Real‐World Adverse Event Reporting Patterns of Tirzepatide Versus Semaglutide: A Stratified Study of General and Healthcare Professional Cohorts in FAERS

ABSTRACT Background Both the GLP‐1 receptor agonist semaglutide and the novel dual GIP/GLP‐1 receptor agonist tirzepatide have emerged as first‐line therapeutic options for metabolic diseases. However, their real‐world comparative safety profiles are difficult to interpret due to differential reporting composition in spontaneous reporting databases. This study compared their post‐marketing adverse event (AE) reporting patterns and examined how reporter identity influences signal prominence. Methods AE reports (May 2022–June 2026) from FAERS were analysed using ROR, PRR, information component (IC) and empirical Bayes geometric mean (EBGM); a signal required simultaneous four‐method convergence; additionally, the Benjamini–Hochberg false discovery rate (FDR) procedure was used to ensure signal robustness against multiple testing. Head‐to‐head comparisons used the ratio of reporting odds ratios (RORR) with 95% CIs, run in parallel across general population and healthcare professional (HCP)‐restricted subset, with sensitivity analyses by indication, seriousness, geography and calendar quarter. Results A total of 151 654 tirzepatide and 64 987 semaglutide reports were analysed (HCP: 5.04% vs. 23.42%). Only semaglutide met four‐method criteria for gastrointestinal (ROR 3.64) and metabolic (ROR 4.25) disorders in the general population (GI RORR 0.58, 95% CI 0.57–0.59). Pancreatitis signalled for both agents but attenuated to equivalence within T2DM (RORR 0.98, 95% CI 0.83–1.15). Diabetic ketoacidosis signalled exclusively for semaglutide in the HCP cohort (ROR 3.52); tirzepatide showed higher hypoglycaemia reporting (RORR 1.91, 95% CI 1.49–2.44). In the HCP cohort, tirzepatide GI ROR rose to 2.53 and semaglutide acquired eye disorder reporting signals (ROR 2.61). All sensitivity analyses (stratified by indication, seriousness, geography restriction and calendar quarter) confirmed directional stability of these comparative reporting patterns across subgroups. Conclusion This FAERS‐based analysis identifies distinct AE reporting patterns between tirzepatide and semaglutide that are sensitive to reporter type; all findings are hypothesis‐generating and require confirmation with defined exposure denominators.