Comparative Renal Safety of Tirzepatide and Semaglutide: An FDA Adverse Event Reporting System (FAERS)—Disproportionality Study

<b>Background:</b> Acute kidney injury (AKI) remains a serious complication among individuals with type 2 diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed and often regarded as kidney-protective, yet post-marketing reports have linked them to AKI. Tirzepatide, a newer dual GIP/GLP-1 agonist, shows well-documented metabolic benefits, but its renal safety in real-world use is not well characterized. <b>Methods:</b> We conducted a disproportionality analysis of the U.S. FDA Adverse Event Reporting System (FAERS) from January 2022 to September 2025. Reporting odds ratios (RORs) and proportional reporting ratios (PRRs) were used to compare AKI reporting between tirzepatide and semaglutide. <b>Results:</b> Among 133,872 reports (92,807 tirzepatide; 41,065 semaglutide), AKI was listed in 432 (0.47%) and 440 (1.07%) cases, respectively. The ROR for tirzepatide versus semaglutide was 0.44 (95% CI, 0.38-0.50), suggesting a lower reporting frequency for AKI with tirzepatide. <b>Conclusions:</b> In this real-world pharmacovigilance analysis, semaglutide but not tirzepatide showed a disproportionality signal for AKI. While causality cannot be confirmed, clinicians should ensure hydration and renal monitoring when initiating GLP-1 RAs, particularly semaglutide. Semaglutide showed a higher AKI reporting rate than tirzepatide, though these findings should be interpreted cautiously given reporting bias and potential confounders. Both agents appear safe, with low AKI frequency in practice. Further studies should determine if differences reflect biological or reporting effects. These findings support the need for larger epidemiologic studies to define risk modifiers and optimize clinical safety strategies.