GLP-1 receptor agonists and the risk of acute pancreatitis: a living systematic review and meta-analysis

Abstract Background There are concerns that glucagon-like peptide-1 receptor agonists (GLP1s) increase the risk of acute pancreatitis. Methods We searched Medline and clinicaltrials.gov in March 2026 for placebo-controlled randomized trials of semaglutide and tirzepatide reporting the incidence of acute pancreatitis, according to a pre-specified protocol (PROSPERO ID 1346039). The primary analysis used a fixed-effect Mantel–Haenszel odds ratio. Heterogeneity was assessed using Cochran’s Q and I-squared. Results 1635 studies were found, 31 placebo-controlled trials of which were included, totalling 40,274 patients. There were 59 acute pancreatitis events in GLP1 groups (of 22,841 patients) and 50 in placebo groups (of 17,433 patients). The pooled fixed-effect Mantel–Haenszel odds ratio was 0.99 (95% confidence interval 0.67 to 1.45; p=0.95). Active-treatment exposure totaled 51,346 patient-years, including 47,749 patient-years for semaglutide and 3,598 patient-years for tirzepatide. Sensitivity analysis for risk ratio, and subgroup analysis divided by drug class, disease focus, or dose, did not reveal any significant differences. Conclusions Semaglutide and tirzepatide were not associated with an increased risk of acute pancreatitis versus placebo. These findings are reassuring, but small differences in risk cannot be fully excluded given the rarity of events. Given the rapidly-evolving nature of this field and the importance of the dataset, this review will be updated as further randomized trials are published.