Safety Signals of GLP-1 Receptor Agonists: A Multi-Method Pharmacovigilance Analysis of FAERS (2018-2025) With Sensitivity-Stratified Prioritisation, Notoriety-Bias Assessment, and Cross-Database Validation.
The study identifies potential safety signals for GLP-1 RAs, notably gastrointestinal and psychiatric effects, but these findings are preliminary and require further investigation.
Where it sits
this study against the rest of the exenatide corpusSummary and findings
The study analyzed 288,408 GLP-1 RA reports from FAERS to identify safety signals using multiple disproportionality methods. It found 544 PT-class pairs meeting the signal criterion, with gastrointestinal and hepatobiliary effects being prominent. The study emphasized that these signals are hypothesis-generating and not indicative of causality.
Abstract
<h4>Background</h4>GLP-1 receptor agonists (GLP-1 RAs) are widely prescribed for type 2 diabetes and obesity, but their post-marketing safety profile-particularly psychiatric, vascular, neoplastic and rare ophthalmic events-remains incompletely characterised and is vulnerable to confounding by indication, secondary-suspect attribution and notoriety bias.<h4>Methods</h4>We analysed 32 quarterly FAERS files (2018Q1-2025Q4): 288408 unique GLP-1 RA reports versus 11 319 150 non-GLP-1 RA reports. Disproportionality used four methods (reporting odds ratio [ROR]; proportional reporting ratio [PRR]; Bayesian Confidence Propagation Neural Network information component, lower 95% bound [BCPNN IC025]; Multi-item Gamma Poisson Shrinker empirical Bayes lower 5th-percentile bound [MGPS EB05]; signal = ≥ 3 of 4). The top 30 ROR-ranked signals were stratified by primary-suspect (PS) sensitivity. Triangulation included active-comparator, intra-class psychiatric comparison, interrupted time-series assessment of reporting around the 2023 EMA announcement, Weber-effect evaluation with Cochran-Armitage trend testing, and external validation in JADER.<h4>Results</h4>Of 22 059 PT-class pairs, 544 met the ≥ 3-of-4 criterion. PS-stratification retained 21 of the top 30 signals and demoted 9 as secondary-suspect-driven (e.g., capillaritis ROR 18.6 → 0.27; heart sounds 84.3 → 0.55). PS-stable headline signals were dominated by gastrointestinal/hepatobiliary effects: cyclic vomiting syndrome (ROR 64.8; semaglutide-dominant), gallbladder injury (84.2), impaired gastric emptying (45.1), plus liraglutide-concentrated medullary thyroid cancer (41.1) and semaglutide-concentrated optic ischaemic neuropathy (26.5). Only semaglutide carried a class-level suicidal-ideation signal (ROR 2.30). Interrupted time series detected no level (p = 0.39) or slope change (p = 0.75) at the 2023 EMA announcement; psychiatric time-to-onset (median 47 days) aligned with early GI reactions. Sixteen of 17 priority signals (94.1%) replicated in JADER. As disproportionality analyses, these are hypothesis-generating safety signals and cannot establish incidence, relative risk, or causality.
Background
GLP-1 receptor agonists are commonly used for managing type 2 diabetes and obesity, but their safety profile, particularly concerning psychiatric, vascular, neoplastic, and rare ophthalmic events, is not fully understood. This study addresses the need for a comprehensive post-marketing safety evaluation of these drugs, considering potential biases and confounding factors.
Methods
The study analyzed 32 quarterly FAERS files from 2018 to 2025, comparing 288,408 GLP-1 RA reports to 11,319,150 non-GLP-1 RA reports. It employed four disproportionality methods: ROR, PRR, BCPNN IC025, and MGPS EB05, with a signal defined as meeting at least three of the four criteria. The top 30 ROR-ranked signals were further stratified by primary-suspect sensitivity and validated using external databases and various statistical methods.
Results
Of the 22,059 PT-class pairs analyzed, 544 met the ≥3-of-4 signal criterion. Gastrointestinal and hepatobiliary effects were prominent, with cyclic vomiting syndrome, gallbladder injury, and impaired gastric emptying showing high RORs. Semaglutide showed a class-level suicidal-ideation signal. The study found no significant changes in reporting trends around the 2023 EMA announcement, and most priority signals were replicated in JADER.
Interpretation
The findings suggest potential safety concerns with GLP-1 RAs, particularly gastrointestinal and psychiatric effects, but these are hypothesis-generating signals that require further investigation. The study's reliance on disproportionality methods limits its ability to establish causality or incidence rates. The results align with known side effects but highlight the need for cautious interpretation due to potential biases and confounding factors.
Key findings
- 544 PT-class pairs met the ≥3-of-4 signal criterion.
- Cyclic vomiting syndrome had an ROR of 64.8, semaglutide-dominant.
- Gallbladder injury had an ROR of 84.2.
- Impaired gastric emptying had an ROR of 45.1.
- Semaglutide had a class-level suicidal-ideation signal with an ROR of 2.30.
Limitations
- Hypothesis-generating, not causal.
- Relies on disproportionality analysis.
- Potential for notoriety bias.
- Confounding by indication possible.
- No incidence or relative risk established.