Dalcetrapib Benefits Genetic Subgroup of ACS Patients: Analysis

January 22, 2015

MONTREAL, QC — Data from a pharmacogenomic analysis hints at the possibility that dalcetrapib, which boosts levels of HDL cholesterol but didn't seem to affect the risk of cardiovascular events in a large morbidity and mortality trial, might still have clinical benefits.

In a new genetic analysis of the dal-OUTCOMES trial, as well as the dal-PLAQUE-2 imaging study, investigators suggest a benefit of dalcetrapib might exist in a group of patients with a certain genetic profile. Specifically, individuals homozygous for variant in the ADCY9 gene responded positively to dalcetrapib and experienced a significant reduction in cardiovascular risk when treated with the cholesteryl ester transfer protein (CETP) inhibitor.

"This pharmacogenomic study demonstrates that cardiovascular responses to dalcetrapib are determined by the genetic profile of patients with coronary artery disease," according to lead investigator Dr Jean-Claude Tardif (Montreal Heart Institute, QC). "Indeed, several polymorphisms in the ADCY9 gene influenced the effects of dalcetrapib on cardiovascular clinical outcomes and changes over time in carotid atherosclerosis."

As reported previously by heartwire , the dal-OUTCOMES study, which was published in 2012 in the New England Journal of Medicine, showed dalcetrapib raised HDL-cholesterol levels 30% but did not reduce clinical events among the nearly 8000 ACS patients who received the drug.

In their genomewide-association study, which is published January 12, 2015 in Circulation: Cardiovascular Genetics, the researchers identified a single nucleotide polymorphism (SNP) on chromosome 16 in ADCY9 that was associated with cardiovascular events among patients treated with dalcetrapib (rs1967309).

When they stratified by genotypes in the dalcetrapib arm, individuals homozygous with the AA genotype (minor allele) in ADCY9 had a statistically significant 39% relative reduction in the risk of the composite end point of coronary heart disease death, resuscitated cardiac arrest, nonfatal MI, nonfatal stroke, unstable angina, or urgent coronary revascularization compared with placebo. For homozygous wild-type patients with the GG genotype (major allele), there was a significant 27% increase in risk. For those with the AG genotype, these heterozygous patients had a nonsignificant intermediate response to therapy.

Next, the researchers evaluated samples from the dal-PLAQUE-2 study, an imaging trial showing that dalcetrapib did not positively alter atherosclerosis as measured by carotid intima-media thickness (IMT). Again, individuals homozygous for rs1967309 showed a significant reduction in IMT when treated with dalcetrapib. In contrast, the ACS patients with a wild-type genotype showed a progression in coronary atherosclerosis.

The researchers say that patients homozygous with the protective genotype made up approximately 20% of the participants in the dal-OUTCOMES study. They are currently in the planning stages of a genetics-based clinical trial conducted in patients responsive to dalcetrapib that would prospectively test the CETP inhibitor once again. As Tardif and colleagues point out, a successful outcome in such a trial would open the door for personalized cardiovascular therapy.

Dalcetrapib was the second CETP inhibitor to fail in clinical development. As reported previously by heartwire , torcetrapib was abandoned when studies showed it appeared to increase the risk of cardiovascular events despite substantially increasing HDL-cholesterol levels.

The dal-OUTCOMES and dal-PLAQUE-2 studies were funded by Hoffman-La Roche. A patent was submitted based on these findings and Tardif is mentioned as an author. Disclosures for the coauthors are listed in the article.

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