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

Type 2 diabetes mellitus 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 type 2 diabetes mellitus and obesity, populations already at elevated baseline risk for CRC. This raises important questions regarding their long-term 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.