Antidiabetic Drugs Differentially Modulate Colorectal Cancer Risk: Metformin Protective, Insulin Harmful, GLP-1 RAs Neutral

Patients with Type 2 diabetes mellitus (T2DM) face a significantly elevated risk of colorectal cancer (CRC), a leading cause of cancer-related mortality. This increased risk is attributed to shared underlying metabolic and inflammatory pathways, including hyperinsulinemia, chronic inflammation, and altered gut microbiota. Given that individuals with T2DM often take glucose-lowering medications for life, understanding the long-term oncological effects of these drugs is crucial. Current standard-of-care for T2DM primarily focuses on glycemic control, but the potential for drug repurposing or risk stratification based on their impact on CRC risk represents a critical unmet need.

This systematic review synthesized epidemiological evidence and clinical outcomes to evaluate the impact of eight distinct antidiabetic drug classes on colorectal cancer (CRC) risk. The review focused on summarizing their pharmacological mechanisms and associated oncological effects. It systematically analyzed existing literature to identify drug-specific modulations of CRC risk, considering factors like AMPK/mTOR pathway activation, direct cytotoxicity, and metabolic benefits. The study design was a comprehensive literature review, not an interventional trial, thus no specific n or dose was applied in this review itself, but rather synthesized from prior studies.

The systematic review revealed diverse and often opposing effects of antidiabetic drug classes on colorectal cancer (CRC) risk. Metformin consistently demonstrated chemopreventive potential, likely acting through activation of the AMPK/mTOR pathway and immune reprogramming. SGLT-2 inhibitors showed promise via direct cytotoxicity and indirect metabolic benefits. GLP-1 Receptor Agonists (RAs) exhibited class-wide neutrality regarding CRC risk, with the notable exception of high-dose semaglutide, which showed a potential for increased risk in some contexts. DPP-4 inhibitors presented a complex profile, displaying dual pro- and anti-tumor effects depending on the specific agent and context. Conversely, insulin and most secretagogues were associated with an elevated CRC risk, primarily attributed to hyperinsulinemia. Finally, Thiazolidinediones (TZDs) and Alpha-glucosidase inhibitors (AGIs) offered modest chemopreventive effects. This comprehensive analysis highlights the nuanced pharmacological properties of these agents.

Insulin and most secretagogues elevate colorectal cancer risk via hyperinsulinemia, while metformin may act via AMPK/mTOR and immune reprogramming to reduce risk.