotein (HDL) remodeling and transfer of lipids between HDL particles and other lipoproteins. Epidemiologic studies show that both elevated HDL-cholesterol (HDL-C) and reduced CETP activity attenuate cardiovascular risk, making inhibition or modulation of CETP a potential therapeutic target. This study analyzed the effect of dalcetrapib on lipoprotein profile, CETP activity, and cellular cholesterol efflux when co-administered with pravastatin in patients with low or average HDL-C.
METHODS: Patients were randomized in a double-blind fashion to receive placebo or dalcetrapib 300, 600, or 900 mg once daily for 12 weeks. All patients were concomitantly treated to their low-density lipoprotein cholesterol target with pravastatin. Lipoprotein profile was analyzed by nuclear magnetic resonance spectroscopy and polyacrylamide gradient gel electrophoresis. Composition of the HDL fraction was assessed after polyethylene glycol precipitation. Contribution of this fraction to cholesterol efflux was assessed using radiolabeled donor cells.
RESULTS: Co-administration of dalcetrapib with pravastatin increased HDL-C, apolipoproteins (apo) A-I and A-II, and CETP mass, and decreased CETP activity. A relative increase in large HDL and low-density lipoprotein subparticle fractions was observed. High-density lipoprotein composition showed increased association of esterified cholesterol, free cholesterol, phospholipids, apo A-I, and apo E. Adenosine 5'-triphosphate-binding cassette A1- and scavenger receptor type BI-mediated cholesterol efflux increased.
CONCLUSIONS: Dalcetrapib up to 600 mg, combined with pravastatin, increased HDL-C and altered lipoprotein profile, HDL composition, and HDL function, with little further change at a 900-mg dose. The impact on cardiovascular events in dyslipidemic patients is being evaluated.
Authors:
Christie M Ballantyne; Michael Miller; Eric J Niesor; Tracy Burgess; David Kallend; Evan A Stein
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  American heart journal     Volume:  163     ISSN:  1097-6744     ISO Abbreviation:  Am. Heart J.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-03-19     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0370465     Medline TA:  Am Heart J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  515-521.e3     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2012 Mosby, Inc. All rights reserved.
Affiliation:
Baylor College of Medicine, and Methodist DeBakey Heart and Vascular Center, Houston, TX.
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