Are All Incretin Therapies Equal for the Kidney? Comparative FAERS Analysis of Tirzepatide and Semaglutide

Background: Acute kidney injury (AKI) is a frequent and serious complication among individuals with type 2 diabetes, contributing to long-term renal decline and heightened cardiovascular risk. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, are widely prescribed and often regarded as kidney protective, yet post-marketing experience has linked them to AKI in some cases. Tirzepatide, a newer dual GIP/GLP-1 agonist, offers striking metabolic benefits, but its short-term renal safety in routine practice has not been fully characterized. Methods: We performed a disproportionality analysis of the U.S. FDA Adverse Event Reporting System (FAERS) from January 2022 to September 2025. Reports listing tirzepatide or semaglutide as the primary suspect drug were included, and AKI was defined using standardized MedDRA terms. Reporting odds ratios (RORs) and proportional reporting ratios (PRRs) were calculated to assess whether AKI was reported more frequently than expected. Results: A total of 92,807 adverse event reports for tirzepatide and 41,065 for semaglutide were identified. AKI was reported in 432 tirzepatide cases (0.47%) and 440 semaglutide cases (1.07%). Compared with semaglutide, tirzepatide was associated with a significantly lower frequency of AKI reporting (ROR 0.44, 95% CI 0.38–0.50; PRR 0.44). Sex distribution differed between agents, with a higher proportion of females among semaglutide cases. Year on year reporting increased for both drugs, consistent with broader clinical uptake. Serious outcomes, including death, hospitalization, and life threatening events, were more frequently documented with semaglutide. Conclusions: In this real-world pharmacovigilance analysis, semaglutide but not tirzepatide demonstrated a disproportionality signal for AKI. While spontaneous reporting cannot establish causality, these findings suggest a possible renal safety distinction between the two agents These findings support close renal monitoring, particularly when initiating semaglutide in higher-risk patients, and highlight the need for confirmation in well-designed epidemiologic studies.