Metformin as a Chemopreventive Agent for Colorectal Adenoma Recurrence: Evidence from Randomized Controlled Trials

BACKGROUND: Colorectal adenomas are well-established precursors of colorectal cancer (CRC), with recurrence rates of up to 50% following polypectomy. Safe and effective chemopreventive strategies are needed. Metformin, a widely used antidiabetic agent, has demonstrated potential anticancer effects, but its role in adenoma prevention among non-diabetic individuals remains uncertain. OBJECTIVE: To evaluate the efficacy and safety of metformin in preventing metachronous colorectal adenoma recurrence in non-diabetic adults following complete endoscopic polypectomy. METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted in accordance with PRISMA guidelines. Databases including PubMed, Embase, Cochrane CENTRAL, Web of Science, and Scopus were searched from inception to December 2025. Eligible studies included RCTs comparing metformin with placebo or no intervention in non-diabetic adults with prior adenoma resection, reporting recurrence at ≥12 months. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. RESULTS: Two RCTs comprising 405 participants were included. Metformin significantly reduced the risk of adenoma recurrence at 1 year compared with control (RR 0.61, 95% CI 0.48-0.78; I² = 0%). This corresponds to an approximate 39% relative risk reduction. The effect was consistent across different dosing regimens (250-1000 mg/day). Both trials demonstrated low risk of bias and reported good tolerability, with only mild gastrointestinal adverse events and no serious toxicity. CONCLUSION: Metformin significantly reduces metachronous colorectal adenoma recurrence in non-diabetic patients after polypectomy, with a favorable safety profile. These findings support its potential role as a cost-effective chemopreventive agent. Larger, long-term trials are warranted to confirm its impact on colorectal cancer incidence and clinical outcomes.