Galectin‐3 and kidney function in type 2 diabetes treated with dapagliflozin: Analysis from DECLARE‐TIMI 58

Galectin-3 (Gal-3) is a circulating biomarker of fibrosis, with higher levels being associated with an increased risk of progression of heart failure and kidney disease. Patients with type 2 diabetes mellitus (T2DM) are at increased risk of both. DECLARE-TIMI 58 was a randomized, placebo-controlled trial of dapagliflozin in patients with T2DM with or at high risk for atherosclerotic cardiovascular disease and creatinine clearance ≥60 mL/min. In a nested biomarker substudy, Gal-3 was measured at baseline and in adjusted analyses associated with the prespecified kidney-specific composite endpoint [Kidney-EP; sustained ≥40% decrease in estimated glomerular filtration rate (eGFR) to <60 mL/min, new end-stage kidney disease or adjudicated kidney-related death]. Among 14 530 pts, median Gal-3 was 14.9 ng/mL [interquartile range (IQR), 11.9, 18.4]. Gal-3 was weakly associated with urine albumin creatinine ratio (r = 0.098, P < 0.0001) and eGFR (r = -0.27, P < 0.001) at baseline and independently associated with the Kidney-EP:adj hazard ratio (HR) 1.15 [95% confidence interval (CI) 1.03, 1.28] per 1-SD log (Gal-3), P = 0.013. Dapagliflozin significantly reduced the relative risk of the Kidney-EP across quartiles of baseline Gal-3 [overall HR 0.45 (95% CI 0.23, 0.85), P < 0.0001; P interaction = 0.87]. A greater risk difference was observed with dapagliflozin in patients with higher Gal-3, in whom a higher absolute risk at baseline was observed [absolute risk reduction (ARR) Q4 1.9 (95% CI 0.6, 3.2) vs. Q1 0.6% (-0.1, 1.3), ARR P trend 0.048]. Plasma Gal-3 is independently associated with the progression of kidney dysfunction in patients with T2DM and normal kidney function. There was a gradient of greater absolute benefit for reducing kidney disease progression in patients treated with dapagliflozin and with higher Gal-3 concentrations at baseline, in whom a higher absolute risk was observed. clinicaltrials.gov (NCT01730534).