Long-Term Association Between GLP-1 Receptor Agonist Use and Incident Pancreatic Cancer: A Propensity Score-Matched Retrospective Cohort Study Using the TriNetX Network.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed for type 2 diabetes mellitus (T2DM) and obesity. Whether GLP-1 RA use is associated with altered long-term pancreatic cancer risk remains uncertain, with conflicting evidence from prior observational studies. We aimed to evaluate the association between initiation of GLP-1 RA therapy and incident pancreatic cancer risk compared with six classes of antidiabetic agents. METHODS: We conducted a retrospective, new-user cohort study using the TriNetX global federated electronic health record network. Adults with T2DM initiating GLP-1RA therapy were compared with incident users of insulin, metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, sulfonylureas, and thiazolidinediones in six separate propensity score-matched analyses (1:1, greedy nearest-neighbor algorithm, caliper 0.1 pooled standard deviations). Matching was performed on 39 baseline covariates,, including demographics, comorbidities, procedures, and medication exposures. The primary outcome was incident pancreatic cancer (ICD-10-CM C25) occurring between 365 and 7,300 days after the index prescription. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. RESULTS: After propensity score matching, GLP-1 RA users compared with insulin users had a lower hazard of pancreatic cancer (HR 0.43, 95% CI 0.35, 0.53; absolute risk: GLP-1 RA 0.15% vs. insulin 0.11%; absolute risk difference [ARD] 0.04% points). In contrast, users of metformin (HR 1.39, 95% CI 1.16, 1.66; ARD 0.04% points), sulfonylureas (HR 1.37, 95% CI 1.13, 1.65; ARD 0.07% points), thiazolidinediones (HR 1.30, 95% CI 1.001, 1.678; ARD 0.15% points) and DPP-4i (HR 1.31; 95% CI 1.06, 1.61; ARD 0.08% points) had significantly higher hazards of pancreatic cancer compared with GLP-1 RA users. No significant difference was observed between GLP-1 RA users and users of SGLT2 inhibitors (HR 1.08, 95% CI 0.87, 1.34). CONCLUSIONS: In this large, real-world, propensity score-matched analysis, the direction and magnitude of the association between GLP-1 RA use and pancreatic cancer risk varied by comparator agent. GLP-1 RA use was associated with a lower hazard of pancreatic cancer relative to metformin, sulfonylureas, thiazolidinediones, and DPP-4i while no significant difference relative to SGLT2i, and a higher hazard relative to insulin.