Patients with diabetes are at high risk for adverse cardiovascular events after acute coronary syndrome (ACS). Prasugrel is a third generation thienopyridine antiplatelet drug that produces greater and more consistent inhibition of platelet aggregation compared with clopidogrel, which when given with aspirin is the standard of care for reducing the occurrence of cardiovascular events in ACS patients. The TRITON-TIMI 38 study compared prasugrel (60 mg loading dose [LD]/10 mg maintenance dose [MD]) and clopidogrel (300 mg LD/75 mg MD) in ACS patients undergoing scheduled percutaneous coronary intervention (PCI). The primary efficacy endpoint was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; the key safety endpoint was major bleeding. The median duration of follow-up was 14.5 months. Compared with clopidogrel, prasugrel significantly reduced rates of ischemic events, and increased the risk of major bleeding. Of the 13, 608 patients enrolled in TRITON-TIMI 38, 3146 patients had pre-existing diabetes, with 776 patients receiving insulin. The majority of diabetic patients in TRITON-TIMI 38 were Caucasian (89%). For diabetic patients, prasugrel reduced the primary efficacy endpoint compared with clopidogrel (12.2% vs 17.0%; hazard ratio [HR]=0.70; P<0.001). Prasugrel was of benefit in patients receiving insulin (14.3% vs 22.2%; HR=0.63; P=0.009) and in those not receiving insulin (11.5% vs 15.3%; HR=0.74; P=0.009). Prasugrel reduced stent thrombosis in diabetic patients (2.0% vs 3.6 %; HR=0.52; P=0.007), especially in those receiving insulin (1.8% vs 5.7%; HR=0.31; P=0.008). The rate of non-coronary artery bypass grafting-related (non-CABG) TIMI major bleeding was similar between diabetic patients receiving prasugrel or clopidogrel (2.5% vs 2.6%; HR=0.94; P=0.81). Net clinical benefit, defined as occurrence of the primary efficacy endpoint or non-CABG TIMI major bleeding, favored prasugrel in patients receiving insulin (16.8% vs 24.1%; HR=0.66; P=0.01) and in those not receiving insulin (13.9% vs 17.7%; HR=0.78; P=0.02). Prasugrel showed greater net treatment benefit in diabetic patients compared with non-diabetic patients (Pinteraction=0.05). This prespecified subgroup analysis suggests that the more intensive platelet inhibition afforded by prasugrel may be particularly beneficial to diabetic patients presenting with ACS and undergoing PCI.