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Circ Cardiovasc Genet. 2016 Aug;9(4):340-8. doi: 10.1161/CIRCGENETICS.116.001405. Epub 2016 Jul 14.

Genotype-Dependent Effects of Dalcetrapib on Cholesterol Efflux and Inflammation: Concordance With Clinical Outcomes.

Author information

1
From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.). jean-claude.tardif@icm-mhi.org marie-pierre.dube@umontreal.ca.
2
From the Montreal Heart Institute (J.-C.T., D.R., M. Brodeur, M. Boulé, S.A., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal, Faculty of Medicine (J.-C.T., J.C.G., P.L.L., R.I., E.R., M.-P.D.), Université de Montréal Beaulieu-Saucier Pharmacogenomics Center (Y.F.Z., R.F., S.P., I.M., M.-P.D.), Montreal Health Innovations Coordinating Center (MHICC) (M.-C.G.), Montreal, Canada; Linkoping University, Department of Medicine and Health, Stockholm, Sweden (A.G.O.); and Veterans Affairs Medical Center & University of Colorado, School of Medicine, Denver, CO (G.G.S.).

Abstract

BACKGROUND:

Dalcetrapib effects on cardiovascular outcomes are determined by adenylate cyclase 9 gene polymorphisms. Our aim was to determine whether these clinical end point results are also associated with changes in reverse cholesterol transport and inflammation.

METHODS AND RESULTS:

Participants of the dal-OUTCOMES and dal-PLAQUE-2 trials were randomly assigned to receive dalcetrapib or placebo in addition to standard care. High-sensitivity C-reactive protein was measured at baseline and at end of study in 5243 patients from dal-OUTCOMES also genotyped for the rs1967309 polymorphism in adenylate cyclase 9. Cholesterol efflux capacity of high-density lipoproteins from J774 macrophages after cAMP stimulation was determined at baseline and 12 months in 171 genotyped patients from dal-PLAQUE-2. Treatment with dalcetrapib resulted in placebo-adjusted geometric mean percent increases in high-sensitivity C-reactive protein from baseline to end of trial of 18.1% (P=0.0009) and 18.7% (P=0.00001) in participants with the GG and AG genotypes, respectively, but the change was -1.0% (P=0.89) in those with the protective AA genotype. There was an interaction between the treatment arm and the genotype groups (P=0.02). Although the mean change in cholesterol efflux was similar among study arms in patients with GG genotype (mean: 7.8% and 7.4%), increases were 22.3% and 3.5% with dalcetrapib and placebo for those with AA genotype (P=0.005). There was a significant genetic effect for change in efflux for dalcetrapib (P=0.02), but not with placebo.

CONCLUSIONS:

Genotype-dependent effects on C-reactive protein and cholesterol efflux are supportive of dalcetrapib benefits on atherosclerotic cardiovascular outcomes in patients with the AA genotype at polymorphism rs1967309.

CLINICAL TRIALS REGISTRATION:

ClinicalTrials.gov; Unique Identifiers: NCT00658515 and NCT01059682.

KEYWORDS:

C-reactive protein; HDL; cholesterol efflux; dalcetrapib; pharmacogenetics

PMID:
27418594
PMCID:
PMC4982759
DOI:
10.1161/CIRCGENETICS.116.001405
[Indexed for MEDLINE]
Free PMC Article

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