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Background: Sodium-glucose-cotransporter 2 inhibitors (SGLT2is) have revolutionized the treatment of type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD), reducing the risk of cardiovascular and renal end points by up to 40%. The underlying mechanisms are not fully understood. Objective: The study aims to examine the effects of empagliflozin versus placebo on renal hemodynamics, sodium balance, vascular function, and markers of the innate immune system in patients with DM2, DM2 and CKD, and nondiabetic CKD. Methods: We conducted 3 double-blind, crossover, randomized controlled trials, each with identical study protocols but different study populations. We included patients with DM2 and preserved kidney function (estimated glomerular filtration rate >60 mL/min/1.73 m2), DM2 and CKD, and nondiabetic CKD (both with estimated glomerular filtration rate 20-60 mL/min/1.73 m2). Each participant was randomly assigned to 4 weeks of treatment with either 10 mg of empagliflozin once daily or a matching placebo. After a wash-out period of at least 2 weeks, participants were crossed over to the opposite treatment. End points were measured at the end of each treatment period. The primary end point was renal blood flow measured with 82Rubidium positron emission tomography–computed tomography (82Rb-PET/CT). Secondary end points include glomerular filtration rate measured with 99mTechnetium-diethylene-triamine-pentaacetate (99mTc-DTPA) clearance, vascular function assessed by forearm venous occlusion strain gauge plethysmography, measurements of the nitric oxide (NO) system, water and sodium excretion, body composition measurements, and markers of the complement immune system. Results: Recruitment began in April 2021 and was completed in September 2022. Examinations were completed by December 2022. In total, 49 participants completed the project: 16 participants in the DM2 and preserved kidney function study, 17 participants in the DM2 and CKD study, and 16 participants in the nondiabetic CKD study. Data analysis is ongoing. Results are yet to be published. Conclusions: This paper describes the rationale, design, and methods used in a project consisting of 3 double-blind, crossover, randomized controlled trials examining the effects of empagliflozin versus placebo in patients with DM2 with and without CKD and patients with nondiabetic CKD, respectively. Trial Registration: EU Clinical Trials Register 2019-004303-12; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004303-12, EU Clinical Trials Register 2019-004447-80; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004447-80, EU Clinical Trials Register 2019-004467-50; https://www.clinicaltrialsregister.eu/ctr-search/search?query=and+2019-004467-50 International Registered Report Identifier (IRRID): DERR1-10.2196/56067 [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions Trial registration 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).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.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/m5 (95% CI: −94; −1 dyn×s/m5) (p = 0.044). Furthermore, empagliflozin reduced plasma levels of nitrite and urinary levels of NOx.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.EU Clinical Trials Register number: 2019‐004303‐12 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004303-12/DK). [ABSTRACT FROM AUTHOR]