Impact of ADCY9 Genotype on Response to Anacetrapib

Abstract

Background: Exploratory analyses of previous randomized trials generated a hypothesis that the clinical response to CETP inhibitor therapy differs by ADCY9 genotype, prompting the ongoing dal-GenE trial in individuals with a particular genetic profile. The randomized placebo-controlled REVEAL trial demonstrated the clinical efficacy of the CETP inhibitor anacetrapib among patients with pre-existing atherosclerotic vascular disease. In the present study, we have examined the impact of ADCY9 genotype on response to anacetrapib within the REVEAL trial.

Methods: Individuals with stable atherosclerotic vascular disease, who were treated with intensive atorvastatin therapy, received either anacetrapib 100 mg daily or matching placebo. Cox proportional hazards models, adjusted for the first 5 principal components of ancestry, were used to estimate the effects of allocation to anacetrapib on major vascular events (a composite of coronary death, myocardial infarction, coronary revascularization or presumed ischaemic stroke) and the interaction with ADCY9 rs1967309 genotype.

Results: Among 19,210 genotyped individuals of European ancestry, 2,504 (13.0%) had a first major vascular event during 4 years median follow-up: 1,216 (12.6%) among anacetrapib-allocated participants and 1,288 (13.4%) among placebo-allocated participants. Proportional reductions in the risk of major vascular events with anacetrapib did not differ significantly by ADCY9 genotype: HR = 0.92 (95% CI, 0.81-1.05) for GG; HR = 0.94 (95% CI, 0.84-1.06) for AG; and HR = 0.93 (95% CI, 0.76-1.13) for AA genotype carriers respectively; genotypic p for interaction = 0.96. Furthermore, there were no associations between ADCY9 genotype and the proportional reductions in the separate components of major vascular events, or meaningful differences in lipid response to anacetrapib.

Conclusions: The REVEAL trial is the single largest study to date evaluating the ADCY9 pharmacogenetic interaction. It provides no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of the CETP inhibitor anacetrapib. The ongoing dal-GenE study will provide direct evidence as to whether there is any specific pharmacogenetic interaction with dalcetrapib.

Clinical trial registration: URL: https://www.clinicaltrials.gov Unique Identifier: NCT01252953; URL: http://www.isrctn.com Unique Identifier: ISRCTN48678192; URL: https://www.clinicaltrialsregister.eu Unique Identifier: 2010-023467-18.

Keywords: CETP-inhibition; anacetrapib; major vascular events.

Figures

Figure 1.

Effects of anacetrapib on major vascular events, by ADCY9 genotype. Hazard ratios for each genotype are indicated by squares (size inversely proportional to the variance) with horizontal lines indicating 95% CIs. The hazard ratio and 95% CIs for all participants combined is indicated by a diamond.

Figure 2.

Clinical response to CETP inhibition in hypothesis-generating and hypothesis-testing trials, by ADCY9 genotype.P values are taken from published materials for individual studies and from chi-square tests for trend and heterogeneity across genotypes for the combined hypothesis testing studies. dal-OUTCOMES events include coronary heart disease death, resuscitated cardiac arrest, nonfatal myocardial infarction, atherothrombotic stroke, unstable angina with evidence of ischemia or unanticipated coronary revascularization. ACCELERATE events include cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. REVEAL events include coronary death, myocardial infarction, coronary revascularization or presumed ischemic stroke. ACCELERATE indicates Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes; CETP, cholesteryl ester transfer protein; and REVEAL, Randomized Evaluation of the Effects of Anacetrapib through Lipid-Modification.