Empagliflozin (EMPA) Improves Vascular Insulin Sensitivity and Enhances Skeletal and Cardiac Muscle Microvascular Perfusion in Persons with Type 2 Diabetes

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) decreased cardiac events in large clinical trials; however, an understanding of the physiology driving this benefit is lacking. To investigate this, we measured micro- and macrovascular insulin sensitivity in 10 adults with T2DM before and after 12 weeks of EMPA 10 mg daily. We also measured endothelial function (FMD), peripheral and central aortic pressures, and skeletal (SM) and cardiac (CM) muscle microvascular perfusion (MBV- microvascular blood volume; MFV-microvascular flow velocity; MBF-microvascular blood flow) before and during a 120 min euglycemic insulin clamp at weeks 0 and 12. We hypothesized that EMPA would diminish micro- and macro-vascular insulin resistance and improve vascular function. At week 0, insulin infusion lowered peripheral SBP (132±6 vs 125±5, p<0.05) but diminished SM perfusion MBV (1.75±0.2 vs 1.29±0.1, p<0.01) MFV (0.08±0.01 vs 0.05±0.01, p<0.001) and MBF (0.14±3 vs 0.07±0.01, p<0.01). After 12 weeks of EMPA, insulin infusion improved FMD (7.6 ± 1.2 vs 8.7 ±1.6%, p <0.03), lowered peripheral SBP (127±6 vs 107±5, p<0.001); DBP (74±4 vs 65±3, p<0.04); MAP (92±3 vs 79±3, p<0.01); and PP (53±5 vs 42±3, p<0.05) as well as aortic SBP (117±5 vs 96±4, p<0.001); DBP (75±4 vs 66±3, p<0.03); MAP (89±3 vs 76±3, p<0.01); and PP (43±4 vs 30±2, p<0.01). In addition, EMPA improved SM perfusion (MBV: 1.29±0.1 vs 2.02±0.3, p<0.02; MFV: 0.05±0.01 vs 0.08±0.01, p<0.02; MBF: 0.07±0.01 vs 0.18±0.04, p<0.03) and CM perfusion (MBV: 4.51±0.6 vs 5.11±0.4, p=0.18; MFV: 0.37±0.04 vs 0.52±0.06, p<0.05; MBF: 1.80±0.4 vs 2.74±0.5, p<0.05). In conclusion, 12 weeks of EMPA in adults with T2D improved endothelial function (FMD), reduced central and peripheral blood pressures, and augmented SM and CM microvascular perfusion in response to insulin. These changes may contribute to the improved CV outcomes seen with SGLT2i therapy. Disclosure L.Jahn: None. L.Hartline: None. K.W.Aylor: None. W.B.Horton: None. E.Barrett: None. Funding National Institutes of Health (1R01HL142250-01A1)