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.

General Internal Medicine-Primary Care(US) rater

This is the largest (55 RCTs, >106,000 patients) and most rigorous meta-analysis of GI SEs associated with GLP-1 receptor agonists, currently taken by millions with a rapidly growing number. The meta-analysis found a significant but very low absolute risk (<1%) of cholelithiasis and GERD but not of pancreatitis or motility disorders.

Internal Medicine rater

Given the widespread use of GLP-1 receptor agonists in diabetes and obesity, this large meta-analysis of placebo-controlled RCTs is highly relevant to my practice as a general internist. The findings are clinically important, highlighting increased risks of GERD and cholelithiasis but not pancreatitis or intestinal obstruction. Absolute risk increases for GERD and cholelithiasis were notably modest. These results may help better inform patients and clinicians, particularly those who may otherwise overestimate the risk of specific gastrointestinal events. From a methods perspective, the systematic review is well-conducted, considers relevant subgroup effects, evaluates risk of bias of included studies, incorporates certainty of evidence judgements (unclear which system was used, presumably GRADE; could benefit from more clarity) and presents treatment effects in both relative and absolute terms, enhancing interpretability.

Internal Medicine rater

Outstanding review of multiple trials with about 5 years of follow-up. Especially helpful is the infographic on the first page. The take-home message for me: "Clinicians should be aware of the small but increased risks of cholelithiasis and gastroesophageal reflux with GLP-1RA use. However, GLP-1RAs do not appear to increase the risk of other serious gastrointestinal or biliary adverse events."

Special Interest - Obesity -- Physician rater

Not sure how much news this is, almost any kind of rapid weight loss is associated with gallstones. I suppose the lack of association with things like acute pancreatitis may be news.