Pharmacological mechanisms and clinical impacts of antidiabetic drugs on colorectal cancer risk: a systematic review.

Type 2 diabetes mellitus (T2DM) significantly increases colorectal cancer (CRC) risk, driven by shared metabolic and inflammatory pathways. As lifelong glucose-lowering medications are routinely used in T2DM, their pharmacological activities and associated oncological effects have become critical for safety and repurposing. This review systematically summarizes the pharmacological mechanisms, epidemiological evidence, and clinical outcomes of eight antidiabetic drug classes in modulating CRC risk. We highlight drug-specific effects: metformin may act via AMPK/mTOR and immune reprogramming; SGLT-2 inhibitors may exert direct cytotoxicity and indirect metabolic benefits; GLP-1 RAs show class-wide neutrality except high-dose semaglutide; DPP-4 inhibitors display dual pro- and anti-tumor effects; insulin and most secretagogues elevate CRC risk via hyperinsulinemia; while TZDs and AGIs offer modest chemopreventive effects. We conclude that antidiabetic drugs possess pharmacological properties that can inform CRC risk stratification and drug repurposing. Future research should prioritize mechanistic validation and precision pharmacology to translate these findings into clinical practice.