Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib

Circ Cardiovasc Genet. 2015 Apr;8(2):372-82. doi: 10.1161/CIRCGENETICS.114.000663. Epub 2015 Jan 11.

Abstract

Background: Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting high-density lipoprotein as a therapeutic target. Responses to dalcetrapib may vary according to patients' genetic profile.

Methods and results: We conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single-nucleotide polymorphism was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P=2.41×10(-8)), with 8 polymorphisms providing P<10(-6) in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.41-0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten single-nucleotide polymorphism in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness (P<0.05). Marker rs2238448 in ADCY9, in linkage disequilibrium with rs1967309 (r(2)=0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 (P=0.009) and events in dal-OUTCOMES (P=8.88×10(-8); hazard ratio, 0.67; 95% confidence interval, 0.58-0.78).

Conclusions: The effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the ADCY9 gene.

Clinical trial information: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00658515 and NCT01059682.

Keywords: cholesteryl ester transfer protein; dalcetrapib; high-density lipoproteins; pharmacogenetics.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / genetics*
  • Aged
  • Atherosclerosis* / diagnostic imaging
  • Atherosclerosis* / drug therapy
  • Atherosclerosis* / genetics
  • Carotid Intima-Media Thickness
  • Chromosomes, Human, Pair 16 / genetics*
  • Female
  • Humans
  • Linkage Disequilibrium*
  • Male
  • Middle Aged
  • Pharmacogenetics*
  • Polymorphism, Genetic*
  • Sulfhydryl Compounds / administration & dosage*

Substances

  • Sulfhydryl Compounds
  • dalcetrapib
  • Adenylyl Cyclases
  • adenylate cyclase 9

Associated data

  • ClinicalTrials.gov/NCT00658515
  • ClinicalTrials.gov/NCT01059682