Table_1_The Potential Effect of Metformin on Cancer: An Umbrella Review.docx

Background: Metformin has been reported to possess anti-cancer properties in addition to glucose-lowering activity and numerous systematic reviews and meta-analyses have studied the association between metformin use and cancer incidence or survival outcomes. We performed an umbrella review to assess the robustness of these associations to facilitate proper interpretation of these results to inform clinical and policy decisions.
Methods: We searched PubMed and Embase systematic reviews and meta-analyses investigating the effect of metformin use on cancer incidence or survival outcomes published from inception to September 2, 2018. We estimated the summary effect size, the 95% CI, and the 95% prediction interval, heterogeneity, evidence of small-study effects, and evidence of excess significance bias.
Results: We included 21 systematic reviews and meta-analyses covering 11 major anatomical sites and 33 associations. There was strong evidence for the association between metformin use and decreased pancreatic cancer incidence. The association between metformin use and improved colorectal cancer overall survival (OS) was supported by highly suggestive evidence. Seven associations (all cancer incidence, all cancer OS, breast cancer OS, colorectal cancer incidence, liver cancer incidence, lung cancer OS, and pancreatic cancer OS) presented only suggestive evidence. The remaining 24 associations were supported by weak or not-suggestive evidence.
Conclusions: Associations between metformin use and pancreatic cancer incidence or colorectal cancer OS are supported by strong or highly suggestive evidence, respectively. However, these results should be interpreted with caution due to the poor methodological quality of the systematic reviews and meta-analyses.

背景：二甲双胍（Metformin）除具备降糖活性外，还被报道具有抗癌特性；目前已有大量系统评价（systematic review）与荟萃分析（meta-analysis）探讨了二甲双胍使用与癌症发病率或生存结局之间的关联。本研究开展了一项伞状综述（umbrella review），以评估上述关联的稳健性，助力对研究结果的合理解读，从而为临床与政策决策提供参考。

方法：本研究检索了自建库至2018年9月2日发表的、探讨二甲双胍使用对癌症发病率或生存结局影响的PubMed与Embase数据库中的系统评价及荟萃分析。我们估算了合并效应量、95%置信区间（95% CI）、95%预测区间、异质性、小样本效应证据以及过量显著性偏倚证据。

结果：本研究共纳入21项系统评价与荟萃分析，涵盖11个主要解剖部位及33项关联分析。现有强有力证据表明，二甲双胍使用与胰腺癌发病率降低存在关联。二甲双胍使用与结直肠癌总生存期（overall survival, OS）改善之间的关联则得到高度提示性证据的支持。7项关联分析（涵盖所有癌症发病率、所有癌症总生存期、乳腺癌总生存期、结直肠癌发病率、肝癌发病率、肺癌总生存期及胰腺癌总生存期）仅获得提示性证据支持。剩余24项关联分析仅得到弱证据或非提示性证据支持。

结论：二甲双胍使用与胰腺癌发病率、结直肠癌总生存期之间的关联分别得到强有力证据与高度提示性证据的支持。但由于纳入的系统评价与荟萃分析方法学质量欠佳，对本研究结果的解读应保持谨慎。