Glucagon-Like Peptide-1 Receptor Agonists and Gastrointestinal Adverse Events: A Systematic Review and Meta-Analysis

Jun 11, 2025Gastroenterology

Digestive Side Effects of Drugs That Activate Glucagon-Like Peptide-1 Receptors: A Comprehensive Review and Analysis

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Abstract

GLP-1 receptor agonists are associated with an increased risk of cholelithiasis (1.46 risk ratio) and probably increase the risk of gastroesophageal reflux disease (2.19 risk ratio).

GLP-1 receptor agonists may lead to 2 additional cases of cholelithiasis per 1000 patients compared to placebo.
The risk of gastroesophageal reflux disease could increase by 4 more cases per 1000 patients taking GLP-1 receptor agonists.
There is probably little or no effect of GLP-1 receptor agonists on other gastrointestinal or biliary events.
Increased risks for cholelithiasis and gastroesophageal reflux disease were noted particularly in patients with overweight/obesity or metabolic dysfunction-related liver disease.
Higher doses and weight-loss-inducing formulations of GLP-1 receptor agonists may further elevate these risks, although these findings were not statistically significant.

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BACKGROUND & AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for glycemic control or weight management in patients with type 2 diabetes mellitus or overweight/obesity. However, there are concerns regarding their association with serious gastrointestinal adverse events, although findings have been inconsistent.

METHODS: We systematically searched 5 databases for placebo-controlled randomized controlled trials assessing GLP-1RAs in patients with type 2 diabetes mellitus, overweight/obesity, or metabolic dysfunction-associated steatohepatitis/metabolic dysfunction-associated steatotic liver disease. We included trials that reported cholecystitis, cholelithiasis, cholangitis, cholestasis, pancreatitis, gastroesophageal reflux disease (GERD), gastritis, esophagitis, gastrointestinal ischemia, gastrointestinal hemorrhage, intestinal obstruction, paralytic ileus, gastrointestinal ulceration, gastrointestinal perforation, or gastroparesis. Meta-analyses were performed using a random-effects model, with subgroup analyses evaluating risks based on patient population, GLP-1RA vs dual-agonist formulation, weight-loss profile, dosing, and duration of action.

RESULTS: We included 55 randomized controlled trials involving 106,395 participants. GLP-1RAs increased the risk of cholelithiasis (risk ratio [RR], 1.46; 95% CI, 1.09-1.97; 2 more cases per 1000) and probably increased the risk of GERD (RR, 2.19; 95% CI, 1.48-3.25; 4 more cases per 1000) compared with placebo. GLP-1RAs probably have little or no effect on the risk of other gastrointestinal or biliary events. Subgroup analyses showed that the increased risks of cholelithiasis and GERD were more pronounced in trials including individuals with overweight/obesity or metabolic dysfunction-associated steatohepatitis/metabolic dysfunction-associated steatotic liver disease, weight-loss-inducing GLP-1RAs, or high-dose formulations, although these subgroup effects were not statistically significant.

CONCLUSIONS: 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.

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Glucagon-Like Peptide-1 Receptor Agonists and Gastrointestinal Adverse Events: A Systematic Review and Meta-Analysis

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