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Original Investigation
May 2018

ADCY9 Genetic Variants and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular DiseaseA Nested Case-Control Study

Author Affiliations
  • 1The Cleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
  • 2Eli Lilly, Indianapolis, Indiana
  • 3South Australian Heart and Medical Research Institute, University of Adelaide, Adelaide, Australia
  • 4School of Medical Sciences, University of New South Wales, Sydney, Australia
  • 5BioStat Solutions Inc, Frederick, Maryland
JAMA Cardiol. 2018;3(5):401-408. doi:10.1001/jamacardio.2018.0569
Key Points

Question  Does the rs1967309 single-nucleotide polymorphism, reported to show a strong interaction for dalcetrapib, influence cardiovascular outcomes for patients treated with the cholesteryl ester transfer inhibitor evacetrapib?

Findings  In this nested case-control study, this single-nucleotide polymorphism was examined in 1427 cases and 1532 matched controls selected from the 12 092–patient evacetrapib cardiovascular outcome trial. The conditional logistic regression odds ratio for major adverse cardiovascular events for evacetrapib-treated patients with the AA genotype was not significant.

Meaning  Although directionally similar to the dalcetrapib analysis, there was no significant interaction between genotype and cardiovascular outcome with evacetrapib.

Abstract

Importance  A pharmacogenetic analysis of dalcetrapib, a cholesteryl ester transfer protein inhibitor, reported an association between a single-nucleotide polymorphism (SNP) in the ADCY9 gene (rs1967309) and reduction in major adverse cardiovascular events despite a neutral result for the overall trial.

Objective  To determine whether the association between the SNP in the ADCY9 gene and a reduction in major adverse cardiovascular events could be replicated for another cholesteryl ester transfer protein inhibitor, evacetrapib, in patients with high-risk vascular disease.

Design, Setting, and Participants  A nested case-control study examining the rs1967309 SNP in 1427 cases and 1532 matched controls selected from the 12 092–patient Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial, a randomized, double-blind, placebo-controlled phase 3 trial conducted in patients with high-risk vascular disease randomized from October 2012 through December 2013. The genotyping was conducted from January 2017 to March 2017, and the data analyses were conducted from July 2017 to November 2017.

Exposures  Evacetrapib, 130 mg, or matching placebo.

Main Outcomes and Measures  The primary analyses used a conditional logistic regression model to assess the odds ratio (OR) for major adverse cardiovascular events for evacetrapib compared with placebo for each genotype. The basic model included adjustment for age, sex, and the top 5 principal components. An additional model included cardiovascular risk factors to adjust for potential bias in selecting control patients. The primary major adverse cardiovascular event end point was the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.

Results  For patients with the AA genotype reported to demonstrate a beneficial effect from dalcetrapib, the OR for evacetrapib compared with placebo was 0.88 (95% CI, 0.69-1.12). For patients with the AG genotype, the OR was 1.04 (95% CI, 0.90-1.21). For patients with the GG genotype reported to show evidence for a harmful effect from dalcetrapib, the OR for evacetrapib was 1.18 (95% CI, 0.98-1.41). The interaction P value among the 3 genotypes was P = .17 and the trend P value was P = .06. When adjusted for cardiovascular risk factors, the OR for evacetrapib was 0.93 (95% CI, 0.73-1.19) for the AA genotype, 1.05 (95% CI, 0.91-1.22) for the AG genotype, and 1.02 (95% CI 0.85-1.24) for the GG genotype; interaction P = .71 and trend P = .59.

Conclusions and Relevance  Pharmacogenetic analysis did not show a significant association between the ADCY9 SNP (rs1967309) and cardiovascular benefit or harm for the cholesteryl ester transfer protein inhibitor evacetrapib.

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