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Introduction Chronic pancreatitis (CP) patients are at increased risk for exocrine/endocrine pancreatic insufficiency, recurrent acute pancreatitis (RAP), pancreatic cancer, and mortality. Concerns exist that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may exacerbate pancreatic injury, but robust real-world data in established CP are limited. The aim of this study is to evaluate the association between GLP-1 RA therapy and pancreatic, gastrointestinal, and mortality outcomes in adults with CP using a large federated electronic health record network.Methods We conducted a retrospective cohort study using the TriNetX US Collaborative Network. Adults ≥18 years with CP (ICD-10-CM K86.0 or K86.1) were stratified into: Cohort 1 (CP+GLP-1 RA, n=10,978) with prescriptions for dulaglutide, semaglutide, or tirzepatide; and Cohort 2 (CP without GLP-1 RA, n=245,024) with no GLP-1 RA exposure. After 1:1 propensity score matching on age, sex, race, and 25 comorbidities, 10,625 patients remained in each cohort (standardised differences <0.075). Outcomes (exocrine pancreatic insufficiency, endocrine pancreatic insufficiency, RAP, pancreatic cancer, ED visits, hospitalisations, gastroparesis, composite GI cancers, DKA/HHS, all-cause mortality) were assessed over 3 years. Risk analyses calculated risk differences, ratios, and odds ratios. Kaplan-Meier analysis estimated survival probabilities.Results Over 3 years, GLP-1 RA users had significantly lower incidence of exocrine insufficiency (3.1% vs 6.3%; RR 0.491, 95% CI 0.429–0.562, p<0.001), endocrine insufficiency (6.0% vs 8.2%; RR 0.742, 95% CI 0.664–0.829, p<0.001), RAP (5.8% vs 10.5%; RR 0.554, 95% CI 0.487–0.631, p<0.001), and pancreatic cancer (2.0% vs 3.9%; RR 0.498, 95% CI 0.421–0.590, p<0.001). ED visits occurred in 17.4% vs 22.4% (RR 0.778, p<0.001) and hospitalisations in 18.0% vs 26.3% (RR 0.684, p<0.001). Gastroparesis developed in 2.3% vs 3.0% (RR 0.771, p=0.003). Critically, all-cause mortality was 6.9% in GLP-1 RA users versus 16.4% in non-users (RR 0.423, 95% CI 0.390–0.459, p<0.001), with 3-year survival of 88.6% versus 79.1%.Conclusions In a large propensity-matched cohort, GLP-1 RA therapy was not associated with increased risk of pancreatic complications, gastroparesis, or metabolic derangements. Instead, GLP-1 RA use was associated with substantially lower risks of pancreatic insufficiency, RAP, pancreatic cancer, healthcare utilisation, and dramatically improved overall survival. These real-world findings support the safety of GLP-1 RAs in established chronic pancreatitis and suggest potential protective pancreatic effects warranting further investigation.Abstract FP39 Figure 1Key pancreatic outcomes and all-cause mortality in GLP-1 RA users vs non-users with chronic pancreatitis