Impact of concomitant GLP-1 receptor agonist use on overall survival and chemotherapy-related adverse events in colorectal cancer: A real-world pharmacoepidemiologic cohort study.

Abstract

3661 Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for diabetes and obesity and exert pleiotropic metabolic and anti-inflammatory effects. While prior studies have focused on their role in cancer prevention, limited data exist regarding their impact on cancer treatment outcomes. We evaluated the association between concomitant GLP-1 RA use and overall survival (OS) in patients with colorectal cancer (CRC) receiving standard first-line chemotherapy. Methods: Using the Blue Diamond Global Collaborative Network, adult patients with CRC initiating first-line FOLFOX or FOLFIRI between 2015 and 2024 were identified. Patients were classified as GLP-1 RA users if they received a GLP-1 RA (e.g., semaglutide, liraglutide, dulaglutide) within 90 days before or after chemotherapy initiation, and non-users otherwise. Cohorts were 1:1 propensity score matched for age, sex, BMI, diabetes status, line of therapy, comorbidities, and baseline corticosteroid use. The primary endpoint was OS. Kaplan–Meier methods and Cox proportional hazards models were used for analysis. Results: After matching, 4,824 patients were included (2,412 per cohort). Baseline characteristics were well balanced (mean age 61.8 years; 46% female; mean BMI 31.2 kg/m²; 58% with diabetes). At a median follow-up of 24.6 months, patients receiving concomitant GLP-1 RAs demonstrated significantly improved overall survival compared with non-users. Median OS was 28.4 months among GLP-1 RA users versus 23.6 months among non-users (log-rank p <0.001). GLP-1 RA use was independently associated with improved OS (HR 0.82, 95% CI 0.76–0.89). Regarding safety outcomes, GLP-1 RA users experienced a lower incidence of neutropenia (18.9% vs 23.7%; RR 0.80, p =0.002) and reduced chemotherapy-induced neuropathy (14.2% vs 18.6%; RR 0.76, p =0.004). Subgroup analyses demonstrated consistent OS benefit across chemotherapy backbone: FOLFOX (HR 0.81) and FOLFIRI (HR 0.84), and the most pronounced effect in patients with BMI ≥30 kg/m². Sensitivity analyses restricting sustained GLP-1 RA exposure (>6 months) yielded similar results. Conclusions: In this large real-world cohort of patients with colorectal cancer, concomitant GLP-1 receptor agonist use was associated with improved overall survival and reduced chemotherapy-related toxicity. These findings suggest a potential adjunctive therapeutic role for GLP-1 RAs during active cancer treatment, potentially mediated through metabolic stabilization, reduced systemic inflammation, and improved treatment tolerance. Prospective studies are warranted to confirm these observations.