ACCELERATE nested case-control study finds no significant ADCY9 genotype interaction with evacetrapib, unlike the dalcetrapib signal (JAMA Cardiol 2018)

Original title: ADCY9 Genetic Variants and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease: A Nested Case-Control Study

JAMA Cardiol · 1 May 2018 · 7

Nissen SE, Pillai SG, Nicholls SJ, Wolski K, Riesmeyer JS, Weerakkody GJ, Foster WM, McErlean E, Li L, Bhatnagar P, Ruotolo G, Lincoff AM

A pharmacogenetic analysis of dalcetrapib had reported that the ADCY9 gene variant rs1967309 associated with reduced major adverse cardiovascular events despite an overall neutral trial result, prompting this study to test whether the same association replicates for another CETP inhibitor, evacetrapib. A nested case-control study examined rs1967309 in 1,427 cases and 1,532 matched controls from the 12 092-patient ACCELERATE trial of evacetrapib 130 mg versus placebo. For the AA genotype, previously linked to benefit from dalcetrapib, the odds ratio for evacetrapib versus placebo was 0.88 (95% CI, 0.69 to 1.12); for AG, 1.04; and for GG, previously linked to harm from dalcetrapib, 1.18 (interaction P = .17, trend P = .06). After adjusting for cardiovascular risk factors, odds ratios were 0.93, 1.05 and 1.02 respectively (interaction P = .71, trend P = .59). The authors conclude this pharmacogenetic analysis found no significant ADCY9 SNP association with cardiovascular benefit or harm for evacetrapib, narrowing the earlier dalcetrapib signal toward a drug-specific rather than class-wide effect.

Original 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.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.