Clopidogrel-Mediated P2Y12 Inhibition According to Renal Function in Patients With Diabetes Mellitus and CAD

• Published in: JACC. Basic to translational science 2024-07, Vol.9 (7), p.865-876
• Main Authors: Ortega-Paz, Luis, Franchi, Francesco, Rollini, Fabiana, Galli, Mattia, Been, Latonya, Ghanem, Ghussan, Shalhoub, Awss, Ossi, Tiffany, Rivas, Andrea, Zhou, Xuan, Pineda, Andres M., Suryadevara, Siva, Soffer, Daniel, Zenni, Martin M., Mahowald, Madeline K., Langaee, Taimour, Jakubowski, Joseph A., Cavallari, Larisa H., Angiolillo, Dominick J.
• Format: Article
• Language: English
• Subjects: chronic kidney disease; clopidogrel; coronary artery disease; diabetes mellitus; Original Research - Clinical; pharmacodynamic; pharmacokinetic; platelets
• ISSN: 2452-302X; 2452-302X
• DOI: 10.1016/j.jacbts.2024.03.003

[Display omitted] •Patients with DM have impaired clopidogrel-mediated platelet P2Y12 inhibition, exacerbated if CKD is present.•Potential mechanism(s) include altered drug absorption and/or metabolism and/or platelet P2Y12 activity.•CKD was associated with increased maximal platelet aggregation, which was not reflected in differences in the PRI or PRUs.•These findings could be attributed partially to upregulation of the P2Y12 signaling pathway but not to differences in drug absorption or metabolism.•Further studies are needed to determine the mechanism(s) by which CKD can lead to upregulation of P2Y12 signaling activity in DM patients. This prospective ex vivo and in vitro pharmacodynamic (PD)/pharmacokinetic investigation was conducted in patients with diabetes mellitus with (n = 31) and without chronic kidney disease (n = 30). PD assessments included platelet reactivity index, maximum platelet aggregation, and P2Y12 reaction units. Ex vivo pharmacokinetic assessments included plasma levels of clopidogrel and its active metabolite. In vitro PD assessments were conducted on baseline samples incubated with escalating concentrations of clopidogrel and its active metabolite. Among patients with diabetes mellitus treated with clopidogrel, impaired renal function was associated with increased maximum platelet aggregation. This finding could be attributed partially to upregulation of the P2Y12 activity without differences in drug absorption or metabolism. (Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus; NCT03774394)