Modulation of circulating extracellular vesicles by antihyperglycemic therapies: A pilot randomized controlled trial.

AIMS: Circulating extracellular vesicles (EVs) are emerging biomarkers of vascular dysfunction in diabetes. However, the impact of different antihyperglycemic treatments on EV profiles in individuals with type 2 diabetes (T2D) remains poorly investigated. This study aimed to compare circulating EV concentration between individuals with T2D and healthy controls, and to evaluate the effects of liraglutide, empagliflozin, and gliclazide on EV subpopulations. METHODS: In this single-centre clinical study, we enrolled 60 individuals with T2D and 20 healthy controls. Baseline concentrations of total, endothelial- (CD31+/CD41-), platelet- (CD31+/CD41+), and leukocyte-derived (CD45+) EVs were measured by flow cytometry on whole blood. In the interventional phase, sixty individuals with T2D were randomized to receive liraglutide (n = 20), empagliflozin (n = 20), or gliclazide (n = 20), in add on to metformin, for 12 weeks. EV subpopulations were assessed as exploratory mechanistic outcomes, alongside metabolic parameters, which were re-assessed post-treatment. RESULTS: At baseline, individuals with T2D had significantly higher concentrations of total, endothelial-, and platelet-derived EVs compared to healthy controls (p < 0.0001). After 12 weeks, liraglutide significantly reduced total EVs (-57%), endothelial-EVs (-85%), and platelet-EVs (-55%) (all p < 0.002), independently of changes in HbA1c or body weight. All subjects completed the study treatment. No significant EV changes were observed with empagliflozin or gliclazide. Leukocyte-derived EVs remained unchanged across all groups. CONCLUSIONS: Circulating EVs are elevated in individuals with T2D even in the absence of overt vascular complications, suggesting early endothelial activation. Among antihyperglycemic agents, only liraglutide significantly reduced EV concentrations, pointing to potential direct vascular benefits. This study provides proof-of-concept data supporting EVs as translational markers of vascular health and treatment response in T2D.