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

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.

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.

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.

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.

EU Clinical Trials Register 2019-004303-12, 2019-004447-80 and 2019-004467-50.