Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib

Tardif, J.-C. et al. (2020) Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib. American Heart Journal, 222, pp. 157-165. (doi: 10.1016/j.ahj.2020.01.007) (PMID:32087417)

Abstract

The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene. [Abstract copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.]

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McMurray, Professor John
• Authors: Tardif, J.-C., Dubé, M.-P., Pfeffer, M. A., Waters, D. D., Koenig, W., Maggioni, A. P., McMurray, J. J.V., Mooser, V., White, H. D., Heinonen, T., Black, D. M., and Guertin, M.-C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: American Heart Journal
• Publisher: Elsevier
• ISSN: 0002-8703
• ISSN (Online): 1097-6744
• Published Online: 17 January 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in American Heart Journal 222:157-165
• Publisher Policy: Reproduced under a Creative Commons License