Genetic Analysis of Evacetrapib Outcomes Fails to Confirm Findings with Dalcetrapib

The significant association between the ADCY9 genetic variant and reduced cardiovascular events observed with dalcetrapib could not be replicated in a pharmacogenetic analysis of patients from the ACCELERATE trial of fellow CETP inhibitor evacetrapib, reported a Cleveland Clinic-led research team.

The finding leaves the nature of the pharmacogenetic relationships reported for dalcetrapib uncertain pending results of the ongoing cardiovascular outcome trial of dalcetrapib in patients with the AA genotype, noted the senior author of the ACCELERATE analysis, Steven Nissen, MD, in a late-breaking trial presentation March 11 at the American College of Cardiology’s 67th Scientific Session. The analysis was simultaneously published online by JAMA Cardiology.

“Genome-wide association studies are now commonly performed for large outcome trials,” said Dr. Nissen, Chair of Cardiovascular Medicine at Cleveland Clinic. “Replication of results is a key component required to confirm preliminary findings, which is why we conducted this analysis.”

Study backdrop

The results his team sought to replicate were from a 2015 post hoc genetic analysis (Circ Cardiovasc Genet. 2015;8:372-382) of the large cardiovascular outcome trial of dalcetrapib. That analysis suggested an association between a single-nucleotide polymorphism (SNP) in the ADCY9 gene on chromosome 16 (rs1967309) and cardiovascular outcomes. Specifically, patients with the AA genotype who received dalcetrapib had a 39 percent reduction in the primary composite cardiovascular end point relative to placebo, while patients with the GG genotype had a 27 percent increase in the primary end point.

This finding prompted initiation of an ongoing cardiovascular outcome trial, known as dal-GenE (NCT02525939), to evaluate the cardiovascular effects of dalcetrapib relative to placebo exclusively in patients with the AA genotype.

Investigation of dalcetrapib in this subpopulation has been pursued against the backdrop of the failure of four different CETP inhibitors — torcetrapib, dalcetrapib, evacetrapib and anacetrapib — to exhibit any significant positive effect on major adverse cardiovascular events (MACE) in large outcome trials.

“Studies like the genetic analysis of the dalcetrapib trial might identify a subgroup of patients who show a more favorable response to therapy, but they also raise the risk of false discovery,” stated Dr. Nissen.

So his team used a nested case-control study design to draw on the large ACCELERATE outcome trial of evacetrapib (summarized in this previous post) to see if genetic findings similar to those with dalcetrapib could be detected with evacetrapib. Both ACCELERATE and the current analysis were directed by the Cleveland Clinic Coordinating Center for Clinical Research (C5Research).

Design of the current analysis

ACCELERATE randomized 12,092 patients with high-risk vascular disease to evacetrapib or placebo. The trial was terminated for futility after 1,555 final primary MACE had occurred (hazard ratio = 1.01; 95% CI, 0.91-1.11).

In the present analysis, genotyping (using the Axiom Biobank™ assay) was performed in 1,427 ACCELERATE enrollees who had experienced events (719 evacetrapib recipients and 708 placebo recipients) and 1,532 matched ACCELERATE enrollees who had not (controls; 763 evacetrapib recipients and 769 placebo recipients).

The primary end point was the odds ratio (OR) for five MACE components (death from cardiovascular causes, myocardial infarction [MI], stroke, coronary revascularization and hospitalization for unstable angina) comparing evacetrapib and placebo for each genotype using conditional logistic regression analysis. The model included adjustment for age, sex and the five principal components. An additional model adjusted for cardiovascular risk factors.

Results

For patients with the AA genotype (which was associated with benefit in the dalcetrapib genetic analysis), the unadjusted OR for five-component MACE comparing evacetrapib with placebo was 0.88 (95% CI, 0.69-1.12). After adjustment for cardiovascular risk factors, the OR was 0.93 (95% CI, 0.73-1.19).

The five-component MACE end point demonstrated a directional trend across genotypes that was similar to findings with dalcetrapib, but this trend was no longer evident after adjusting for cardiovascular risk factors or for the three-component MACE end point (death from cardiovascular causes, MI or stroke) that served as the key secondary end point from ACCELERATE.

Genetic effects of each minor (A) allele showed no significant relationship to cardiovascular outcomes.

For final word, look to the outcome trial

Dr. Nissen noted that the ability to compare these evacetrapib findings with those from the genetic analysis of dalcetrapib is limited in several ways. These include potential differences in the two CETP inhibitors’ on- or off-target drug effects and the fact that dalcetrapib was studied in patients with acute coronary syndrome whereas evacetrapib was studied in individuals with high-risk vascular disease.

Yet he added that a strength of the current evacetrapib analysis is that it had nearly three times the number of events in genotyped patients as did the dalcetrapib analysis. “The larger numbers may provide more reliable estimates of genotyped frequencies,” he said.

The biggest takeaway, he noted, is that clarity will rest on the dal-GenE outcome trial of dalcetrapib. “Whether the pharmacogenetic relationships reported for dalcetrapib represent a paradigm-shifting discovery or a false signal awaits the results of the current outcome trial in patients with the AA genotype,” he concluded.