Background: Sodium-Glucose-Cotransporter 2 inhibitors (SGLT2i) have revolutionized treatment of type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD), reducing risk of cardiovascular and renal endpoints by up to 40%. The underlying mechanisms are not fully understood.
Objective: 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 non-diabetic CKD.
Methods: We conducted three randomized, double-blind, placebo controlled cross over trials, each with identical study protocol but different study populations. We included patients with DM2 and preserved kidney function (estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73 m2), DM2 and CKD and non-diabetic CKD (both with eGFR 20-60 ml/min/1.73 m2). Each participant was randomly assigned to four weeks of treatment with either empagliflozin 10 mg once daily or matching placebo. After a wash-out period of at least two weeks, participants were crossed over to the opposite treatment. Endpoints were measured at the end of each treatment period. The primary endpoint was renal blood flow (RBF) measured with 82Rubidium positron emission tomography/ computed tomography (82Rb-PET/CT). Secondary endpoints include glomerular filtration rate (GFR) 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. 49 participants completed the project; 16 in the DM2 and preserved kidney function study, 17 in the DM2 and CKD study and 16 in the non-diabetic CKD study. Data analysis is ongoing. Results are yet to be published.
Conclusions: This article describes the rationale, design and methods used in a project consisting of three randomized, double-blind, placebo controlled cross over trials examining the effects of empagliflozin versus placebo in patients with DM2 with and without CKD and patients with non-diabetic CKD, respectively.
Clinicaltrial: EU Clinical Trials Register 2019-004303-12, 2019-004447-80 and 2019-004467-50.