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March 13, 2018

Analysis From ACCELERATE Trial Evaluates ADCY9 Genetic Variants and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease

March 12, 2018—Steven E. Nissen, MD, presented findings from an analysis of the ACCELERATE trial of ADCY9 genetic variants and cardiovascular outcome with evacetrapib in a featured clinical research session at the American College of Cardiology's (ACC) 67th annual scientific session held March 10-12 in Orlando, Florida. The study was simultaneously published online in Journal of the American Medical Association (JAMA): Cardiology.

The background of the presentation is that large cardiovascular outcome trials have studied four drugs that inhibit cholesteryl ester transfer protein (CETP): torcetrapib, dalcetrapib, evacetrapib, and anacetrapib. The CETP inhibitors markedly raised high-density lipoprotein cholesterol levels, ranging from 30% to 130%. With the exception of dalcetrapib, these drugs also reduced low-density lipoprotein cholesterol levels, ranging from 21% to 37%. However, none of the four trials resulted in sufficiently favorable clinical benefits to support further development.

A pharmacogenetic analysis in 30% of patient in the dalcetrapib trial reported a strong association between a single nucleotide polymorphism (SNP) in the ADCY9 gene (rs1967309) and reduction in major cardiovascular events despite a neutral overall result. A new cardiovascular outcome trial is currently underway studying only the 17% of patients with the AA genotype that was reported to show benefit.

In the current analysis, the investigators sought to determine if this genetic association could be independently replicated for another cholesteryl ester transfer protein inhibitor, evacetrapib, in the ACCELERATE trial. They tested whether the association between the SNP in the ADCY9 gene and a reduction in major adverse cardiovascular events could be replicated with evacetrapib in patients with high-risk vascular disease.

As summarized by the investigators in JAMA: Cardiology, this nested case-control study examined the rs1967309 SNP in 1,427 cases and 1532 matched controls selected from the 12,092-patient ACCELERATE 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.

The primary analyses used a conditional logistic regression model to assess the odds ratio (OR) for major adverse cardiovascular events for evacetrapib 130 mg compared with placebo for each genotype. The basic model included adjustment for age, sex, and the top five principal components. An additional model included cardiovascular risk factors to adjust for potential bias in selecting control patients.

The primary major adverse cardiovascular event endpoint was the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.

The investigators found that the OR for evacetrapib compared with placebo was 0.88 (95% confidence interval [CI], 0.69–1.12) for patients with the AA genotype who had demonstrated a beneficial effect from dalcetrapib.

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 three 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.

The investigators concluded that the 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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