Impact of metformin on clinical outcomes among men with prostate cancer: a systematic review and meta-analysis

BACKGROUND: Conflicting evidence exists regarding the beneficial effects of metformin in prostate cancer. To determine the association between metformin and clinical outcomes in prostate cancer using systematic review and meta-analysis. METHODS: Original articles published in English until third week of July, 2014 were searched in electronic databases (Medline-Ovid, Scopus, The Cochrane Library, Web of Science, ProQuest) for studies on metformin use in prostate cancer. The clinical outcomes assessed were: development of biochemical recurrence, metastases or castration-resistant metastatic cancer, all-cause and prostate cancer-specific mortality. Meta-analysis was performed to calculate the pooled hazard ratio (pHR) and their 95% confidence interval (95% CI). Heterogeneity between the studies was examined using I-2 statistics. Sensitivity analysis was conducted to assess the robustness of findings and publication bias was assessed by the Egger's regression asymmetry test and contour plot. RESULTS: Out of 230 retrieved citations, eight retrospective cohort studies and one nested-case-control study met the inclusion criteria. Metformin use was marginally associated with reduction in the risk of biochemical recurrence (pHR: 0.82, 95% CI: 0.67, 1.01, P-value = 0.06, I-2 = 25%, five studies). Metformin use was not significantly associated with metastases (pHR: 0.59, 95% 0.30-1.18, P-value = 0.14, I-2 = 74%, three studies), all-cause mortality (pHR: 0.86; 95% CI, 0.67, 1.10, P-value = 0.23, I-2: 73%, six studies) and prostate cancer-specific mortality (pHR: 0.76, 95% CI: 0.43, 1.33, P-value = 0.33, I-2 = 60%, four studies). Pooled estimates for all outcomes varied in sensitivity analysis by diabetes status and primary treatment of prostate cancer. Systematic review revealed mixed findings on metformin use and the risk of CRPC. CONCLUSIONS: Metformin may reduce the risk of biochemical recurrence in prostate cancer. Given the potential of selection bias in the observational studies, randomized trials should be designed to assess the efficacy of metformin use in prostate cancer.