Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers

Claire C J Dekkers, Sergei Petrykiv, Gozewijn D Laverman, David Z Cherney, Ron T Gansevoort, Hiddo J L Heerspink, Claire C J Dekkers, Sergei Petrykiv, Gozewijn D Laverman, David Z Cherney, Ron T Gansevoort, Hiddo J L Heerspink

Abstract

The mechanisms by which SGLT-2 inhibitors lower albuminuria are incompletely understood. We assessed in a post-hoc analysis of a cross-over trial the effects of the SGLT2 inhibitor dapagliflozin on glomerular markers (IgG to IgG4 and IgG to albumin), tubular markers (urinary KIM-1, NGAL and LFABP) and inflammatory markers (urinary MCP-1 and IL-6) to provide more insight into kidney protective effects. Dapagliflozin decreased albuminuria by 43.9% (95% CI, 30.3%-54.8%) and eGFR by 5.1 (2.0-8.1) mL/min/1.73m2 compared to placebo. Dapagliflozin did not change glomerular charge or size selectivity index compared to placebo. Dapagliflozin decreased urinary KIM-1 excretion by 22.6% (0.3%-39.8%; P = .05) and IL-6 excretion by 23.5% (1.4%-40.6%; P = .04) compared to placebo, whereas no changes in NGAL, LFABP and MCP-1 were observed. During dapagliflozin treatment, changes in albuminuria correlated with changes in eGFR (r = 0.36; P = .05) and KIM-1 (r = 0.39; P = .05). In conclusion, the albuminuria-lowering effect of 6 weeks of dapagliflozin therapy may be the result of decreased intraglomerular pressure or reduced tubular cell injury.

Keywords: KIM-1; MCP-1; SGLT-2; acute kidney injury; dapagliflozin; type 2 diabetes.

Conflict of interest statement

C. C. J. D., S. P. and R. T. G. report no conflicts of interest. H. J. L. H. is a consultant for and has received honoraria from AbbVie, Astellas, Astra Zeneca, Boehringer Ingelheim, Fresenius, Janssen and Merck; he has a policy that all honoraria are paid to his employer. D. Z. I. C. has received speaker/consultant honoraria from Boehringer‐Ingelheim, Eli Lilly, AstraZeneca, Sanofi, Merck, Mitsubishi‐Tanabe and Janssen and has received operational funding for clinical trials from Boehringer Ingelheim, Merck and AstraZeneca. G. L. has received lecture fees from Sanofi, Astra Zeneca and Jansen, and has served as a consultant for Abbvie, Sanofi, Novo Nordisk, Astra Zeneca, Boehringer Ingelheim and MSD.

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Change in eGFR (ml/min/1.73m2) A; percent change in 24 h UAE B; in IgG/IgG4 C; in IgG/Albumin D; in KIM‐1 E; in NGAL F; in LFABP G; in IL‐6 H; and in MCP‐1 I during placebo and dapagliflozin treatment. Boxes show mean change within the 25th and 75th percentile. Mean differences and 95% confidence intervals of eGFR, 24 h UAE and kidney injury markers, compared to placebo, are shown under each sub‐figure. One subject with an IgG/IgG4 change of 4860% is not shown in this figure C, and one subject with an LFABP change of 857% is not shown in this figure G

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