Empagliflozin improves vascular insulin sensitivity and muscle perfusion in persons with type 2 diabetes

Sodium glucose cotransporter 2 inhibitors (SGLT2is) improved major adverse cardiovascular events (MACE), heart failure, and renal outcomes in large trials; however, a thorough understanding of the vascular physiological changes contributing to these responses is lacking. We hypothesized that SGLT2i therapy would diminish vascular insulin resistance and improve hemodynamic function, which could improve clinical outcomes. To test this, we treated 11 persons with type 2 diabetes for 12 wk with 10 mg/day empagliflozin and measured vascular stiffness, endothelial function, peripheral and central arterial pressures, skeletal and cardiac muscle perfusion, and vascular biomarkers before and at 120 min of a euglycemic hyperinsulinemic clamp at weeks 0 and 12. We found that before empagliflozin treatment, insulin infusion lowered peripheral and central aortic systolic pressure (P < 0.05) and muscle microvascular blood flow (P < 0.01), but showed no effect on other vascular measures. Following empagliflozin, insulin infusion improved endothelial function (P = 0.02), lowered peripheral and aortic systolic (each P < 0.01), diastolic (each P < 0.05), mean arterial (each P < 0.01), and pulse pressures (each P < 0.02), altered endothelial biomarker expression, and decreased radial artery forward and backward pressure amplitude (each P = 0.02). Empagliflozin also improved insulin-mediated skeletal and cardiac muscle microvascular perfusion (each P < 0.05). We conclude that empagliflozin enhances insulin's vascular actions, which could contribute to the improved cardiorenal outcomes seen with SGLT2i therapy.NEW & NOTEWORTHY The physiological underpinnings of the cardiovascular benefits of SGLT2 inhibitors remain uncertain. We tested whether empagliflozin mitigates vascular insulin resistance in patients with type 2 diabetes. Aortic and peripheral systolic, diastolic, mean and pulse pressures, endothelial function, vascular stiffness, and heart and muscle microvascular perfusion were measured before and during an insulin infusion at baseline and after 12 wk of empagliflozin. After empagliflozin, vascular responses to insulin improved dramatically.