Impaired Responsiveness to the Platelet P2Y12 Receptor Antagonist Clopidogrel in Patients With Type 2 Diabetes and Coronary Artery Disease
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Background Several studies have shown that patients with diabetes mellitus (DM) exhibit an impaired response to clopidogrel. This may contribute to their increased risk of recurrent atherothrombotic events, despite the use of dual-antiplatelet therapy. The mechanisms for impaired clopidogrel response in DM patients have not been fully elucidated.Objectives The aim of this study was to explore the mechanisms for impaired clopidogrel-mediated platelet inhibition in patients with DM using a comprehensive methodological approach embracing both pharmacokinetic (PK) and pharmacodynamic (PD) assessments as well as ex vivo and in vitro investigations.Methods Patients (DM, n = 30; non-DM, n = 30) with stable coronary artery disease taking aspirin 81 mg/day and P2Y12 antagonist naive were enrolled. Blood was collected before and at various times (0.5, 1, 2, 4, 6, and 24 h) after a 600-mg loading dose of clopidogrel. PD assessments included vasodilator-stimulated phosphoprotein, light transmission aggregometry, and VerifyNow P2Y12 ex vivo, before and after dosing and following in vitro incubation with escalating concentrations (1, 3, and 10 μM) of clopidogrel's active metabolite (Clop-AM). Exposure to Clop-AM was also determined.Results PD assessments consistently showed that during the overall 24-h study time course, residual platelet reactivity was higher in DM patients compared with non-DM patients. In vitro incubation with Clop-AM revealed altered functional status of the P2Y12 signaling pathway in DM platelets as measured by vasodilator-stimulated phosphoprotein, but not with other PD assays. Clop-AM exposure was ∼40% lower in DM patients than in non-DM patients.Conclusions The present study suggests that among DM patients, impaired P2Y12 inhibition mediated by clopidogrel is largely attributable to attenuation of clopidogrel's PK profile. This is characterized by lower plasma levels of Clop-AM over the sampling time course in DM patients compared with non-DM patients and only modestly attributed to altered functional status of the P2Y12 signaling pathway.
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Abnormal platelet receptor density and signaling affecting adhesion, activation, and aggregation lead to greater platelet activity and weaker antiplatelet treatment effects.
“dysregulation of platelet receptor density and signaling effects on adhesion, activation, and aggregation30 result in enhanced platelet activity31 and impaired antiplatelet therapeutic effect.32,33”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [32]
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- Authors
- Angiolillo, D. J., Jakubowski, J. A., Ferreiro, J. L., Tello-Montoliu, A., Rollini, F., Franchi, F., Ueno, M., Darlington, A., Desai, B., Moser, B. A., Sugidachi, A., Guzman, L. A., & Bass, T. A.
- Affiliations
- University of Florida (US)
- Eli Lilly (United States) (US)
- Daiichi-Sankyo (Japan) (JP)
- Corresponding author
- Angiolillo, Dominick J.
- ORCID
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 64
- Issue
- 10
- Pages
- 1005-1014
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W1964067479
- Cited by
- 182
- References
- 49
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 10 · 2023: 8 · 2022: 18 · 2021: 16 · 2020: 19 · 2019: 20 · 2018: 14 · 2017: 23 · 2016: 18 · 2015: 19 · 2014: 1
- FWCI
- 13.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- AstraZeneca
- Sanofi
- Gilead Sciences
- Sunovion
- Medicines Company
- St. Jude Medical
- Abbott Vascular
- Daiichi Sankyo Europe
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Antiplatelet Therapy and Cardiovascular Diseases
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- clopidogrel, P2Y12 receptor, type 2 diabetes, coronary artery disease, clopidogrel metabolite, pharmacokinetics, pharmacodynamics, platelet aggregation inhibition, residual platelet reactivity, VASP, dual antiplatelet therapy, atherothrombosis
- MeSH terms
- Clopidogrel, Adult, Aged, Aspirin, Coronary Artery Disease, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Male, Middle Aged, Platelet Aggregation, Platelet Aggregation Inhibitors, Platelet Function Tests, Prospective Studies, Reference Values, Ticlopidine, Cohort Studies, Treatment Outcome, Risk Assessment, Purinergic P2Y Receptor Antagonists
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