Dual antiplatelet therapy (DAPT) with a combination of aspirin and P2Y12 inhibitors is the cornerstone of treatment for patients with acute coronary syndrome (ACS). The current ACC/AHA guidelines recommend aspirin with clopidogrel, prasugrel, or ticagrelor for all patients receiving percutaneous coronary intervention (PCI). Clinical studies have demonstrated the effectiveness of extended DAPT (>12 months) in preventing thrombotic events in ACS and peripheral artery diseases (PAD), but at the expense of increased risks of bleeding. Despite the availability of three P2Y12 inhibitors, the efficacy and bleeding risks of DAPT significantly differ between Caucasian and East Asian patients. Heterogeneity of platelet response profiles is also apparent in patients with obesity and diabetes. Although clinical studies have associated diabetes with poor responsiveness to P2Y12 inhibitors, the underlying mechanism for this impairment is unclear. This proposal would represent the first systematic analysis of the PK/PD of P2Y12 inhibitors in a mouse model of obesity and diabetes. We expect to establish whether the PK/PD of P2Y12 inhibitors are altered in a diet-induced obesity mouse model and whether elimination of CYP-mediated metabolism overcomes impaired platelet responsiveness without increasing bleeding risk. Results from this pilot study will provide a better understanding of the variability in response to P2Y12 inhibitors and accelerate development of new antiplatelet drugs to overcome interpatient variability in response to DAPT.

• We have developed an obese, insulin resistant murine model in which the effects of clopidogrel and DT-678 can be tested towards clinically relevant endpoints of both platelet aggregation and arterial thrombosis. This finding is clinically important considering millions of obese patients are treated with clopidogrel.