Aims/hypothesis Glucagon-like peptide-1 receptor agonists (GLP-1ras) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown kidney-protective effects. Improved kidney oxygenation and haemodynamic changes are suggested mechanisms; however, human data are scarce. We therefore investigated whether semaglutide (GLP-1ra), empagliflozin (SGLT2i) or their combination improve kidney oxygenation and perfusion. Methods The trial was undertaken at Aarhus University Hospital, Denmark. A total of 120 people with type 2 diabetes (HbA 1c ≥48 mmol/mol [6.5%]) and at high risk of CVD (age ≥50 years) were randomised into four parallel groups (n=30 in each group) for 32 weeks: 1.0 mg semaglutide (open label); 10 mg empagliflozin (blinded to participants, caregivers, examiners and outcome assessors); their combination (1.0 mg semaglutide open label plus 10 mg empagliflozin blinded to participants, caregivers, examiners and outcome assessors); and placebo tablet (blinded to participants, caregivers, examiners and outcome assessors). Sequentially numbered, sealed envelopes containing computer-generated randomisation codes, provided by Glostrup Pharmacy, Glostrup, Denmark, determined the intervention. The two co-primary outcomes were change in kidney oxygenation and change in arterial stiffness. This paper reports on kidney oxygenation, for which 80 individuals as prespecified, 20 in each group, underwent MRI. We primarily hypothesised that kidney oxygenation would be improved in the active treatment groups compared with placebo after 32 weeks. Secondary outcomes included changes in kidney perfusion, erythropoietin, haematocrit, urine albumin/creatinine ratio (UACR) and GFR (measured using technetium-99m) compared with baseline and between treatment groups at week 32. Results Our model estimated a common baseline R2* value across all four groups in the cortex and the medulla. At baseline, the value was 24.5 (95% CI 23.9, 24.9) Hz in the medulla. After 32 weeks, the R2* values in the medulla were estimated to be 25.4 (95% CI 24.7, 26.2) Hz in the empagliflozin group and 24.5 (95% CI 23.9, 25.1) Hz in the placebo group (p=0.016) (higher R2* corresponds to a lower oxygenation). Semaglutide decreased perfusion in both the cortex and the medulla. Empagliflozin increased erythropoietin and haematocrit. All three active treatments decreased GFR but not UACR. Ten serious adverse events were reported, among them two occurrences of semaglutide-associated obstipation.

Background Diabetic kidney disease (DKD) accounts for approximately 50% of end-stage kidney disease. Renal hypoxia is suggested as a main driver in the pathophysiology underlying chronic DKD. Blood Oxygenation Level Dependent Magnetic Resonance Imaging (BOLD-MRI) has made non-invasive investigations of renal oxygenation in humans possible. Whether diabetes per se contributes to measurable changes in renal oxygenation by BOLD-MRI remains to be elucidated. We investigated whether renal oxygenation measured with BOLD-MRI differs between people with type 2 diabetes (T2DM) with normal to moderate chronic kidney disease (CKD) (Stages 1–3A) and matched controls. The repeatability of the BOLD-MRI method was also assessed. Methods In this matched cross-sectional study, 20 people with T2DM (age 69.2 ± 4.7 years, duration of diabetes 10.5 ± 6.7 years, Male 55,6%) and 20 matched non-diabetic controls (Mean age 68.8 ± 5.4 years, Male 55,6%). underwent BOLD-MRI analyzed with the Twelve layer concentric object method. To investigate the repeatability, 7 in the T2DM group and 9 in the control group were scanned twice. Results A significant reduction in renal oxygenation from cortex to medulla was found in both groups P < 0.01, no inter-group difference was detected (0.71[s-1], [95% CI; (-0.28;1.7 s-1)], P = 0.16). Median intra individual coefficient of variation (CV) varied from 1.2% to 7.0%. Conclusion T2DM patients with normal to moderate CKD does not seem to have lower renal oxygenation when measured with BOLD-MRI and TLCO. BOLD-MRI has a low intra-individual CV and seems like a reliable method for investigation of renal oxygenation in T2DM.

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