Alterations of Platelet MicroRNAs Associated With Dapagliflozin Treatment in Individuals With Type 2 Diabetes Mellitus

Background Platelet hyperactivity contributes to elevated cardiovascular risk in type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter-2 inhibitors, including dapagliflozin, exert beneficial effects on platelet function and cardiovascular outcomes. As platelet microRNAs (miRNAs) are established during megakaryopoiesis, we aimed to characterize the platelet miRNA expression in T2DM and after dapagliflozin treatment. Methods Platelet miRNA profiles were compared between T2DM patients and controls using microarray, with qRT-PCR validation in an independent cohort (25 T2DM and 19 controls). T2DM patients were re-evaluated after 3-month dapagliflozin treatment. Results Exploratory microarray identified 602 candidate miRNAs with >2-fold differences between T2DM and control pools. qRT-PCR confirmed significant changes in miR-15b-3p, miR-146a-5p, miR-155-5p, and miR-223-3p (all q < 0.05), as well as nominally significant changes in miR-21-5p and miR-320a (both q = 0.052). In T2DM, miR-320a negatively correlated with mean platelet volume, platelet distribution width, and platelet large cell ratio, whereas miR-146a-5p showed positive correlations with platelet size parameters. Additionally, miR-21-5p positively and miR-223-3p negatively associated with soluble P-selectin. In an uncontrolled pre–post analysis, platelet miR-223-3p and miR-320a levels were significantly higher after dapagliflozin treatment. In silico target prediction yielded putative enrichment in pathways related to transcriptional regulation, insulin signaling, and autophagy, which likely reflects regulatory programs established in parent megakaryocytes and warrants functional validation. Conclusion Altered levels of miR-15b-3p, miR-146a-5p, miR-155-5p, and miR-223-3p are associated with platelet activation and maturation in T2DM patients. Dapagliflozin treatment may be associated with changes in platelet levels of miR-223-3p and miR-320a, hypothetically reflecting alterations in megakaryocytic programming during therapy.