The Effect of Metformin on Bladder Cancer Incidence and Outcomes: A Systematic Review and Meta-Analysis

BACKGROUND: Effective oral treatment options for urothelial bladder cancer (BC) are lacking. Metformin, the most frequently used oral drug in type II diabetes mellitus, has putative anticancer properties and could, therefore, influence BC incidence and treatment outcomes. We systematically reviewed the current literature regarding the effect of metformin on BC incidence and oncological outcomes in non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). METHODS: This review was conducted according to the PRISMA guidelines. Literature was gathered through a systematic search in PubMed/Medline, EMBASE and the Cochrane library. Risk of bias was determined using the Cochrane risk-of-bias tool for randomized trials and the Newcastle-Ottawa Scale for non-randomized trials. Hazard ratios (HRs) were extracted and pooled in a random-effects meta-analysis. RESULTS: We reviewed 13 studies, including 3,315,320 patients, considering the risk of developing BC after metformin exposure and 9 studies, including 4,006 patients, on oncological outcomes of patients with BC. Metformin did not affect BC incidence (HR 0.97, 95% CI 0.87 -1.09) or oncological outcomes for NMIBC but did show a reduced risk of recurrence (HR 0.52, 95% CI 0.32 -0.84), cancer-specific mortality (HR 0.58, 95% CI 0.43 -0.78) and overall mortality (HR 0.66, 95% CI 0.47 -0.92) in MIBC. CONCLUSIONS: The role of metformin in the prevention and treatment of BC in patients remains unclear. Although a beneficial effect of metformin on treatment outcomes of certain stages of BC may exist, a definitive conclusion cannot be drawn. Prospective clinical trials are needed to assess the efficacy of metformin for BC treatment.