dal-GenE: the MI benefit of dalcetrapib in ADCY9 AA-genotype patients survives adjustment for an 18-variable risk prediction index (Eur J Prev Cardiol 2025)

Original title: Future myocardial infarction after an acute coronary syndrome and pharmacogenetic response to dalcetrapib

Eur J Prev Cardiol · 14 October 2025 · 7

Tardif JC, Pfeffer MA, Kouz S, Koenig W, Maggioni AP, McMurray JJV, Waters DD, Jukema JW, White HD, Heinonen T, Kallend D, Laghrissi-Thode F et al.

Using data from the Dal-Outcomes and Dal-GenE dalcetrapib trials, the authors built a prediction index for future myocardial infarction after acute coronary syndrome from Dal-Outcomes placebo patients (n = 7,086), settling on 18 of 36 candidate baseline variables (Harrell's C-index 0.72, 95% CI, 0.69 to 0.75), including prior coronary events, LDL-C, blood pressure, A1c, hs-CRP, smoking and age. Applied to the 5,989 Dal-GenE participants carrying the AA genotype at rs1967309 in ADCY9, the index was strongly predictive of MI (hazard ratio 1.92 per SD increase, 95% CI, 1.78 to 2.08). After adjusting for the prediction index, dalcetrapib still reduced MI versus placebo in these AA-genotype patients (hazard ratio 0.77, 95% CI, 0.63 to 0.94), independent of the other risk markers. The pharmacogenetic MI-reduction signal for dalcetrapib in ADCY9 AA carriers holds up under adjustment; a follow-up Dal-GenE 2 trial is designed to confirm the hypothesis prospectively.

Original abstract

Background: Acute coronary syndrome (ACS) survivors have heightened risk for subsequent cardiovascular events.

Methods: All baseline characteristics collected in both the Dal-Outcomes and Dal-GenE trials were considered as potential risk markers. A prediction index for subsequent fatal and non-fatal myocardial infarction (MI) following ACS was developed using Cox proportional hazards modeling on data from Dal-Outcomes placebo patients (n=7086). This prediction index was then applied in all Dal-GenE participants (n=5989) to determine whether the reduction in MI observed with dalcetrapib (versus placebo) in patients with the AA genotype at rs1967309 in the ADCY9 gene remained significant, independent of the other markers integrated into the prediction index.

Results: Of the 36 baseline variables considered as potential risk markers, 18 contributed to the prediction index with a Harrell's C-index of 0.72 (95% CI, 0.69-0.75) in Dal-Outcomes placebo patients. Prior history of coronary events, LDL-C, blood pressure, A1c, hs-CRP, smoking and age were contributors. The prediction index was strongly predictive when applied to the 5989 AA genotype patients from Dal-GenE, with a HR for MI of 1.92 (95%CI: 1.78-2.08) for each SD increase in score. When adjusting for the prediction index, the HR for dalcetrapib versus placebo was 0.77 (95% CI, 0.63-0.94) in Dal-GenE.

Conclusion: Despite guideline directed therapy following ACS, history of prior coronary events and on-treatment LDL-C, A1c, hs-CRP and blood pressure remain determinants of future MI. In the Dal-GenE AA genotype patients, dalcetrapib reduced the rate of MI, independently of those variables. The Dal-GenE 2 trial is designed to confirm this pharmacogenetic hypothesis.

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