GLP-1 Receptor Agonists Linked to Increased Risk of Gallstones and GERD
A new systematic review and meta-analysis raises concerns that glucagon-like peptide-1 receptor agonists (GLP-1RAs modestly increase the risk of cholelithiasis and gastroesophageal reflux disease (GERD), especially in patients using higher doses or seeking weight loss.
“Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for glycemic control or weight management,” the study authors noted. “However, there are concerns regarding their association with serious gastrointestinal adverse events.”
Researchers reviewed 55 placebo-controlled randomized trials involving 106,395 participants across indications including type 2 diabetes, overweight/obesity, and metabolic liver disease. The review focused on 14 prespecified gastrointestinal and biliary adverse events.
GLP-1RAs were associated with:
- Cholelithiasis: Risk ratio (RR) 1.46 (95% CI, 1.09–1.97), translating to 2 more cases per 1000
- GERD: RR 2.19 (95% CI, 1.48–3.25), or 4 more cases per 1000
For all other GI and biliary outcomes—such as pancreatitis, intestinal obstruction, gastroparesis, and GI bleeding—the data suggested little to no increased risk compared with placebo.
Subgroup analyses indicated that these adverse effects were more pronounced in studies involving:
- Patients with overweight/obesity or metabolic liver disease
- Weight-loss-promoting or high-dose GLP-1RAs
- Long-acting formulations
However, none of these subgroup effects reached statistical significance.
“GLP-1RAs are associated with an increased risk of cholelithiasis and GERD, but do not appear to increase the risk of other gastrointestinal or biliary adverse events.”
As the use of GLP-1RAs expands beyond diabetes into weight loss and metabolic disease prevention, clinicians should remain aware of these modest but measurable risks—particularly in patients using high-dose or long-acting formulations.
Reference
Chiang CH, Jaroenlapnopparat A, Colak SC, Yu CC, Xanthavanij N, Wang TH, See XY, Lo SW, Ko A, Chang YC, Song J, Hsia YP, Chiang CH. Glucagon-Like Peptide-1 receptor agonists and gastrointestinal adverse events: A systematic review and meta-analysis. Gastroenterology. 2025 Nov;169(6):1268-1281. doi: 10.1053/j.gastro.2025.06.003. Epub 2025 Jun 9. PMID: 40499738.
