The effects of empagliflozin on systemic haemodynamic function: three randomized, placebo-controlled trials

Background: Sodium glucose cotransporter 2 inhibitors lower blood pressure. The underlying mechanisms are multifactorial and include effects on vascular function. We examined the systemic hemodynamic effects of empagliflozin in patients with type 2 diabetes mellitus (DM2) with and without chronic kidney disease (CKD) and in patients with nondiabetic CKD. Methods: Three double-blinded, randomized, placebo-controlled cross-over trials, including patients with DM2 and preserved renal function ( n = 16), DM2 and CKD ( n = 17) and nondiabetic CKD ( n = 16). Participants were randomized to 4 weeks of empagliflozin 10 mg or placebo and crossed over after a 2-week washout. We measured brachial and central 24-h ambulatory blood pressure (ABP), pulse wave velocity (PWV), augmentation index (AIx@75), markers of nitric oxide and erythrocyte sodium sensitivity (ESS), a marker of endothelial glycocalyx function. Results: Empagliflozin reduced PWV [-0.16 m/s, 95% confidence interval (95% CI): -0.26; -0.06, P = 0.002], AIx@75 (-2.17%, 95% CI: -3.31; -1.02, P < 0.001) and brachial and central ABP in the combined study population ( n = 49). Changes in PWV and AIx@75 correlated to changes in systolic brachial ABP. Markers of nitric oxide did not increase, but empagliflozin decreased ESS, which was correlated to an increase in haematocrit. Conclusion: Empagliflozin decreased arterial stiffness, mediated partly by a decrease in brachial ABP. We found no increase in nitric oxide activity, but ESS decreased. While this may be explained partly by a change in haematocrit, it could indicate an improvement in endothelial glycocalyx function. Trial registration: EU Clinical Trials Register 2019-004303-12, 2019-004447-80 and 2019-004467-50