INTRODUCTION: Type 2 diabetes mellitus (T2DM) can lead to structural pancreatic changes potentially predisposing to acute pancreatitis (AP), increasing morbidity and mortality. Scarce data exist on the outcomes of AP in patients with T2DM who are taking glucagon-like peptide-1 receptor agonists (GLP-1 RAs). The study aim was to evaluate AP outcome and all-cause mortality in patients with T2DM using GLP-1 RAs. METHODS: A retrospective cohort study was performed using population-based data from the TriNetX platform. Patients with T2DM receiving GLP-1 RAs drugs (semaglutide, liraglutide, dulaglutide, and tirzepatide) between January 1, 2015, and October 31, 2023, were included. This patient cohort was matched with patients with T2DM who did not receive GLP-1 RAs according to age, demographics, comorbidities, and medication by using 1:1 propensity matching. To avoid confounding, etiologies of AP including alcohol-induced, trauma, biliary, class Ia drug-induced, hypertriglyceridemia, and postendoscopic retrograde cholangiopancreatography were excluded from both cohorts. Primary outcomes were risk of developing AP, need for parenteral nutrition, systemic complications (sepsis, systemic inflammatory response syndrome, shock, mechanical ventilation, acute kidney injury), and local pancreatic complications. The secondary outcome was all-cause mortality. Cox proportional hazards models were used to estimate hazard ratios (HRs). RESULTS: A total of 740,370 patients with T2DM were identified with 29,423 on GLP-1 RAs; 20,459 of those 29,423 (mean [SD] age, 58.1 [11.9] years; 10,190 [49.85%] female) were matched with 20,459 individuals (mean [SD] age, 57.5 [13.9] years; 10,301 [50.35%] female) who did not take GLP-1 RAs. The GLP-1 RAs group had lower risk of complicated pancreatitis (HR 0.32; 95% confidence interval [CI] 0.14-0.74), parenteral nutrition needs (HR 0.28; 95% CI 0.09-0.83), sepsis (HR 0.71; 95% CI 0.59-0.84), acute kidney injury (HR 0.54; 95% CI 0.49-0.60), shock (HR 0.52; 95% CI 0.36-0.75), and mechanical ventilation support during admission (HR 0.23; 95% CI 0.16-0.33) compared with the non-GLP-1 RAs group. In addition, all-cause mortality was decreased in the GLP-1 agonist group compared with the non-GLP-1 agonist group (HR 0.45; 95% CI 0.41-0.49). Important to note that the GLP-1 RAs group had a tendency of lower risk of uncomplicated pancreatitis (HR 0.71; 95% CI 0.49-1.01) but without statistically significant result. No difference was found between the groups in risk of developing systemic inflammatory response syndrome if it occurs. DISCUSSION: GLP-1 RAs use does not increase AP risk is associated with lower complications in those who developed AP and linked with lower all-cause mortality in patients with T2DM. Prospective studies are needed to determine the mechanisms behind these findings.