Personalized Genetic Profile Determines Benefit of Dalcetrapib for Heart Disease

Jean-Claude Tardif MD Professor of Medicine Director of the Research Centre Montreal Heart Institute Montreal, Quebec Interview with:
Jean-Claude Tardif MD
Professor of Medicine
Director of the Research Centre
Montreal Heart Institute Montreal, Quebec Canada What is the background for this study? What are the main findings?

Dr. Tardif: Epidemiological and mechanistic studies have suggested that high-density lipoproteins (HDL) could have beneficial cardiovascular properties. However, several medications targeting HDL have failed in recent clinical trials, including the CETP inhibitor dalcetrapib in the dal-Outcomes trial. We hypothesized that dalcetrapib would be beneficial in the subset of patients with the appropriate genetic profile. We conducted the pharmacogenomic analysis of approximately 6000 patients from the dal-Outcomes study which showed that patients with the AA genotype at a specific genetic location (rs1967309) of the adenylate cyclase (ADCY9) gene benefited from a 39% reduction in cardiovascular events including cardiovascular death, myocardial infarction, stroke, unstable angina and the need for coronary revascularization when treated with dalcetrapib compared to placebo. In contrast, patients with the GG genotype had a 27% increase in cardiovascular events. We then obtained confirmatory evidence from the dal-Plaque-2 imaging study which revealed that patients with the protective genotype (AA) had a reduction in their carotid artery wall thickness and that those with the genotype associated with clinical harm (GG) had an increase in their wall thickness. What should clinicians and patients take away from your report?

Dr. Tardif: The effects of dalcetrapib on cardiovascular events are determined by the patients’ genetic profile, specifically polymorphisms in the ADCY9 gene. A dramatic reduction (39%) in cardiovascular events was observed when patients with the favorable genetic profile (AA at polymorphism rs1967309) were treated with dalcetrapib compared to placebo. What recommendations do you have for future research as a result of this study?

Dr. Tardif: We will launch the Dal-Gene clinical trial to test prospectively dalcetrapib in the population with the favorable genotype and allow review by health regulatory agencies and ultimately provide large benefits to patients with coronary artery disease.


Pharmacogenomic Determinants of the Cardiovascular Effects of Dalcetrapib

Jean-Claude Tardif, Éric Rhéaume, Louis-Philippe Lemieux Perreault, Jean C. Grégoire, Yassamin Feroz Zada, Géraldine Asselin, Sylvie Provost, Amina Barhdadi, David Rhainds, Philippe L. L’Allier, Reda Ibrahim, Ruchi Upmanyu, Eric J. Niesor, Renée Benghozi, Gabriela Suchankova, Fouzia Laghrissi-Thode, Marie-Claude Guertin, Anders G. Olsson, Ian Mongrain, Gregory G. Schwartz, and Marie-Pierre Dubé
Circ Cardiovasc Genet published January 11, 2015, doi:10.1161/CIRCGENETICS.114.000663

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Last Updated on January 15, 2015 by Marie Benz MD FAAD