Obesity affects 15%-40% of adults with Crohn's disease (CD) and is associated with worse outcomes. GLP-1 receptor agonists (GLP-1RAs) have pleiotropic anti-inflammatory effects, yet their clinical impact in CD with comorbid obesity is incompletely characterized. We evaluated whether GLP-1RA initiation was associated with mortality, health care utilization, and TNF inhibitor use as a proxy measure of treatment intensity. Retrospective new-user cohort study using the TriNetX Global Collaborative Network (162 organizations, 2015-2024). Adults (≥ 18 years) with CD and obesity without prior GLP-1RA exposure were included. Nonusers received calendar-time-matched index dates to minimize immortal time bias. Propensity score matching (1:1) incorporated > 30 covariates including comorbidities, CD treatment intensity proxies, and inflammatory markers. Outcomes were assessed at 1 year (days 1-365 post-index) and 5 years (days 1-1,825 post-index); both time windows were analyzed as fixed horizons under an intention-to-treat framework using separate TriNetX query runs. Patients were censored at last recorded EHR encounter or study end (2024). Due to database constraints, detailed longitudinal exposure data (adherence, discontinuation, agent switching) were not available. Among 10,550 GLP-1RA users and 108,944 nonusers, 9,766 pairs were matched at 1 year and 9,320 at 5 years (the latter representing a subset of the base population with sufficient follow-up). After matching, covariates were well-balanced (all SMDs < 0.1 except BMI by design). At 1 year, GLP-1RA initiation was associated with lower mortality (0.7% vs. 4.2%; RR 0.17, 95% CI 0.13-0.22), hospitalization (10.0% vs. 24.7%; RR 0.40, 95% CI 0.38-0.43), ED visits (18.9% vs. 25.3%; RR 0.75, 95% CI 0.71-0.79), and TNF inhibitor use (7.1% vs. 10.9%; RR 0.65, 95% CI 0.60-0.72); corticosteroid rates were similar (RR 1.00, 95% CI 0.96-1.03). At 5 years, all utilization associations were sustained; corticosteroid use was modestly lower (RR 0.91, 95% CI 0.89-0.94). E-value for 1-year mortality upper CI: 8.56; healthy-user bias cannot be excluded. In adults with CD and obesity, GLP-1RA initiation was associated with lower health care utilization and lower TNF inhibitor use at 1 and 5 years; the latter should not be interpreted as evidence of reduced treatment escalation given inability to distinguish new initiation from continuation. The observed mortality difference is unlikely to reflect a true causal effect and should be treated as hypothesis-generating. These findings support GLP-1RA metabolic safety in this population and warrant prospective evaluation.
