SGLT2 inhibition improves endothelium‐independent vasodilatory function in type 2 diabetes: A double‐blind, randomized, placebo‐controlled crossover trial

Abstract Aims The objective of this study was to examine the effects of empagliflozin on endothelium‐dependent and endothelium‐independent vasodilatation and systemic hemodynamic parameters and to assess the role of the nitric oxide (NO) system in patients with type 2 diabetes (T2DM). Materials and Methods In this double‐blind, placebo‐controlled cross over trial, patients with T2DM were treated with either empagliflozin 10 mg or matching placebo for 4 weeks. Following a 2‐week washout, participants were crossed over to 4 weeks of the opposite treatment. Forearm blood flow (FBF) was measured after each treatment period using venous occlusion plethysmography. Acetylcholine and sodium nitroprusside (SNP) were infused into the brachial artery to assess endothelium‐dependent and endothelium‐independent vasodilatory function, respectively. Total peripheral resistance, 24‐h blood pressure (BP) and biochemical markers of NO activity were measured as well. Results Sixteen participants completed the trial. The mean age was 68 ± 8 years, and 69% were male. The SNP response increased by 21% (geometric mean ratio 1.21, 95% CI: 1.09; 1.33) during treatment with empagliflozin compared to placebo ( p ≤ 0.001), but not during acetylcholine infusion ( p = 0.290). Empagliflozin decreased 24‐h systolic BP by 5 mmHg (95% CI: −9; −1 mmHg) ( p = 0.015), diastolic BP by 2 mmHg (95% CI: −5; 0 mmHg) ( p = 0.029) and systemic vascular resistance by 48 dyn×s/m 5 (95% CI: −94; −1 dyn×s/m 5 ) ( p = 0.044). Furthermore, empagliflozin reduced plasma levels of nitrite and urinary levels of NOx. Conclusions Empagliflozin improves endothelium‐independent vasodilation, reduces vascular resistance and lowers 24‐h BP in patients with T2DM, whereas no change in endothelial‐dependent vasodilation was observed. Trial registration EU Clinical Trials Register number: 2019‐004303‐12 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004303-12/DK ).