Evaluating the Rates of Pancreatitis and Pancreatic Cancer Among GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.
This systematic review and meta-analysis examined the risk of pancreatitis and pancreatic cancer associated with GLP-1 receptor agonists (GLP-1 RAs), including dulaglutide, exenatide, liraglutide, semaglutide, beinaglutide, retatrutide, and tirzepatide. Following PRISMA guidelines, the authors searched PubMed, Embase, and the Cochrane Library, ultimately including 62 randomised controlled trials encompassing 66,232 patients with a mean age of 58.3 years and a mean follow-up of approximately 43.5 weeks. The pooled analysis found a statistically significant increase in pancreatitis risk overall (RR: 1.44, 95% CI 1.09–1.89); however, this significance disappeared when results were stratified by background medication use, suggesting that concomitant medications may be a confounding factor. For pancreatic cancer, no significant overall association was identified (RR: 1.30, 95% CI 0.86–1.97), though a significant signal emerged in the subgroup taking background medications (RR: 1.85, 95% CI 1.05–3.26). The authors note this subgroup finding may be an artifact, as many excluded trials had zero events in both arms. Key limitations include variable follow-up durations, heterogeneous patient populations, and the influence of concomitant therapies, which complicate causal attribution to GLP-1 RAs alone.
Why this grade: Although this meta-analysis pools data from 62 RCTs with over 66,000 human participants, the evidence is graded moderate rather than strong due to heterogeneity in follow-up durations, patient populations, concomitant medication use, and the exclusion of zero-event trials, all of which limit the precision and generalisability of the risk estimates.
Aims This meta-analysis evaluates the rates of pancreatitis/pancreatic cancer among glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in randomised controlled trials (RCTs). Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), a systematic search was performed in PubMed, Embase, and Cochrane Library for GLP-1 RA RCTs that evaluated pancreatitis/pancreatic cancer. A meta-analysis was conducted to evaluate this risk; subgroup analysis was performed with and without background medications. Results 62 studies utilising dulaglutide, exenatide, liraglutide, semaglutide, beinaglutide, retatrutide, or tirzepatide, with 66,232 patients, mean age of 58.3 years (14.4 to 68), and mean follow-up of 43.5 weeks (1 to 198) were included in this study. Meta-analysis showed a significantly increased risk of pancreatitis (RR: 1.44, 95% CI 1.09-1.89, p = 0.009), but not when stratified by background medications (RR: 1.28, 95% CI 0.87-1.87) and without background medications (RR: 1.37, 95% CI 0.91-2.05). Pancreatic cancer and GLP-1 RA use showed no significant association (RR: 1.30, 95% CI 0.86-1.97). However, a significant increase was found with background medications (RR: 1.85, 95% CI 1.05-3.26, p = 0.03), but not without (RR: 0.81, 95% CI 0.43-1.55). Conclusion GLP-1 RAs carry a slightly increased risk of pancreatitis, which is not significant when stratified by background medication use. Overall risk for pancreatic cancer was not observed, but a slight association was found when stratified with background medications. However, this difference is likely minimal, given the numerous studies excluded from the meta-analysis where both treatment arms had zero events.
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