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BACKGROUND: Individuals with diabetes mellitus (DM) may be susceptible to non-steroidal anti-inflammatory drug (NSAID)-induced acute kidney injury (AKI) but data on NSAID-related adverse renal events is sparse. OBJECTIVE: We aimed to evaluate the risk of acute kidney injury and/or hyperkalemia after systemic NSAID among individuals with DM and diabetic chronic kidney disease (CKD). METHODS: Retrospective cohort study of 3896 adults with DM with incident prescriptions between July 2015 and December 2017 from Singapore General Hospital and SingHealth Polyclinics. Laboratory, hospitalization and medication data were retrieved from electronic medical records. The primary outcome was the incidence of AKI and/ or hyperkalemia within 30 days after prescription. RESULTS: AKI and/or hyperkalemia occurred in 13.5% of all DM and 15.8% of diabetic CKD. The association between systemic NSAID >14 days and 30-day risk of AKI and/or hyperkalemia failed to reach statistical significance in unselected DM (adjusted OR 1.62, 95% CI 0.99–2.65, p = 0.05) and diabetic CKD (adjusted OR 0.64, 95% CI 0.15–2.82, p = 0.64), but the odds of AKI and/or hyperkalemia were markedly and significantly increased when NSAID was prescribed with renin-angiotensin-aldosterone system (RAAS) blocker (adjusted OR 4.17, 95% CI 1.74–9.98, p = 0.001) or diuretic (adjusted OR 3.31, 95% CI 1.09–10.08, p = 0.04) and in the absence of diabetic CKD (adjusted OR 1.98, 95% CI 1.16–3.36, p = 0.01). CONCLUSION: NSAID prescription >14 days in individuals with DM with concurrent RAAS blockers or diuretics was associated with higher 30-day risk of AKI and/or hyperkalemia. [ABSTRACT FROM AUTHOR]