Extracellular vesicles number and cell subtype may be influenced by diabetes mellitus and metformin in patients at high cardiovascular risk

Background and aims: Extracellular vesicles (EV) represent a population of small vesicles deriving from all types of cells, generated by the extroflection of the plasma membrane, and released into the circulation. EV can have both pro- and anti-atherothrombotic effects depending on the clinical setting, origin cell, stimuli, and different treatments might affect their levels. The primary endpoint of our study was to compare the amount of circulating EV and specific EV subtypes derived from platelets, endothelial cells, and leucocytes in subject at high CV risk, with and without T2DM, and if any ongoing anti-diabetic drugs could affect the levels of EV. Methods and results: The levels of total EV (d Z 0.576; p Z 0.049), total Annexin þ EV (d Z 0.519; p Z 0.011), CD41aþ/AnnexinVþ platelet derived EV (d Z 0.482; p Z 0.0187) and CD31 endothelial derived EV (d Z 0.590; p Z 0.0041) were lower in diabetic patients vs. those without T2DM. Interestingly, after adjustment for variables no significantly different between groups, including HbA1c, differences in EV subtypes were no longer observed. Linear regression analysis showed that HbA1c was inversely related to total EV to (beta coefficients Z 10969; p Z 0.0170), CD41aþ/AnnexinVþ platelet-derived EV (beta coefficients Z 352.71125; p Z 0.0529) and CD31þ endothelial-derived EV (beta coefficients Z 188.01952; p Z 0.0095) in all patients. Among subjects with diabetes, CD41þ platelet-derived EV and CD41aþ/AnnexinVþ platelet-derived EV (p Z 0.0644 and p Z 0.0635) were lower in patients on metformin treatment, even after adjustment for gender, hypertension, weight, waist circumference, total cholesterol, diuretics and statins use). Conclusion: Our study showed that, among high CV risk patients, treated with the state-of-theart preventive strategies, T2DM is associated with lower levels of total, platelet-and endothelialderived EV, and that this difference may be accounted for, at least in part, by hyperglycemia and ongoing treatment with metformin, the most widely prescribed oral antidiabetic agent.