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

Al Darraji Raad Kareem Alwan; Al Luaibi Abeer Issa Mohammed; Davron Makhmudov; Rizamat Mirzayev; Ruzakhon Melibayeva; Dilbar Najmutdinova; Nodir Ibragimov; Madina Ganikhanova; Miraziz Jumayev; Nurmukhammad Mamazulunov; Seyede Zahra Safahendi; Muxlisa Sultanova; Mohsen Mir

doi:10.31557/APJCB.2026.11.3.931

Authors

Al Darraji Raad Kareem Alwan Al-Manara College for Medical Sciences, University of Manara, Iraq.
Al Luaibi Abeer Issa Mohammed Al-Manara College for Medical Sciences, University of Manara, Iraq. Department of Toxicology, Pusat Kanser Tun Abdullah Ahmad Badawi, Universiti Sains Malaysia, Bertam, 13200, Kepala Batas, Penang, Malaysia.
Davron Makhmudov Department of Pediatric Infectious Diseases, Tashkent State Medical University, Tashkent, Uzbekistan.
Rizamat Mirzayev Department of Internal Diseases and Cardiology No. 2, Samarkand State Medical University, Samarkand, Uzbekistan.
Ruzakhon Melibayeva Department of Pedagogy and Psychology, Tashkent State Medical University, Tashkent, Republic of Uzbekistan.
Dilbar Najmutdinova Tashkent State Medical University, Tashkent, Republic of Uzbekistan.
Nodir Ibragimov Department of Mathematics and Informatics, Termez State Pedagogical Institute, Termez, Republic of Uzbekistan.
Madina Ganikhanova Tashkent State Technical University, Uzbekistan.
Miraziz Jumayev Department of Histology, Cytology and Embryology, Bukhara State Medical Institute named after Abu Ali ibn Sino, Bukhara, Republic of Uzbekistan.
Nurmukhammad Mamazulunov Kokand University Andijan Branch, Republic of Uzbekistan.
Seyede Zahra Safahendi Master Student in Operating Room, Faculty of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran.
Muxlisa Sultanova Department of Practical English Language, Tashkent State Technical University, Tashkent, Republic of Uzbekistan.
Mohsen Mir Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

DOI:

https://doi.org/10.31557/APJCB.2026.11.3.931

Keywords:

Antidiabetic drug; Cancer therapy; Metformin; SGLT2 inhibitors; GLP-1 agonists; Glucose metabolism; Immunomodulation

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.