BACKGROUND: Limited knowledge exists regarding nephrotoxic risks associated with the combination of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and potentially nephrotoxic drugs. This study evaluates acute renal failure (ARF) events linked to such combinations using data from the FDA Adverse Event Reporting System (FAERS). METHODS: Signal mining was performed by estimating reporting odds ratios (ROR), with validation through additive, multiplicative, and proportional reporting ratio (PRR) models. Logistic regression assessed mortality risk factors. RESULTS: Among 4,417,195 reports, 1,636 ARF cases were associated with SGLT2i combinations, primarily involving diuretics, lipid-lowering agents, and anticoagulants. The highest ARF risk was observed with dapagliflozin-cefazolin [ROR adjusted (a) 59.63, 95% CI (9.96, 356.87)
ROR adjusted (b) 19.88, 95% CI (1.80, 219.21)
additive model (0.53)
multiplicative model (8.36)
PRR (8.53)]. Consistent associations were found for empagliflozin-allopurinol and canagliflozin-vancomycin. Among single drugs, 12, including canagliflozin, met all four significance criteria for ARF signals. Logistic regression revealed male patients had higher mortality risk (OR = 0.356, CONCLUSION: This study confirms prior evidence of ARF associated with the combined use of SGLT2i with diuretics or NSAIDs and identifies new risks with proton pump inhibitors (PPIs), antigout medications, and anticoagulants. Male gender was a significant risk factor.