Pharmacogenomic Determinants of the Cardiovascular Effects of Dalcetrapib
Background—Dalcetrapib did not improve clinical outcomes despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting HDL 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 SNP 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 eight 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 to placebo (HR=0.61; 95%CI 0.41, 0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten SNPs 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 (r2=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; HR=0.67, 95%CI 0.58, 0.78).
Conclusions—The effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the ADCY9 gene.
- cholesteryl ester transfer protein
- cardiovascular pharmacogenomics
- high-density lipoprotein
- Received May 6, 2014.
- Revision received December 11, 2014.
- Accepted December 16, 2014.