Aspirin hyporesponsiveness in type 2 diabetes mellitus: A systematic review with narrative synthesis of definitions, assessment methods, and clinical relevance

Type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular risk, enhanced platelet activation, and substantial interindividual variability in response to aspirin. However, the term ‘aspirin resistance’ has been used inconsistently and is strongly influenced by the assay applied. In many cases, apparent non-response may reflect exposure-related pseudoresistance rather than true pharmacodynamic failure, particularly in the setting of enteric-coated formulations, impaired absorption, poor adherence or pharmacological interactions. This systematic review with narrative synthesis, conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISRMA) 2020, evaluated the prevalence, determinants, and clinical relevance of aspirin hyporesponsiveness in T2DM. Searches of PubMed, Embase, the Cochrane Library, and Latin American and Caribbean Health Sciences Literature identified 21 eligible studies. The reported prevalence varied widely (0–57%), mainly owing to differences in study populations, aspirin formulations, platelet function assays, and cut-off definitions. Small pharmacodynamic studies suggested that twice-daily aspirin regimens may provide greater suppression of platelet reactivity than once-daily dosing, whereas pharmacokinetic/pharmacodynamic evidence consistently indicated reduced thromboxane B2 suppression with enteric-coated aspirin. However, evidence linking laboratory-defined hyporesponsiveness with clinical outcomes was limited and inconsistent, and the largest available randomised outcome trial did not show a reduction in major cardiovascular events with twice-daily aspirin. Overall, aspirin hyporesponsiveness in T2DM appears to be multifactorial and insufficiently standardised. Current evidence does not support routine platelet function testing or empirical dose escalation. Clinical management should prioritise confirming the indication for aspirin, assessing adherence, selecting the appropriate formulation, avoiding clinically relevant drug interactions, and optimising overall cardiometabolic risk.