GLP-1 RAs associated with increased risk of gallstones, reflux, meta-analysis finds

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with an increased risk of cholelithiasis and gastroesophageal reflux disease (GERD) but do not appear to increase the risk of other gastrointestinal or biliary adverse events, a systematic review and meta-analysis found.

Researchers included 55 placebo-controlled, randomized controlled trials involving 106,395 participants assessing risk of gastrointestinal events in GLP-1 RAs in patients with diabetes, overweight or obesity, or non-alcoholic steatohepatitis (NASH)/metabolic dysfunction-associated steatotic liver disease (MASLD). Studied conditions included cholecystitis, cholelithiasis, cholangitis, cholestasis, pancreatitis, GERD, gastritis, esophagitis, gastrointestinal ischemia, gastrointestinal hemorrhage, intestinal obstruction, paralytic ileus, gastrointestinal ulceration, gastrointestinal perforation, or gastroparesis. The study was published June 9 by Gastroenterology.

GLP-1 RAs were associated with increased the risk cholelithiasis (RR [risk ratio], 1.46 [95% CI, 1.09 to 1.97]; two more cases per 1,000) and GERD (RR, 2.19 [95% CI, 1.48 to 3.25]; four more cases per 1,000) compared to placebo. GLP-1 RAs probably have little or no effect on the risk of other gastrointestinal or biliary events, the review found. Subgroup analyses showed non-statistically significant increased risks of cholelithiasis and GERD in trials including patients with overweight/obesity or NASH/MASLD or using high-dose formulations.

The study authors noted that there was a diverse cohort of patients from various regions and ethnic backgrounds and a comprehensive range of gastrointestinal and biliary adverse events, with a large-enough sample size to power multiple subgroup and sensitivity analyses of different patient characteristics and GLP-1RA formulations. They also noted heterogeneity in trial design, patient populations, inclusion/exclusion criteria, and GLP-1RA dosing, type, and treatment duration.

“In conclusion, GLP-1RAs were associated with an increased risk of GERD and cholelithiasis but did not significantly increase the risk of pancreatitis, cholecystitis, intestinal obstruction, or other serious gastrointestinal or biliary events,” the authors wrote. “Contrary to previous studies, our findings suggest that the risk of serious gastrointestinal and biliary events with GLP-1RAs may be lower than previously reported. These findings provide important insights into the safety profile of GLP-1RAs and may help guide clinical decision-making in patients with [type 2 diabetes], overweight/obesity, or NASH/MASLD.”