Influence of diabetes mellitus and anti-diabetic drugs on pathophysiology and prognosis for primary prostate cancer

PURPOSE: Cancer diseases and type II diabetes mellitus (DM2) are today among the major health problems, particularly in developed countries. DM2 has been historically suggested to protect against the development of prostate cancer (PCa). This study aimed to explore the mechanisms of this relation and assess its impact on treatment and prognosis for patients with PCa. METHODS: The consecutive literature search was performed using PubMed, Cochrane, and Google Scholar for papers published between 2015 and 2025. RESULTS: DM2 might reduce the risk of primary PCa development with a size effect depending on the duration of DM2. Patients with type 2 diabetes often exhibit low levels of testosterone and SHBG, which has been speculated to constitute a protective effect against PCa development. On the other hand, peripheral insulin resistance might be a protective factor, given its proliferation-promoting properties. What remains, however, the backbone element of the DM-PCa prevalence relation is metformin, which has been described to modulate PCa development through activation of AMPK kinase, reducing the c-MYC oncogene and disrupting the action of androgen receptors. Finally, DM constitutes a well-known predictor of worse surgical outcomes as well as radiotherapy toxicity. CONCLUSION: DM is associated with a modestly lower incidence of prostate cancer, likely mediated by hormonal cross-talk and metabolic changes. Metformin may confer additional protection in a wide range of molecular mechanisms. Nevertheless, diabetes worsens treatment course-raising surgical morbidity and radiotherapy toxicity-necessitating tight metabolic control and thoughtful anti-diabetic drug selection.