Analysis of over 68,000 FDA adverse event reports found DPP-4 inhibitors had significant associations with gallstones and cholecystitis, while GLP-1 receptor agonists like liraglutide and semaglutide showed weaker but notable gallbladder/biliary disease links.
Reporting odds ratio: 2.85Incretin-based therapies showed a pooled 2.85-fold higher odds of hepatobiliary adverse event reports compared to other drugs in the FDA safety database — a significant safety signal warranting further study.
What the researchers found
Among 68,351 incretin therapy case reports in FAERS, 1,327 (1.94%) involved hepatobiliary adverse events, with a pooled reporting odds ratio of 2.85 indicating a positive correlation.
DPP-4 inhibitors showed statistically significant associations with cholelithiasis (gallstones), chronic cholecystitis, and biliary diseases. GLP-1 receptor agonists showed weaker overall associations but were linked to gallbladder/biliary disorders and had higher acute cholecystitis risk. Among specific drugs, liraglutide and semaglutide showed stronger positive correlations among GLP-1 agonists, while sitagliptin, linagliptin, and vildagliptin stood out among DPP-4 inhibitors. The associations may be dose-dependent.
Why it matters
As GLP-1 receptor agonists and DPP-4 inhibitors are prescribed to millions of people worldwide for diabetes (and increasingly for weight loss), understanding their safety profile is critical. This large-scale analysis identifies hepatobiliary events as a potential concern — particularly gallbladder problems — that clinicians should monitor for, especially in patients with pre-existing gallbladder risk factors.
How the study worked
This pharmacovigilance study extracted case reports involving incretin therapies and hepatobiliary adverse events from the FDA Adverse Event Reporting System (FAERS) spanning January 2006 to December 2023. Associations were analyzed using reporting odds ratios and empirical Bayesian geometric means. Descriptive analyses characterized demographic and clinical features. Subgroup analyses evaluated specific drug-event associations.
What this study cannot tell us
FAERS is a spontaneous reporting system subject to reporting bias, underreporting, and the inability to establish causation. Reporting odds ratios cannot account for confounding factors like obesity, rapid weight loss, and diabetes itself — all of which are independent risk factors for gallbladder disease. The study cannot determine incidence rates or absolute risk. Duplicate reports may exist in FAERS data. The Weber effect (increased reporting for newer drugs) could inflate associations for more recently approved agents.
How to read the evidence
This is a pharmacovigilance analysis of spontaneous adverse event reports, which can identify safety signals but cannot establish causation. FAERS studies are useful for hypothesis generation but have significant methodological limitations compared to controlled clinical trials or cohort studies.
When this study was published
Published in 2024 using data through December 2023, this is a very current safety analysis that captures recent high-volume prescribing of GLP-1 agonists for both diabetes and weight management.
The bigger picture
As incretin-based therapies expand beyond diabetes to obesity treatment, their safety profile under broader use becomes increasingly important. This study adds to growing pharmacovigilance signals about gallbladder complications with these drug classes. The finding that rapid weight loss from GLP-1 agonists may contribute to gallstone formation has implications for the millions of people using these drugs for weight management.
Questions still open
- Is the gallbladder risk from GLP-1 agonists driven by the drug mechanism itself or by the rapid weight loss they cause?
- Should patients starting GLP-1 RA therapy be screened for pre-existing gallbladder disease?
- Do tirzepatide and other newer dual-agonist drugs share the same hepatobiliary safety signals?
Common questions
Can GLP-1 drugs like semaglutide cause gallbladder problems?
Should I be worried about liver problems from my diabetes medication?
Read the original research
Association of incretin-based therapies with hepatobiliary disorders among patients with type 2 diabetes: a case series from the FDA adverse event reporting system.
Endocrine connections, 13(12)
Citation
Liang, Yankun; Zhang, Zhenpo; Zheng, Jingping; Wang, Yuting; He, Jiaxin; Zhao, Juanzhi; Su, Ling. (2024). Association of incretin-based therapies with hepatobiliary disorders among patients with type 2 diabetes: a case series from the FDA adverse event reporting system.. Endocrine connections, 13(12). https://doi.org/10.1530/EC-24-0404