GLP-1 receptor agonists and pancreatic cancer risk: target trial emulation using real-world data

Background Data on the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on pancreatic cancer incidence are limited and inconsistent. Here we evaluate the association of GLP-1RAs, alone and in combinations, with incident pancreatic cancer risk in a real-world population, stratified by obesity and smoking status. Methods This retrospective cohort included patients with T2DM who were prescribed GLP-1RAs or other non-GLP-1RA anti-diabetes medications between January 2013 and March 2019 and had no prior diagnosis of pancreatic cancer. The incident (first-time) diagnosis of pancreatic cancer during a 5-year follow-up was compared between propensity-score matched cohorts of patients prescribed GLP-1RAs vs other non-GLP-1RA anti-diabetes medications. Subgroup analyses were performed in patients stratified by the status of obesity and tobacco use disorder. We also compared GLP-1RA combination therapies with monotherapies. Time-to-first-event analysis was performed using Cox proportional hazards and Kaplan-Meier survival analysis, with the hazard ratio (HR) and 95% confidence interval (CI) calculated. Results The study population comprised 1,636,056 eligible patients including 167,091 prescribed GLP-1RAs and 1,468,965 prescribed other anti-diabetes medications. GLP-1RAs were associated with a significantly decreased risk for pancreatic cancer incidence compared with each of six non-GLP-1RA anti-diabetes medications with HR ranging from 0.42 to 0.82. The reduction was greater in patients with obesity and tobacco use disorder than in those without. GLP-1RA combination therapies were associated with lower pancreatic cancer risk compared with monotherapies. Conclusions GLP-1RAs were associated with reduced pancreatic cancer incidence in patients with T2DM. Further studies and trials are needed to explore mechanisms and confirm causal effects.