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

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

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.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adenylyl Cyclases / genetics
  • Adenylyl Cyclases / metabolism
  • Aged
  • Animals
  • Anticholesteremic Agents / adverse effects
  • Anticholesteremic Agents / therapeutic use*
  • Atherosclerosis / blood
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / enzymology
  • Atherosclerosis / genetics
  • Biomarkers / blood
  • C-Reactive Protein / metabolism
  • Cell Line
  • Cholesterol / blood*
  • Cholesterol Ester Transfer Proteins / antagonists & inhibitors
  • Cholesterol Ester Transfer Proteins / metabolism
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Double-Blind Method
  • Dyslipidemias / blood
  • Dyslipidemias / drug therapy*
  • Dyslipidemias / enzymology
  • Dyslipidemias / genetics
  • Female
  • Humans
  • Inflammation / blood
  • Inflammation / drug therapy*
  • Inflammation / enzymology
  • Inflammation / genetics
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Male
  • Mice
  • Middle Aged
  • Pharmacogenetics
  • Pharmacogenomic Variants
  • Polymorphism, Single Nucleotide
  • Sulfhydryl Compounds / adverse effects
  • Sulfhydryl Compounds / therapeutic use*
  • Time Factors
  • Treatment Outcome

Substances

  • Anticholesteremic Agents
  • Biomarkers
  • CETP protein, human
  • Cholesterol Ester Transfer Proteins
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Sulfhydryl Compounds
  • dalcetrapib
  • C-Reactive Protein
  • Cholesterol
  • Adenylyl Cyclases
  • adenylate cyclase 9

Associated data

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