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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIAL NUMBER: Not applicable.