Reassessing cancer risk with GLP-1 receptor agonists: a comprehensive meta-analysis of gastrointestinal malignancies

Background and Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed for type 2 diabetes mellitus (T2DM) and obesity. While their metabolic benefits are established, concerns persist about a possible link with gastrointestinal (GI) cancers. This study aimed to clarify the association between GLP-1 RA use and GI cancer risk. Materials and Methods: A systematic search of PubMed, Embase, and Scopus till August 2024 identified randomized controlled trials (RCTs) reporting GI cancer outcomes. Ninety-three RCTs with 1.85 million participants were included. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a random-effects model, with subgroup analyses by cancer type and exposure duration. Results: GLP-1 RA use was not associated with an increased overall risk of GI cancers (HR 0.81: 95% CI: 0.68-0.96). Subgroup analyses indicated reduced risks of colorectal cancer (HR 0.81: 95% CI: 0.68-0.96) and liver cancer (HR: 0.74; 95% CI: 0.62-0.88). Pancreatic cancer risk was not significantly elevated (HR: 0.78; 95% CI: 0.61-0.95). Findings were consistent across sensitivity analyses. Conclusion: This meta-analysis of RCTs provides reassuring evidence that GLP-1 receptor agonists were not associated with an increased risk of gastrointestinal cancers, with signals suggesting a possible reduction in colorectal and liver cancer incidence that should be interpreted cautiously. These results support the continued safe use of GLP-1 RAs in T2DM and obesity, although longer trials with cancer-specific endpoints are warranted. This review was registered in Open Science Framework https://osf.io/3rv6d/overview. Systematic Review Registration: https://osf.io/3rv6d/overview.