From diabetes to tumor growth: unravelling the impact of glucose-lowering therapies
Abstract
PURPOSE: Diabetes mellitus and cancer are two expanding global health burdens that share upstream determinants, yet diabetes may also contribute to malignancy risk through hyperglycaemia/AGE-related stress, insulin resistance with compensatory hyperinsulinaemia, obesity-related inflammation, and tumour microenvironment modulation. This narrative review synthesizes mechanistic plausibility and critically appraises the highest-level clinical evidence on the oncologic safety signals of glucose-lowering therapies, with a focus on cancer incidence captured within randomized diabetes trials. METHODS: argeted searches of PubMed/MEDLINE and Embase were complemented by manual reference screening. Mechanistic and translational data were summarized separately from clinical evidence. For each drug class, we prioritized pivotal randomized controlled trials and cardiovascular outcome trials (phase 3–4, large, practice-defining), extracting malignancy reporting collected as adverse events/serious adverse events or events of special interest. When randomized evidence was limited, high-quality meta-analyses and selected real-world studies were used for context, clearly distinguished from prespecified randomized evidence. RESULTS: Metformin shows a predominantly neutral effect on cancer incidence, with possible indirect protective signals but no trials specifically designed to assess chemoprevention. Thiazolidinediones demonstrate an overall neutral malignancy profile, with early concerns…
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