Relationship between GLP-1 receptor agonists on cancer recurrence and survival of patients with stage I-III colorectal cancer: A retrospective cohort study using the TriNetX database.

Abstract

3636 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide, and obesity is a known risk factor. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are increasingly used for obesity and diabetes management, making it critical to understand their long-term implications. Preclinical studies suggest a protective effect of GLP-1RA in risk for developing obesity-related malignancies, including CRC, but their long-term influence on recurrence and survival among those with CRC is not well characterized. Methods: A retrospective cohort study was conducted using TriNetX, a federated health research network of real-world data. Data were queried on January 22, 2026, from the Global Collaborative Network, encompassing over 190 million de-identified electronic medical records. Adult patients (> 18 years) with a diagnosis of stage I-III CRC between April 1, 2005, and April 1, 2025, were identified. The exposure group was defined as patients prescribed GLP-1RA following their CRC diagnosis. The control group was GLP-1RA nonusers. Propensity score matching (PSM) was employed, achieving balance across demographics, comorbidities, and confounding variables. The primary outcome was recurrence free survival (RFS), and the secondary outcome was overall survival (OS). Kaplan–Meier survival analysis, log-rank test, hazard ratios (HR) with 95% confidence intervals (CI), and risk ratios (RR) were used to estimate outcomes over 5-years of follow-up. Results: Among 20,383 patients with CRC across 19 HCOs, 839 patients per group with mean age 63.0 years remained after 1:1 PSM and exclusions, with comparable median follow-up times (710 vs 1160 days). GLP-1RA use was significantly associated with a lower risk of recurrence compared with nonusers (RR, 0.33; 95% CI, 0.25-0.45; p < 0.001) and improved RFS probabilities (89.0% vs 72.8%; [HR, 0.37; 95% CI, 0.27-0.50; p < 0.001]) at the 5-year follow-up. A significant improvement in OS was also observed in GLP-1RA users compared with nonusers (82.5% vs 71.4%; [HR 0.45; 95% CI, 0.34-0.60; p < 0.001]), and reduced mortality risk (RR, 0.35; 95% CI, 0.27-0.46; p < 0.001) compared with nonuse. Secondary analysis with 15-year median follow-up period demonstrated that these survival and recurrence benefits were sustained long term with median OS of 4,382 and 3,931 days in GLP-1RA users vs nonusers respectively. Conclusions: In this real-world analysis, GLP-1RA use in patients with stage I-III CRC was associated with improved RFS and OS compared to nonusers. These findings were consistent across both 5-year and 15-year follow-up periods, demonstrating a sustained association with improved outcomes in CRC. Prospective trials are needed to strengthen the evidence base for GLP-1RA use in patients with CRC and to define the underlying biological mechanisms.