Glucagon-Like Peptide-1 Receptor Agonists and Gastrointestinal Adverse Events: A Systematic Review and Meta-Analysis.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of placebo-controlled randomized controlled trials
PubMed 40499738 · doi:10.1053/j.gastro.2025.06.003
What was done
A systematic review and random-effects meta-analysis of 5 databases was conducted to evaluate placebo-controlled randomized controlled trials of GLP-1 receptor agonists in patients with type 2 diabetes mellitus, overweight/obesity, or metabolic dysfunction-associated steatotic liver disease/steatohepatitis. Eligible trials reported predefined gastrointestinal and biliary adverse outcomes including cholecystitis, cholelithiasis, pancreatitis, gastroesophageal reflux disease (GERD), gastroparesis, intestinal obstruction, and gastrointestinal bleeding or perforation. Subgroup analyses examined patient populations, dual agonists, weight-loss profile, dose, and duration of action.
What was found
Across 55 randomized controlled trials with 106,395 participants, GLP-1RAs increased the risk of cholelithiasis (risk ratio [RR] 1.46, 95% CI 1.09–1.97; absolute increase of 2 cases per 1,000) and probably increased the risk of GERD (RR 2.19, 95% CI 1.48–3.25; absolute increase of 4 cases per 1,000) relative to placebo. GLP-1RAs showed little to no effect on the risk of other biliary or gastrointestinal events. Subgroup trends toward higher risks in patients with overweight/obesity or liver disease, higher doses, or weight-loss-inducing agents were not statistically significant.
Why it matters
This large meta-analysis clarifies that while GLP-1 receptor agonists cause modest absolute increases in gallstones and GERD, they do not appear to increase the risk of other serious gastrointestinal adverse events.
Limits
The abstract does not provide numerical effect estimates or confidence intervals for the non-significant outcomes (such as pancreatitis, gastroparesis, or intestinal obstruction). It also omits trial-level treatment durations, definitions used for adverse events, and head-to-head comparisons between individual agents.
Cited by
- supports Eating large solid meals close to bedtime while on GLP-1 receptor agonists leads to severe heartburn and gastrointestinal discomfort due to delayed gastric emptying.