Written by Mary Marschner
Spoon Feed
GLP-1 receptor antagonists likely increase the risk of cholelithiasis and GERD when compared to placebo, but this meta-analysis of RCTs suggests that the risk of pancreatitis, cholecystitis, and intestinal obstruction may be lower than previous studies.
Exploring GI/biliary side effects of GLP-1 receptor antagonists
GLP-1 receptor antagonists are everywhere! They are effective, expensive, and being prescribed in huge numbers, which means understanding side effects and risks of complications are very important.
Current indications to initiate GLP-1 therapy are obesity, type 2 diabetes, and cardiovascular risk reduction for patients with type 2 diabetes. NASH/NAFLD is under investigation, but I have started seeing many of these patients on GLP-1s already. GI/ biliary side effects have been the most widely reported, which is what this review focused on.
In this 2025 systematic review and meta-analysis of 55 RCTs (106,395 participants), GLP‑1 receptor agonists (e.g., semaglutide, liraglutide) were assessed for gastrointestinal adverse events in patients with diabetes, obesity, or NASH. Compared to placebo, GLP‑1RAs significantly increased cholelithiasis (RR 1.46; 95%CI 1.09–1.97; ~2 additional cases/1,000) and GERD (RR 2.19; 95%CI 1.48–3.25; ~4 additional cases/1,000), but did not significantly elevate risk of pancreatitis, cholecystitis, intestinal obstruction, or other serious GI/biliary events.
This review is limited. It is always hard to compare different RCTs, and the individual trials looked at varied GLP-1 RAs, doses, and durations, so it’s hard to know the risk of particular drugs or the timeline of developing these adverse events.
How does this change my practice?
Despite GI side effects, GLP-1s are so effective, and the longterm risks of obesity/diabetes outweigh the risks in my mind. I mainly find the study encouraging, that not many patients who are prescribed GLP-1s will experience cholecystitis, pancreatitis, or obstruction. I see GERD and cholelithiasis as inconvenient but manageable. I do think there should be more studies looking at the mechanism behind gallstone formation as well as pancreatitis––is it the GLP-1, the rapid weight loss? Answering the mechanistic questions will help us to be better informed on whether the GLP-1 should be discontinued indefinitely after experiencing these side effects or restarted at a later date.
Source
Glucagon-Like Peptide-1 Receptor Agonists and Gastrointestinal Adverse Events: A Systematic Review and Meta-Analysis. Gastroenterology. 2025 Jun 9:S0016-5085(25)00845-5. doi: 10.1053/j.gastro.2025.06.003. Epub ahead of print. PMID: 40499738
