SGLT2 inhibitors attenuate nephrin loss and enhance TGF-β1 secretion in type 2 diabetes patients with albuminuria: A Randomized Clinical Trial

Abstract

Objective: To evaluate the effect of SGLT2 inhibitor (SGLT2i) on albuminuria, nephrin (NPH) and transforming-growth-factor-beta1 (TGF-β1) levels in urine and low-grade inflammation in type 2 diabetes (T2D ) patients.Methods: A randomized, blank-controlled clinical trial included 68 T2D patients and 10 controls. Based on the urinary albumin-to-creatinine ratio (UACR), 68 diabetic patients were stratified into three levels, UACR<30 mg/g, UACR≧30 mg/g to≦300 mg/g and UACR˃300 mg/g, who were randomized(1:1:1) to receive SGLT2i treatment for 12 weeks. The concentrations of NPH and TGF-β1 in urine were measured as indications of podocyte injury and renal fibrosis. Low-grade inflammation was assessed by the levels of IL-6, TNFα and hsCRP.Results: After 12 weeks of SGLT2i treatment, the levels of UACR and NPH decreased, UTGF-β1 increased in the T2D with microalbuminuria and macroalbuminuria groups, NPH (1.12[0.59,1.29] vs 0.71[0.41,1.07] ug/ml, P=0.022) and (1.29[0.99,1.96] vs 0.93[0.57,1.31] ug/ml, P=0.002), UTGF-β1 (4.88±1.31vs 7.27±1.21 pg/ml, P˂0.001) and (4.30±1.34 vs 6.78±2.59 pg/ml, P˂0.001), respectively. The changes in NPH were positively correlated with the UACR and negatively correlated with UTGF-β1 in T2D with albuminuria.Conclusions: SGLT2i alleviate nephrin loss and enhance TGF-β1 excretion in urine in T2DM with albuminuria. The anti-albuminuric effect of SGLT2i could be attributed to mitigating podocyte apoptosis and attenuating renal fibrosis.Trial registration:This clinical trial was registered on 15/10/2019, in ClinicalTrials.gov, and the registry number is NCT04127084.