Discovery study links the ADCY9 rs1967309 polymorphism to a 39% cardiovascular benefit from dalcetrapib (Circ Cardiovasc Genet 2015)

Original title: Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib

Circ Cardiovasc Genet · 11 January 2015 · 9

Tardif JC, Rhéaume E, Lemieux Perreault LP, Grégoire JC, Feroz Zada Y, Asselin G, Provost S, Barhdadi A, Rhainds D, L'Allier PL, Ibrahim R, Upmanyu R et al.

Although dalcetrapib raised HDL cholesterol by 30% in the dal-OUTCOMES trial, it did not improve clinical outcomes overall. This pharmacogenomic study used a genome-wide approach in the dal-OUTCOMES discovery cohort (n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging cohort (n=386) to test whether genetics explain the neutral result. A polymorphism in the ADCY9 gene on chromosome 16 (rs1967309) was significantly associated with cardiovascular events in the dalcetrapib arm (P=2.41x10-8), with 8 additional ADCY9 polymorphisms reaching P<10-6. Patients with the AA genotype had a 39% reduction in the composite cardiovascular endpoint with dalcetrapib versus placebo (hazard ratio, 0.61; 95% CI, 0.41-0.92), while GG-genotype patients had a 27% increase in events. Ten ADCY9 polymorphisms were also associated with the effect of dalcetrapib on carotid intima-media thickness (P<0.05), and marker rs2238448 was linked to both intima-media thickness in dal-PLAQUE-2 (P=0.009) and events in dal-OUTCOMES (P=8.88x10-8; hazard ratio, 0.67; 95% CI, 0.58-0.78), establishing that ADCY9 genotype determines the atherosclerotic outcome effects of dalcetrapib.

Original abstract

Background: Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting high-density lipoprotein as a therapeutic target. Responses to dalcetrapib may vary according to patients' genetic profile.

Methods And Results: We conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single-nucleotide polymorphism was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P=2.41×10(-8)), with 8 polymorphisms providing P<10(-6) in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.41-0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten single-nucleotide polymorphism in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness (P<0.05). Marker rs2238448 in ADCY9, in linkage disequilibrium with rs1967309 (r(2)=0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 (P=0.009) and events in dal-OUTCOMES (P=8.88×10(-8); hazard ratio, 0.67; 95% confidence interval, 0.58-0.78).

Conclusions: The effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the ADCY9 gene.

Clinical Trial Information: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00658515 and NCT01059682.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.