Comparative Post-Marketing Pharmacovigilance of Five GLP-1 Receptor Agonists: A Disproportionality Analysis of 412,643 FDA Adverse Event Reports (2004-2024)
This large pharmacovigilance study extracted 412,643 adverse event reports for five GLP-1 receptor agonists (semaglutide, tirzepatide, liraglutide, dulaglutide, and exenatide) from the FDA Adverse Event Reporting System (FAERS) spanning 2004–2024, comparing disproportionality signals using proportional reporting ratios (PRR) and reporting odds ratios (ROR). The study identified 154 drug-event signals overall. The most notable finding was a strong gastroparesis signal for semaglutide (PRR 88.9, 95% CI 85.4–92.6), which the authors describe as substantially higher than prior published estimates and as robust across three pre-specified sensitivity analyses using different comparator groups. All five agents showed statistically significant gastroparesis signals. Gastroparesis reports were consistently female-predominant across all agents (female-to-male ratio 2.7–3.6×). Tirzepatide's adverse event profile was notably dominated by device-usability reports rather than clinical events. Case-fatality rates varied across agents (0.6% to 3.7%). Key limitations include inherent FAERS biases (underreporting, stimulated reporting, lack of denominator data, and confounding by indication), which preclude causal inference or incidence estimation. The authors acknowledge the preprint status of this work.
Why this grade: Although this observational disproportionality analysis uses a very large human dataset (412,643 reports), FAERS-based pharmacovigilance cannot establish causality, incidence, or comparative effectiveness, and the work has not yet undergone peer review.
Abstract Background: GLP-1 receptor agonists (GLP-1 RAs) are the fastest-growing drug class in the United States, yet comparative real-world safety profiles across agents — particularly for gastrointestinal events — remain incompletely characterized in published pharmacovigilance literature. Objective: To characterize and compare disproportionality signals across five GLP-1 RAs using the FDA Adverse Event Reporting System (FAERS), including temporal trends, sex stratification, and pre-specified sensitivity analyses. Methods: All reports for semaglutide, tirzepatide, liraglutide, dulaglutide, and exenatide were extracted from FAERS (Q1 2004–Q4 2024) via the openFDA API, yielding 412,643 reports against a background of 20,328,575 total FAERS reports. Proportional reporting ratios (PRR) and reporting odds ratios (ROR) with 95% confidence intervals were calculated. Signal detection required PRR ≥ 2, χ² ≥ 4, N ≥ 3 (Evans 2001). Three pre-specified sensitivity analyses evaluated antidiabetic-drug and within-GLP-1-class comparators and a 7-PT MedDRA gastroparesis cluster. Results: We identified 154 drug-event signals. Semaglutide showed the strongest gastroparesis signal (PRR 88.9, 95% CI 85.4-92.6; ROR 92.1, 95% CI 88.3-96.0; N=3,058), substantially exceeding all prior published estimates (range 2-15). The signal remained robust across all three sensitivity analyses. All five agents showed statistically significant gastroparesis signals. Gastroparesis reports were disproportionately female across all agents (F:M ratio 2.7-3.6x). Tirzepatide's signal profile was dominated by device-usability events rather than clinical adverse events. Case-fatality rates ranged from 0.6% (tirzepatide) to 3.7% (liraglutide). Conclusions: This comparative analysis of 412,643 FAERS reports — the largest to date — identifies clinically meaningful between-agent heterogeneity in safety profiles. Semaglutide's gastroparesis signal is robust across all comparator specifications. The consistent female predominance of gastroparesis reporting warrants sex-stratified investigation in future studies.
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