Metformin and Cancer Risk Reduction: A Systematic Review of Epidemiological Evidence and Biological Mechanisms

Background

Metformin, the most widely prescribed oral antidiabetic medication, has attracted considerable interest as a potential cancer chemopreventive agent. Epidemiological studies have consistently reported lower cancer incidence among metformin-treated diabetic patients compared with those receiving other glucose-lowering therapies. This systematic review comprehensively evaluates the epidemiological evidence and underlying biological mechanisms.

Methods

We conducted a systematic review following PRISMA guidelines. PubMed, Embase, and Web of Science were searched from inception through March 2025. We included observational studies (cohort and case-control) with at least 1,000 participants and randomized controlled trials evaluating metformin use and cancer incidence or mortality. Studies were stratified by cancer type. Quality assessment used the Newcastle-Ottawa Scale for observational studies and Cochrane Risk of Bias 2 for randomized trials. A narrative synthesis was performed given heterogeneity in study designs and cancer types.

Results

One hundred and twelve observational studies and 8 randomized controlled trials met inclusion criteria. For colorectal cancer, 28 cohort studies involving 2.4 million participants showed a pooled risk reduction of 23% (RR 0.77; 95% CI, 0.69-0.86). For hepatocellular carcinoma, 15 studies demonstrated a 46% risk reduction (RR 0.54; 95% CI, 0.43-0.68), the strongest association observed. For breast cancer, 22 studies showed a 17% risk reduction (RR 0.83; 95% CI, 0.76-0.91). For lung and prostate cancers, results were inconsistent. The 8 randomized trials, including the large-scale MA.32 trial in breast cancer, showed mixed results, with most failing to demonstrate significant benefit of metformin as adjuvant cancer therapy. Proposed mechanisms include AMPK activation leading to mTOR inhibition, reduced circulating insulin and IGF-1 levels, direct mitochondrial complex I inhibition, and immunomodulatory effects enhancing antitumor immunity.

Conclusions

While epidemiological evidence consistently supports an association between metformin use and reduced cancer risk, causality remains unestablished. The disconnect between observational and randomized trial findings may reflect time-related biases in observational studies or insufficient dosing and treatment duration in trials. Ongoing large-scale randomized trials will be critical for resolving this question.