Glucagon-like Peptide-1 Receptor Agonists and Colorectal Cancer Risk

Type 2 diabetes mellitus (T2DM) is a highly prevalent metabolic disorder and a well-established risk factor for colorectal cancer (CRC), mediated by hyperglycemia, hyperinsulinemia, chronic inflammation, and obesity-related metabolic dysfunction.Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for the treatment of T2DM and obesity, populations already at elevated baseline risk for CRC.This raises important questions regarding their longterm oncologic safety.This review summarizes mechanistic, preclinical, and clinical evidence evaluating the association between GLP-1RA therapy and CRC risk.Mechanistic studies largely suggest antitumor effects through metabolic reprogramming, suppression of oncogenic signaling pathways, inhibition of angiogenesis and epithelial-mesenchymal transition, immune modulation, epigenetic remodeling, and systemic improvements in insulin sensitivity and inflammation.However, real-world studies show mixed results.Many randomized controlled trials, meta-analyses, and large population-based cohort studies demonstrate a neutral association between GLP-1RA use and CRC risk.Several large observational studies report a protective association, particularly among individuals with obesity or those treated with insulin.In contrast, a smaller number of studies, including select randomized trials, retrospective cohorts, and genetic analyses, have suggested a potential increase in CRC risk, often attributed to detection bias or confounding variables rather than a clear causal mechanism.Overall, current evidence suggests that GLP-1RAs are unlikely to meaningfully increase CRC risk and may offer protective metabolic and anti-inflammatory benefits in select populations.Continued long-term surveillance and further studies are needed to further clarify this relationship.