FDA adverse event data revealed that semaglutide and liraglutide were associated with significantly higher rates of biliary disorders, including gallbladder and gallstone problems, compared to other drugs in the database.
ROR 4.06Semaglutide's reporting odds ratio for biliary disorders in 11 years of FDA adverse event data
What the researchers found
Among 2,215 biliary adverse event reports, 1,709 involved GLP-1 RAs and 506 involved DPP-4 inhibitors. Key reporting odds ratios:
- Semaglutide: ROR 4.06 (95% CI 3.76–4.39) for biliary disorders
- Liraglutide: ROR 3.88 (95% CI 3.50–4.29)
- DPP-4 inhibitors overall: ROR 3.09 (95% CI 2.83–3.37)
- Sitagliptin specifically: ROR 3.46 (95% CI 3.13–3.83)
Both semaglutide and liraglutide showed significant associations with gallbladder disorders, gallstone disorders, and infectious biliary disorders. Liraglutide, alogliptin, sitagliptin, and linagliptin were also linked to biliary malignant tumors. DPP-4 inhibitors had a higher proportion of serious outcomes (76.88%) compared to GLP-1 RAs (51.55%).
Why it matters
With tens of millions of people now taking GLP-1 receptor agonists, even rare adverse effects can affect large numbers of patients. This analysis raises a safety signal that gallbladder and biliary problems may be more common with semaglutide and liraglutide than previously appreciated, warranting clinical awareness.
How the study worked
Researchers extracted adverse event reports from the FDA Adverse Event Reporting System (FAERS) between Q1 2013 and Q1 2024 using OpenVigil 2.1. They used four standard signal detection methods (ROR, PRR, BCPNN, and EBGM) to assess whether biliary adverse events were reported more frequently than expected for these drug classes.
What this study cannot tell us
FAERS data has well-known limitations: it relies on voluntary reporting (under-reporting is common), cannot establish causation, may be influenced by reporting biases (e.g., higher awareness of GLP-1 RA side effects drives more reports), and lacks denominators to calculate true incidence rates. Confounders like obesity itself (a gallstone risk factor) and rapid weight loss cannot be controlled for in this analysis.
How to read the evidence
This is a pharmacovigilance analysis using FDA adverse event reporting data. While it uses rigorous signal detection methods, FAERS data cannot establish causation, calculate true incidence rates, or control for confounders. It generates safety signals that warrant further investigation.
When this study was published
Published in 2025 in Frontiers in Pharmacology, this analysis covers 11 years of FAERS data through Q1 2024, providing a comprehensive and up-to-date safety signal assessment.
The bigger picture
Gallbladder problems have been an emerging concern with GLP-1 receptor agonists, potentially related to rapid weight loss or direct effects on gallbladder motility. This pharmacovigilance study adds quantitative evidence from real-world data, joining clinical trial observations that have noted elevated cholecystitis and cholelithiasis rates with these drugs.
Questions still open
- Should patients starting semaglutide or liraglutide receive baseline gallbladder screening, especially those with existing risk factors?
- Is the biliary risk driven by rapid weight loss, direct GLP-1 receptor effects on the gallbladder, or both?
- How do these biliary risks compare to the cardiovascular and metabolic benefits when evaluating overall risk-benefit?
Common questions
Should I be worried about gallbladder problems on semaglutide?
What is a Reporting Odds Ratio (ROR)?
Read the original research
Association between GLP-1 RAs and DPP-4 inhibitors with biliary disorders: pharmacovigilance analysis.
Frontiers in pharmacology, 16, 1509561
Citation
He, Long; Li, Jinwei; Cheng, Xiong; Luo, Li; Huang, Yilan. (2025). Association between GLP-1 RAs and DPP-4 inhibitors with biliary disorders: pharmacovigilance analysis.. Frontiers in pharmacology, 16, 1509561. https://doi.org/10.3389/fphar.2025.1509561