Semaglutide's Effect on Renal Hemodynamics and Function in Patients With Type 2 Diabetes Mellitus and Nephropathy

Mechanistic studies conducted in healthy humans demonstrate a Glucagon-like peptide-1 (GLP-1)-mediated gut-kidney crosstalk. The expansion of extracellular fluid volume uncovers a natriuretic action of GLP-1. This feed-forward natriuretic system is associated with high renal extraction of GLP-1, suppression in circulating angiotensin II levels, and increased renal medullary and cortical perfusion and oxygenation. Besides potent glucose-lowering actions, Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve body weight, blood pressure, and dyslipidemia, and cardiovascular and renal outcome trials demonstrate beneficial actions of GLP-1RAs used in patients with type 2 diabetes mellitus (T2DM). Thus the beneficial cardiovascular effects of GLP-1 may partly be related to renoprotection and might represent the restoration of the gut-kidney crosstalk. The aim of the present study is to investigate possible mechanisms behind the renal effects of semaglutide in patients with type 2 diabetes mellitus and moderate chronic kidney disease. This is a double-blinded, placebo-controlled, crossover study and patients will participate in two independent and randomized study periods with a washout period of around 4 weeks in between. Fifteen male participants with type 2 diabetes mellitus in the age group 20-60 years are screened, randomized, and expected to complete the present study. Informed consent is obtained before the screening meeting followed by a 30-day run-in period prior to study days. The two study periods each extend over 8 days, where all participants consume a controlled diet with fixed salt intake corresponding to a daily intake of 50-70 mmol + 2 mmol/kg sodium for 7 days. On the fourth day before each of the two baseline trials, 24-hour urine collection will be performed. Throughout the 7 days, water intake will be ad libitum and physical activity will not be allowed. Each period consists of Baseline day (day 5) and Intervention day (day 8) Renal flow, perfusion, and oxygenation are measured on both days, using multiparametric MRI. Glomerular filtration rate (GFR) is measured, using Tc99m-Diethylenetriamine pentaacetic acid (DTPA) plasma clearance. After conducting the baseline study, the participant is given a subcutaneous injection of either semaglutide or placebo. During the intervention study, MRI is followed by catheterization of a renal vein via the femoral vein (the Seldinger technique) for blood sampling.