Pharmacogenomic Determinants of the Cardiovascular Effects of Dalcetrapib

Abstract

H igh-density lipoprotein (HDL)-based therapies have yielded disappointing results, [1][2][3][4] which have led to questioning of the HDL hypothesis. Cholesteryl ester transfer protein mediates the transfer of cholesteryl esters from HDL to apolipoprotein B-containing particles, such as low-density lipoproteins (LDLs).5 Torcetrapib, the first cholesteryl ester transfer protein inhibitor to be evaluated in a large clinical trial, caused excess morbidity and mortality despite increasing HDL-cholesterol levels by ≈70% although elevations of aldosterone levels and blood pressure observed in some patients may have contributed to the negative findings.3 Dalcetrapib is another cholesteryl ester transfer protein inhibitor that raises HDL-cholesterol levels by ≈30%, without effects on circulating neurohormones. 6 The dal-OUTCOMES trial was designed to test whether dalcetrapib could modify cardiovascular risk in patients with a recent acute coronary syndrome. 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 Tardif et al Pharmacogenomic Determinants of Dalcetrapib 373Dalcetrapib failed to improve clinical outcomes among the 15 871 patients of the dal-OUTCOMES study, with no subgroups defined by baseline clinical or biochemical characteristics appearing to benefit from therapy. 4 These results are ...

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…218 In a recent post hoc analysis of the dal-OUTCOMES trial, Tardif et al revealed that genetic differences in the adenylate cyclase 9 (ADCY9) locus stratifies recipients of dalcetrapib towards cardiovascular outcome. 219 Dalcetrapib treatment decreased the cardiovascular event rate by 39% in patients with the AA genotype at rs1967309 but increased cardiovascular event rates by 27% in patients with the GG genotype. 219 The ADCY9 gene encodes an adenylate cyclase that catalyzes the formation of the signaling molecule cAMP from ATP.…”

“…219 Dalcetrapib treatment decreased the cardiovascular event rate by 39% in patients with the AA genotype at rs1967309 but increased cardiovascular event rates by 27% in patients with the GG genotype. 219 The ADCY9 gene encodes an adenylate cyclase that catalyzes the formation of the signaling molecule cAMP from ATP. Since cAMP regulates ABCA1, Tardiff et al…”

Are Genetic Tests for Atherosclerosis Ready for Routine Clinical Use?

“…One recent example, which has yet to be successfully replicated, is a genetic reanalysis of neutral trial data for dalcetrapib, which claimed a significant effect interaction with treatment by genotype. 139 Until such effects are tested in further prospective trials, it is unclear whether such post hoc hypothesis-free stratification of trial results on the basis of genome-wide scanning will represent a wild goose chase or evolve into a useful new tool for drug development.…”

Biomarkers in Pharmaceutical Research

“…Multiple large-scale array-based profiling technologies can be used to conduct these studies. One example is the recent identification of genomic determinants of cardiovascular effects of the cholesteryl ester transfer protein inhibitor dalcetrapib (48 ). Tardif and colleagues conducted a genome-wide association study in the phase 3 clinical trial dal-OUTCOMES (efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome) and a targeted genotyping in the dal-PLAQUE-2 [dalcetrapib and plaque imaging in 2 vascular beds (a study of the effect of dalcetrapib on artherosclerotic disease in patients with coronary artery disease)] imaging trial.…”