Abstract 10276: Impaired Responsiveness to Clopidogrel in Type 2 Diabetes: A Mechanistic Study
Background: Type 2 diabetes mellitus (T2DM) patients are at increased risk for recurrent atherothrombotic events. This may be in part due to their impaired response to clopidogrel (Clop). However, the mechanisms for impaired Clop response in T2DM remain poorly elucidated. The current study aimed to explore the potential mechanism for impaired Clop response by determining the levels of clopidogrel active metabolite (C-AM) generated following dosing and the sensitivity of platelets from T2DM patients to exogenously added C-AM.
Methods: A total of 60 patients with stable coronary artery disease (T2DM, n=30; non-T2DM, n=30) on aspirin 81mg/day and free of P2Y12 antagonists prior to study were included. Blood was collected before and at various times (30 min, 1hr, 2hrs, 4hrs, 6hrs and 24hrs) after a 600mg clopidogrel loading dose. Platelet reactivity to ADP was determined by light transmission aggregometry, VerifyNow P2Y12 and VASP phosphorylation before and after dosing, and following the in vitro addition of increasing concentrations of C-AM (1μM, 3μM, and 10μM). In vivo exposure to C-AM was determined in plasma prepared from blood samples in which C-AM was stabilized upon collection.
Results: By all platelet reactivity tests T2DM patients demonstrated higher on-treatment platelet reactivity, ie lower inhibition, during the overall 24hr observation period compared with non-T2DM patients (p<0.05 for all assays). Both the maximum concentration (Cmax) and the total exposure (AUC) to C-AM were ~50% lower in the T2DM patients compared to non-T2DM patients. In vitro addition of increasing concentrations of C-AM, showed similar decreases in platelet reactivity between T2DM and non-T2DM patients with all assays except for a marginally significant lower degree of platelet inhibition in T2DM patients by VASP phosphorylation.
Conclusions: The present study confirms, using several platelet function tests, that T2DM patients exhibit an impaired platelet inhibitory response to clopidogrel. The present mechanistic study suggests that decreased in vivo exposure to C-AM, rather than platelet “resistance” to C-AM, underlies the impaired platelet inhibitory effects of clopidogrel in patients with T2DM.
- © 2013 by American Heart Association, Inc.