Effects of SGLT2 inhibitors on NSAID-associated acute kidney injury in type 2 diabetes: a claims-based cohort study

Sodium–glucose cotransporter-2 inhibitors (SGLT2is) reduce the risk of acute kidney injury (AKI) in diverse populations; however, their effects on drug-induced AKI remain unclear. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a major cause of nephrotoxicity, and combining them with renin–angiotensin–aldosterone system inhibitors and diuretics increases the risk. Given the natriuretic action of SGLT2is, their impact on NSAID-related AKI requires evaluation. We performed this retrospective cohort study using the nationwide Japanese claims database (2015–2023). Adults with type 2 diabetes initiated on NSAIDs while receiving either SGLT2is or dipeptidyl peptidase-4 inhibitors (DPP4is) were included. Inverse probability of treatment weighting balanced 60 covariates. The primary outcome was 90-day AKI, identified by International Classification of Diseases 10th edition codes, and the secondary outcomes were 30-day risk and on-treatment incidence during NSAID use. We identified 39,251 SGLT2i and 256,298 DPP4i users. After weighting, the covariates were well balanced. The occurrence rates of 90-day AKI were 0.17% and 0.24% in SGLT2i and DPP4i users, respectively (risk ratio 0.70, 95% confidence interval: 0.62–0.79). Consistent protection was observed at 30 days and during on-treatment exposure. Subgroup analyses showed greater benefit in younger patients and those with chronic kidney disease, higher BMIs, and shorter exposure. None of the subgroups demonstrated excess risk. SGLT2i therapy was associated with a significantly lower risk of NSAID-induced AKI than DPP4is. These findings indicate an observed association between SGLT2i therapy and a lower incidence of drug-induced nephrotoxicity, which may inform safer NSAID prescribing in patients with type 2 diabetes. Not applicable. Keypoints Sodium–glucose cotransporter-2 inhibitors (SGLT2is) were associated with a significantly lower risk of acute kidney injury (AKI) after nonsteroidal anti-inflammatory drug (NSAID) use in patients with type 2 diabetes. This association was consistent across multiple analyses and patient subgroups, suggesting that SGLT2is may be linked to lower risk of drug-induced kidney injury when NSAIDs are clinically required. These findings extend t current knowledge of SGLT2i renal safety and provide real-world evidence of an association between SGLT2i use and reduced NSAID-related nephrotoxicity.