P2Y12 inhibition in diabetes across the acute-to-chronic coronary syndrome continuum: toward a personalized antiplatelet strategy

Diabetes mellitus (DM) is a major determinant of adverse cardiovascular outcomes across the continuum of coronary artery disease, from acute coronary syndromes (ACS) to chronic coronary syndromes (CCS). Enhanced platelet reactivity, increased thrombin generation, and variable responsiveness to antiplatelet agents contribute to persistent thrombotic risk and complicate the selection, intensity, and duration of antiplatelet therapy. We performed a narrative review of randomized clinical trials, prespecified subgroup analyses, real-world registries, and contemporary consensus documents evaluating P2Y12 inhibitor–based strategies in patients with DM across the ACS-to-CCS continuum. In the acute phase of ACS, potent P2Y12 inhibition with ticagrelor or prasugrel is generally favored over clopidogrel because of the heightened thrombotic burden associated with DM. However, despite pharmacodynamic differences between potent P2Y12 inhibitors, available comparative outcome data do not establish a consistent clinical superiority of one agent across diabetic populations, and ethnicity and comorbidities may further modify their net benefit. After early stabilization, antiplatelet therapy becomes increasingly dependent on the evolving balance between ischemic and bleeding risk. Aspirin withdrawal followed by P2Y12 inhibitor monotherapy can reduce bleeding in selected patients without an apparent ischemic penalty, whereas very short dual antiplatelet therapy and de-escalation to clopidogrel require more selective application, particularly in patients with persistent high thrombotic risk. Conversely, prolonged intensified therapy may provide greater absolute benefit in selected patients with prior myocardial infarction, previous percutaneous coronary intervention, or extensive coronary disease, while simplified regimens may be preferable when high bleeding risk predominates. DM should not be considered a binary determinant of antiplatelet intensity. P2Y12-directed therapy should instead be dynamically individualized according to clinical phase, ischemic and bleeding risk, coronary anatomy and PCI complexity, comorbidities, renal function, treatment tolerability, and ethnicity.