Effect of empagliflozin on urinary albumin excretion and hypoxic biomarkers in early diabetic kidney disease: A randomised double‐blind, placebo‐controlled trial

Abstract Aims The precise mechanism of sodium glucose co‐transporter 2 (SGLT2) inhibitor on reno‐protective effect has been still unclear. In this study, we hypothesised that SGLT2 inhibitor prevents diabetic kidney disease via reduction of hypoxia‐induced factors. Materials and Methods In this multicenter, prospective, randomised, double blinded clinical trial, people with type 2 diabetes and microalbuminuria were randomised equally to empagliflozin (10 mg/day) ( n = 40) and placebo ( n = 39) and followed 24 weeks. The primary endpoint was change in urinary albumin creatinine ratio (ACR) and urinary liver type fatty acid binding protein (L‐FABP) excretion from baseline to 24 weeks. Major secondary outcome was change in serum vascular endothelial growth factor (VEGF), angiopoietin‐like proteins 2 (ANGPTL2), angiopoietin‐like proteins 4 (ANGPTL4), and adrenomedullin (AM) levels. Results Although the reduction of ACR was significantly greater in the empagliflozin group than the placebo group at 4 and 12 weeks, the difference of change at 24 weeks between the two groups was not statistically significant (Empagliflozin group—Placebo group: −0.3643, 95% CI: −0.7571 to 0.0285, p = 0.0686). There was no difference in urinary L‐FABP excretion between the empagliflozin and placebo groups. Serum VEGF and ANGPTL2 decreased significantly more in the empagliflozin group, whereas there were no significant differences in AM and ANGPTL4. Conclusions These results demonstrated that empagliflozin partially suppressed the hypoxia‐induced angiogenic factors overproduction in addition to a declining trend in ACR in the early stage of diabetic kidney disease, which might contribute to the mechanisms of reno‐protective effects of this agent (jRCTs051200147).