Multi-Database Pharmacovigilance Analysis of Gastroesophageal Reflux Disease Associated with GLP-1 Receptor Agonists: A Cross-National Signal Validation Study.
Clinicians should monitor for GERD symptoms in patients on GLP-1 RAs, particularly in the elderly, but exenatide may pose a lower risk.
Where it sits
this study against the rest of the exenatide corpusSummary and findings
The study analyzed GERD signals associated with GLP-1 RAs using data from FAERS, JADER, and Canada Vigilance. Exenatide showed an inverse association with GERD in FAERS. The study found significant GERD signals for other GLP-1 RAs across all databases.
Abstract
<h4>Background/aims</h4>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed for type 2 diabetes and obesity. Gastrointestinal adverse events are common; however, the association with gastroesophageal reflux disease (GERD) has not been validated across diverse populations. We aimed to assess GERD signals associated with GLP-1 RAs using disproportionality analysis across three national adverse event reporting systems.<h4>Methods</h4>We analyzed FAERS, JADER, and Canada Vigilance. GLP-1 RAs were compared against dipeptidyl peptidase-4 inhibitors as active comparators. GERD was identified using MedDRA preferred terms. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated. Subgroup analyses were performed by drug, age, and sex.<h4>Results</h4>Among 260,417 GLP-1 RA reports, significant GERD signals were detected across all databases: FAERS (ROR, 2.83; 95% CI, 2.39 to 3.35; 9,245 vs 139), JADER (4.76; 95% CI, 2.45 to 9.27; 19 vs 16), and Canada Vigilance (2.91; 95% CI, 1.97 to 4.31; 206 vs 29). All signals met both ROR and proportional reporting ratio detection criteria. Drug-specific analyses revealed the strongest signals for semaglutide across all databases (3.44 to 6.93), followed by liraglutide (2.36 to 5.90), tirzepatide (2.76 to 5.77), and dulaglutide (2.35 to 3.32). Exenatide showed an inverse association in FAERS (ROR, 0.60; 95% CI, 0.46 to 0.77). Age-stratified analysis demonstrated increasing signal strength with age (≥65 years: ROR, 3.01; p-trend=0.028). Sensitivity analysis confirmed consistent signal directions.<h4>Conclusions</h4>This first multi-database pharmacovigilance analysis confirms consistent GERD signals for GLP-1 RAs across Western and Asian populations, demonstrating approximately 2- to 5-fold higher reporting. Clinicians need to monitor for reflux symptoms during GLP-1 RA therapy, particularly in elderly patients.
Background
GLP-1 receptor agonists are commonly used to treat type 2 diabetes and obesity, but their association with GERD has not been consistently validated. Gastrointestinal side effects are known, but this study seeks to clarify the specific risk of GERD across different populations. Understanding this association is important for managing potential side effects in patients using these medications.
Methods
The study conducted a disproportionality analysis using data from three national adverse event reporting systems: FAERS, JADER, and Canada Vigilance. GLP-1 RAs were compared to dipeptidyl peptidase-4 inhibitors. GERD was identified through MedDRA preferred terms, and reporting odds ratios with 95% confidence intervals were calculated. Subgroup analyses by drug, age, and sex were also performed.
Results
Significant GERD signals were detected for GLP-1 RAs across all databases, with RORs ranging from 2.83 to 4.76. Exenatide showed an inverse association with GERD in FAERS, with an ROR of 0.60. Drug-specific analyses indicated the strongest signals for semaglutide, followed by liraglutide, tirzepatide, and dulaglutide. The signal strength increased with age, particularly in those aged 65 and older.
Interpretation
The study confirms a consistent association between GLP-1 RAs and GERD across different populations, although the effect size varies by specific drug. Exenatide's inverse association suggests it may have a different risk profile compared to other GLP-1 RAs. These findings align with known gastrointestinal side effects but highlight the need for careful monitoring, especially in older patients. The observational nature of the study limits causal inference.
Key findings
- FAERS ROR for GERD with GLP-1 RAs: 2.83; 95% CI, 2.39 to 3.35
- JADER ROR for GERD with GLP-1 RAs: 4.76; 95% CI, 2.45 to 9.27
- Canada Vigilance ROR for GERD with GLP-1 RAs: 2.91; 95% CI, 1.97 to 4.31
- Exenatide ROR in FAERS: 0.60; 95% CI, 0.46 to 0.77
- Age ≥65 years ROR: 3.01; p-trend=0.028
Limitations
- Observational study design
- Reliance on self-reported data
- Potential reporting bias
- Cannot establish causality