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Response to dalcetrapib varied by genotype
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New research demonstrates that the effects of dalcetrapib on atherosclerotic outcomes may be affected by polymorphisms on the ADCY9 gene.
Dalcetrapib (F. Hoffmann-La Roche), a cholesterol ester transfer protein inhibitor developed to raise HDL, was not associated with improvement in clinical outcomes in the phase 3 dal-OUTCOMES trial. Researchers for the new study hypothesized that response to dalcetrapib may vary according to genetic profile.
Jean-Claude Tardif
Jean-Claude Tardif, MD, and colleagues performed a genetic study of 5,749 patients from the dal-OUTCOMES trial used as a discovery cohort, and a genetic study of 386 patients from the dal-PLAQUE-2 study used as a support cohort. The primary endpoint for the discovery cohort was a composite of CV events. The outcome of interest for the support cohort was change from baseline in carotid intima-media thickness based on ultrasonography at 6 and 12 months.
Tardif and colleagues reported an association between the effects of dalcetrapib and the genetic variant rs1967309 on the ADCY9 gene.
Patients with genotype AA at rs1967309 had a 39% reduction in composite CV events on dalcetrapib compared with placebo (HR=0.61; 95% CI, 0.41-0.92) and patients with genotype GG at rs1967309 had a 27% increase in composite CV events on dalcetrapib compared with placebo (HR=1.27; 95% CI, 1.02-1.58).
Ten variants in the ADCY9 gene, most in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on carotid intima-media thickness (P<.05). One marker in ADCY9, rs2238448, was associated with the effects of dalcetrapib on carotid intima-media thickness in the dal-PLAQUE-2 cohort (P=.009) and with CV events in the dal-OUTCOMES cohort (HR=0.67; 95% CI, 0.58-0.78).
“These results will lead to a genetics-guided clinical study in patients with the appropriate genetic background to allow review by health regulatory agencies and to provide personalized therapy with dalcetrapib,” Tardif, director of the research center at Montreal Heart Institute and professor of medicine at the University of Montreal, said in a press release. “It also offers great hope for precision treatments for patients with [CV] diseases and for curbing atherosclerosis, the first cause of mortality in the world.”
Disclosure: The dal-OUTCOMES and dal-PLAQUE-2 studies were funded by F. Hoffmann-La Roche. Two researchers are listed as authors on a patent filing based on these findings, and four researchers are employees of Roche.
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