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

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.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.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/mAfter the 4-month SGLT2i administration, decreased albuminuria level was associated with decreased serum TNFR level in patients with T2DM.UMIN000031947.Previous studies have demonstrated the synergistic proteinuria-reducing effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in combination therapy with renin–angiotensin system blockers; however, the underlying mechanisms of this effect are poorly understood. This study was based on our hypothesis that the proteinuria-reducing effect is associated with the anti-inflammatory effects of SGLT2i beyond the effect on glycemic control. In total, 123 patients with type 2 diabetes mellitus (T2DM) were 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) as markers of glomerular and proximal tubular damage at 4 months from the baseline. Secondary outcomes included changes in kidney injury biomarkers, inflammation, and oxidative stress to examine the effects of treatment on the kidneys. 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. We found that administration of SGLT2i decreased the urine albumin-to-creatinine ratio but did not affect the urine liver-type fatty acid-binding protein-to-creatinine ratio. Further, SGLT2i may exert a proteinuria-reducing effect dependent on the anti-inflammatory effect in patients with T2DM. The inflammation-reducing and renoprotective mechanisms of SGLT2i remain to be fully clarified, but this study provides novel evidence regarding the mechanism. The study findings can help in developing anti-inflammatory agents for metabolic diseases.