Real-world analysis on the impact of GLP-1 receptor agonists on survival and metastatic risk in colorectal cancer.

62 Background: GLP-1 receptor agonists (GLP-1RAs), commonly prescribed for type 2 diabetes (T2DM) and obesity, have demonstrated anti-proliferative effects in colorectal cancer (CRC) cell lines by inhibiting the PI3K/Akt/mTOR pathway. However, clinical data on the impact of GLP-1RAs on CRC outcomes remains limited. This study presents the first real-world analysis evaluating the association between GLP-1RA use and survival and metastatic risk in patients with CRC. Methods: Using the TriNetX database, we utilized de-identified records from 130 million patients across 108 health systems. CRC patients receiving GLP-1RAs (cohort A) were matched to non-users (cohort B). The primary endpoint was all-cause mortality, and the secondary endpoint was the incidence of metastasis. Patients with outcomes prior to the study window were excluded. Subgroup analyses included age, DM2 status, BMI, cancer stage, treatment (surgery alone vs. surgery + first-line chemotherapy), and type of GLP-1RA. Propensity score matching adjusted for demographics, comorbidities, cancer stage, and prior chemotherapy. Multivariate logistic regression and Cox proportional hazards model assessed associations (HR with 95% CI). Results: After matching, 10,340 patients were analyzed (5,170 per cohort). Cohort A had a mean age of 61.4 years, with 51% male, 66.5% White, and 14.8% Black participants—similar to those in Cohort B. GLP-1RA use was associated with a 53% reduction in 10-year all-cause mortality, with 446/5,033 vs 726/5,029 events HR: 0.466 (0.414-0.524). This translates to an ARR of 5.57%, yielding a NNT of 18. This survival benefit was consistent across subgroups: age ≥65 HR:0.569 (0.486-0.665), DM2 HR:0.488 (0.431-0.553), non-DM2 HR:0.286 (0.162-0.504), BMI ≤29 HR 0.538 (0.446-0.649), BMI ≥ 30 HR: 0.515 (0.440-0.602), and with colectomy + chemotherapy HR:0.369 (0.298-0.456). Agent-specific analysis revealed mortality benefit with tirzepatide HR:0.065 (0.015-0.274), semaglutide HR: 0.377 (0.297-0.479, and dulaglutide HR:0.556 (0.447-0.692). Secondary endpoint analysis revealed no significant association with metastases HR:0.895 (0.777-1.032). Conclusions: GLP-1RA therapy was associated with reduced all-cause mortality in patients with CRC, without an observed increase in metastatic risk. These novel real-world findings, consistent across subgroups and agents, highlight a potential oncologic benefit beyond glycemic control and warrant further investigation in prospective randomized trials.