BackgroundDiabetes mellitus (DM) is associated with enhanced platelet reactivity and impaired response to oral antiplatelet therapy, including clopidogrel. This post hoc analysis investigated the pharmacodynamic effects of ticagrelor versus clopidogrel loading dose (LD) in troponin‐negative acute coronary syndrome patients with or without DM undergoing percutaneous coronary intervention in the Ad Hoc PCI study.Methods and ResultsPatients randomized (1:1) to receive ticagrelor 180 mg LD or clopidogrel 600 mg LD were assessed by diabetic status. Platelet reactivity (P2Y12 reaction units [PRU] on VerifyNow® assay) was measured pre‐LD, at 0.5, 2, and 8 hours post‐LD, and at the end of the percutaneous coronary intervention. The primary endpoint was PRU levels 2 hours post‐LD; secondary endpoints included rates of high on‐treatment platelet reactivity (PRU≥208). Of 100 randomized patients, 51 received ticagrelor (DM, n=20; non‐DM, n=31) and 49 clopidogrel (DM, n=16; non‐DM, n=33). At 2 hours post‐LD, mean (SD) PRU levels in DM patients were 130.1 (111.7) with ticagrelor versus 287.6 (71.9) with clopidogrel (mean [95%CI] difference −157.5 [−225.3, −89.8]; P<0.001); in non‐DM patients, they were 75.3 (75.7) versus 243.0 (72.4) (mean difference −167.7 [−207.1, −128.3]; P<0.001). High on‐treatment platelet reactivity rates at 2 hours post‐LD were also significantly (P<0.001) reduced with ticagrelor versus clopidogrel in DM and non‐DM patients. Between‐treatment differences for PRU and high on‐treatment platelet reactivity were not significant at earlier time points but were at 8 hours post‐LD (P<0.001).ConclusionsCompared with clopidogrel, ticagrelor achieved faster, enhanced platelet inhibition and reduced high on‐treatment platelet reactivity rates, in DM and non‐DM patients.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT01603082.