GLP-1 receptor agonists and pancreatic cancer risk: A meta-analysis of real-world and trial evidence.

712 Background: Pancreatic cancer is one of the most lethal gastrointestinal malignancies, with obesity and smoking as key risk factors. The widespread use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for diabetes and obesity has raised concern about pancreatic carcinogenesis. While early data were inconclusive, recent large cohorts suggest reduced risk. We conducted a meta-analysis to provide a pooled hazard ratio quantifying this association. Methods: Randomized trials and large observational cohorts reporting pancreatic cancer outcomes in GLP-1RA users were reviewed through February 2025. Hazard ratios (HRs) were extracted, log-transformed, and pooled using fixed-effects models. New-user, active-comparator, and landmark designs were prioritized. Studies without HRs were summarized qualitatively but excluded from pooling. Results: Dankner et al. reported HR 0.52 (95% CI 0.19–1.41) in a landmark new-user design versus basal insulin, with HR 0.75 (0.37–1.53) in a prevalent new-user analysis. Alchirazi et al. found HR 0.56 (0.44–0.72) versus insulin, HR 0.80 (0.73–0.89) versus DPP-4 inhibitors, HR 0.78 (0.69–0.89) versus SGLT2 inhibitors, and HR 0.84 (0.74–0.95) versus sulfonylureas. Wang et al. reported HRs from 0.42–0.82 across six comparator groups, with stronger effects in obese and smoking populations. Ayoub showed a seven-year risk of 0.1% in GLP-1RA users versus 0.2% in non-users, but no HR was reported. Kristensen’s randomized trial meta-analysis found HR 1.12 (0.77–1.63), consistent with no excess risk but limited by shorter follow-up. When seven HRs from four real-world studies and one trial meta-analysis were combined, GLP-1RA use was associated with a pooled HR of 0.79 (95% CI 0.72–0.86), representing a 21% risk reduction. Absolute incidence remained very low, not exceeding 0.2% at seven years. Conclusions: To our knowledge, this is one of the first pooled synthesis of hazard ratios showing that GLP-1RA therapy is not linked to increased pancreatic cancer risk and instead correlates with a significant reduction, particularly in obese and smoking populations. By integrating large real-world datasets with trial evidence, this analysis reframes GLP-1RAs from a potential liability to a therapy with possible risk-modifying effects on pancreatic carcinogenesis. Further research in GI cancer prevention and survivorship is warranted.