Dual Benefits of Antidiabetic Drugs: Mechanistic Insights Into Blood Glucose Control and Cancer Suppression Publisher



Al Darraji R K A ; Al Luaibi A I M ; Makhmudov D ; Mirzayev R ; Melibayeva R ; Najmutdinova D ; Ibragimov N ; Ganikhanova M ; Jumayev M ; Mamazulunov N ; Safahendi S Z ; Sultanova M ; Mir M
Source: Asian Pacific Journal of Cancer Biology Published:2026

Abstract

Background: Antidiabetic medications, including metformin, SGLT2 inhibitors, GLP-1 receptor agonists (GLP-1 RAs), thiazolidinediones (TZDs), and DPP-4 inhibitors, exhibit potential anticancer properties beyond glycemic control. This review synthesizes their mechanisms, evaluates the strength of evidence across cancer types, and addresses key controversies in the field. This review introduces a novel evidence classification framework and discusses emerging implications for combination immunotherapy, offering a structured appraisal of the field. Materials and Methods: A narrative review was conducted using PubMed, Scopus, and Google Scholar (January 2015–April 2025). Evidence strength was classified as strong, moderate, suggestive, or conflicting based on study design and consistency of findings. Results: Metformin demonstrates moderate observational evidence supporting reduced incidence and mortality in breast, colorectal, and liver cancers, primarily through AMPK/mTOR modulation and insulin/IGF-1 axis suppression. SGLT2 inhibitors show promising preclinical activity in lung and hepatocellular carcinomas via glucose restriction and AMPK activation, though sex-specific adverse effects observed in colorectal cancer models warrant caution. GLP-1 RAs exhibit moderate preclinical and observational support in breast and colorectal cancers, with clinical trials confirming no excess cancer risk. TZDs present a paradox: preclinical models suggest possible cancer-promotive stromal effects, while epidemiological studies indicate neutral or protective outcomes, highlighting their context-dependent actions. DPP-4 inhibitors show conflicting evidence: although preclinical studies raised concerns about pancreatic safety, meta-analyses of randomized trials show no increased cancer risk. A new critical appraisal table reconciles these discrepancies. Conclusion: Antidiabetic drugs exert anticancer effects mainly through indirect metabolic and immunomodulatory mechanisms rather than direct cytotoxicity. The strength of evidence varies substantially across drug classes and cancer types, with metformin having the broadest support. Key limitations include residual confounding, preclinical-clinical translational gaps, and insufficient long-term data. Future research should prioritize cancer-specific trials, combination immunotherapy strategies, and mechanistic studies in relevant human models. In this review, we propose a structured evidence-classification framework integrating preclinical, epidemiological, and clinical trial data to comparatively evaluate the anticancer potential of major antidiabetic drug classes. In addition, we critically assess emerging immunomodulatory mechanisms and discuss their translational relevance in the context of cancer immunotherapy. This work is licensed under a Creative Commons Attribution-Non Commercial 4.0 International License.