Albuminuria and Serum Tumor Necrosis Factor Receptor Levels in Patients with Type 2 Diabetes on SGLT2 Inhibitors: A Prospective Study

Introduction: Large-scale clinical trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrate proteinuria-reducing effects in diabetic kidney disease, even after treatment with renin-angiotensin inhibitors. The precise mechanism for this favorable effect remains unclear. This prospective open-label single-arm study investigated factors associated with a reduction in proteinuria after SGLT2i administration.Methods: Patients with type 2 diabetes (T2DM) who had glycated hemoglobin (HbA1c) levels >= 6.5% despite dietary and/or oral hypoglycemic monotherapy were recruited and administered the recommended daily dose of SGLT2i for 4 months. Dual primary outcomes were changes in the urine albumin-to-creatinine ratio (uACR) and urine liver-type fatty acid-binding protein (L-FABP)-to-creatinine ratio (uL-FABPCR) at month 4 from baseline. Changes in kidney injury, inflammation, and oxidative stress biomarkers were investigated as secondary endpoints to examine the effects of this treatment on the kidney. The correlation between renal outcomes and clinical indicators, including circulating tumor necrosis factor receptors (TNFR) 1 and 2, was evaluated using univariate and multivariate analyses.Results: Participants (n = 123) had a mean age of 64.1 years (SD 13.4), with 50.4% being male. The median BMI was 25.8 kg/m(2) (interquartile range (IQR) 23.1-28.9), and the median HbA1c level was 7.3% (IQR 6.9-8.3). After SGLT2i administration, the uACR declined from 19.2 mg/gCr (IQR 7.1-48.7) to 13.3 mg/gCr (IQR 7.5-31.6), whereas the uL-FABPCR was not influenced. In univariate analysis, the change in log-transformed uACR due to SGLT2i administration showed a positive correlation with the change in serum TNFR1 level (R = 0.244, p < 0.01). Multivariate regression analysis, including confounding factors, showed that the changes in serum TNFR1 level were independently associated with the changes in the log-transformed uACR (independent t = 2.102, p < 0.05).Conclusion: After the 4-month SGLT2i administration, decreased albuminuria level was associated with decreased serum TNFR level in patients with T2DM.Trial Registration Number: UMIN000031947.