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Aims: 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., Methods and Results: 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)., Conclusion: 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., Clinical Trial Registration: Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939., Competing Interests: Conflict of interest: J.C.T. has received research grant and honoraria from Amarin; research grant from AstraZeneca; research grant, honoraria, and minor equity interest from DalCor; research grant from Esperion; research grant from Ionis; research grant and honoraria from Sanofi; research grant and honoraria from Servier; a patent on pharmacogenomics-guided CETP inhibition was obtained, and J.C.T. and M.P.D. are mentioned as authors. M.P.D. has a minor equity interest in DalCor and has received honoraria from DalCor. M.A.P. receives research support from Novartis; he serves as a consultant for AstraZeneca, Corvidia, DalCor, GlaxoSmithKline, Jazz, MyoKardia, Novartis, Novo Nordisk, Roche, Sanofi, Servier, and Takeda; and has equity in DalCor. D.D.W. has received remuneration for participation in clinical trial committees from CSL Ltd, Daiichi Sankyo, DalCor, the Medicines Company, Novo Nordisk, Regeneron, Resverlogix, and Sanofi, and honoraria for lectures from DalCor and Pfizer. W.K. reports personal fees (consulting) from DalCor and consulting fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, Kowa, a Corvidia, Esperion, Genentech, Omeicos, Novo Nordisk, Daiichi Sankyo, and Amgen; personal fees (honorarium for lectures) from AstraZeneca, Novartis, Amgen, Sanofi, Bristol-Myers-Squibb, and Berlin-Chemie; grants and non-financial support (provision of reagents for biomarker measurements free of charge) from Roche Diagnostics, Beckmann, Singulex, and Abbott, outside the submitted work. A.P.M. has received personal fees for participation in study committee from DalCor, and personal fees for participation in study committees from AstraZeneca, Bayer, Novartis, and Fresenius. J.J.V.M. reports grants paid to his institution and fees as steering committee member from DalCor Pharma UK for the Dal-GenE study, during the conduct of the study; grants paid to his institution and fees as steering committee member from Oxford University and Bayer; grants paid to his institution from Theracos; grants paid to his institution and fees as steering committee from Abbvie; grants paid to his institution from Pfizer, Merck AstraZeneca, GlaxoSmithKline, and Novartis. J.W.J. and his department have received research grants from and/or was speaker (with or without lecture fees) in CME-accredited meetings sponsored by Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, The Medicine Company, The Netherlands Heart Foundation, CardioVascular Research The Netherlands (CVON), The Netherlands Heart Institute and the European Community Framework KP7 Programme. H.D.W. reports grants paid to his institution and fees as steering committee member from DalCor Pharma UK for the Dal-GenE study, during the conduct of the study; grants paid to his institution and fees as steering committee member from Sanofi-Aventis, Regeneron Pharmaceutics, National Institutes of Health (USA), CSL Behring, American Regent, Sanofi-Aventis Australia Pty Ltd, and Esperion Therapeutics Inc, outside the submitted work. F.L.T., T.H., and D.M.B. are employed by and have minor equity interest in DalCor. Other authors report no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Background: High-density lipoprotein cholesterol (HDL-C) concentration is inversely related to risk of major adverse cardiovascular events (MACE) in epidemiologic studies but is a poorer predictor of MACE in patients with established coronary heart disease. HDL particle concentration (HDLP) has been proposed as a better predictor of risk. We investigated whether HDLP is associated with risk of MACE after acute coronary syndrome (ACS)., Methods: The dal-Outcomes trial compared the CETP inhibitor dalcetrapib with placebo in patients with recent ACS. In a nested case-cohort analysis, total, large, medium, and small HDLPs were measured by nuclear magnetic resonance spectroscopy at baseline (4-12 weeks after ACS) in 476 cases with MACE and 902 controls. Hazard ratios (HRs; case-control) for 1-SD increment of HDLP or HDL-C at baseline were calculated with and without adjustment for demographic, clinical, laboratory, and treatment variables. Similarly, HRs for MACE were calculated for changes in HDLP or HDL-C from baseline to month 3 of assigned treatment., Results: Over median follow-up of 28 months, the risk of MACE was not associated with baseline HDLP (adjusted HR = 0.98, 95% CI = 0.84-1.15, P = .81), any HDLP subclass, or HDL-C. Dalcetrapib increased HDL-C and total, medium, and large HDLP and decreased small HDLP but had no effect on MACE compared with placebo. There were no association of risk of MACE with change in HDLP or HDL-C and no interaction with assigned study treatment., Conclusions: Neither baseline HDLP nor the change in HDLP on treatment with dalcetrapib or placebo was associated with risk of MACE after ACS., (Published by Elsevier Inc.)

The cholesterol ester transfer protein (CETP) inhibitor dalcetrapib has been under evaluation for its potential to prevent cardiovascular (CV) events for almost two decades. The current clinical development program, representing new advances in precision medicine and focused on a genetically defined population with acute coronary syndrome (ACS), is supported by a large body of pharmacokinetic and pharmacodynamic data as well as substantial clinical experience in over 13,000 patients and volunteers. Dalcetrapib treatment of 600 mg/day produces significant inhibition of CETP activity, and has been utilized in phase II and III studies, including CV endpoint trials. Numerous studies have investigated the interactions between dalcetrapib and most drugs commonly prescribed to CV patients and have not demonstrated any clinically significant effects. Evaluations in patients with renal and hepatic impairment demonstrate a greater exposure to dalcetrapib than in the non-impaired population, but long-term clinical studies including patients with mild to moderate hepatic and renal dysfunction demonstrate no increase in adverse events. Safety pharmacology and toxicology studies as well as the clinical safety experience support the continuing development of dalcetrapib as an adjunct to 'standard of care' for the ACS population. This article provides a full review of the pharmacokinetics, as well as pharmacodynamics and pharmacology, of dalcetrapib in the context of a large clinical program.

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.

Objective: 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.Research Design and Methods: 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 A1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A1c ≥6.5%, or a combination of at least two measurements of serum glucose ≥7.0 mmol/L (fasting) or ≥11.1 mmol/L (random).Results: 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; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes.Conclusions: In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib. [ABSTRACT FROM AUTHOR]