👤 Fouzia Laghrissi-Thode

Acute coronary syndrome (ACS) survivors have heightened risk for subsequent cardiovascular events. 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. 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. 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. Show less

In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98). Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype. Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939. Show less

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3CL protease is a promising target for inhibition of viral replication by interaction with a cysteine residue (Cys145) at its catalytic site. Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of a cholesteryl ester transfer protein. Because 12 free cysteine residues are present in the 3CL protease, we investigated the potential of dalcetrapib to inhibit 3CL protease activity and SARS-CoV-2 replication. Molecular docking investigations suggested that dalcetrapib-thiol binds to the catalytic site of the 3CL protease with a delta Show less

Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome. In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4-12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68-0.88; In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib. Show less