Markers of Kidney Injury, Inflammation, and Fibrosis Associated With Ertugliflozin in Patients With CKD and Diabetes

INTRODUCTION: Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve cardiovascular and kidney outcomes through mechanisms that are incompletely understood. In this exploratory post-hoc analysis of the VERTIS RENAL trial, we report the association between the SGLT2 inhibitor, ertugliflozin, and markers of kidney injury, inflammation, and fibrosis in participants with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD). METHODS: Participants were randomized to ertugliflozin (5 or 15 mg/d) or placebo, and plasma samples for biomarker analysis were collected at baseline, 26 weeks, and 52 weeks. RESULTS: Ertugliflozin-treated participants had lower plasma levels of kidney injury molecule-1 (KIM-1) at 26 weeks (P = 0.044) and 52 weeks (P = 0.007) and higher eotaxin-1 at 52 weeks (P = 0.007) postrandomization compared with placebo. The change in KIM-1 was not associated with the baseline urine albumin to creatinine ratio (UACR) or the estimated glomerular filtration rate (eGFR, P interaction > 0.05). Additionally, the change in KIM-1 was positively correlated with the change in UACR in participants treated with ertugliflozin (P = 0.0071). No other significant associations between ertugliflozin and changes in the markers of tubular injury, inflammation, fibrosis, oxidative stress, and endothelial dysfunction were observed. CONCLUSION: In conclusion, in participants with T2D and stage 3 CKD, ertugliflozin was associated with a sustained lowering of the tubular injury marker KIM-1 regardless of baseline kidney function.