Farmer Ruth E, Ford Deborah, Forbes Harriet J, Chaturvedi Nishi, Kaplan Richard, Smeeth Liam, Bhaskaran Krishnan
Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
MRC Clinical Trials Unit at UCL, London, UK and.
Int J Epidemiol. 2017 Apr 1;46(2):728-744. doi: 10.1093/ije/dyw275.
Existing observational studies provide conflicting evidence for the causal effect of metformin use on cancer risk in patients with type-2 diabetes, and there are concerns about bias affecting a number of studies.
MEDLINE was used to identify observational studies investigating the association between metformin and overall or site-specific cancer in people with type-2 diabetes. A systematic data extraction and bias assessment was conducted, in which risk of eight bias domains (outcome, exposure, control selection, baseline confounding, time-dependent confounding, immortal time, missing data, censoring methods) were assessed against pre-defined criteria, and rated as unlikely, low, medium or high.
Of 46 studies identified, 21 assessed the effect of metformin on all cancer. Reported relative risks ranged from 0.23 to 1.22, with 12/21 reporting a statistically significant protective effect and none a harmful effect. The range of estimates was similar for site-specific cancers; 3/46 studies were rated as low or unlikely risk of bias in all domains. Two of these had results consistent with no effect of metformin; one observed a moderate protective effect overall, but presented further analyses that the authors concluded were inconsistent with causality. However, 28/46 studies were at risk from bias through exposure definition, 22 through insufficient baseline adjustment and 35 from possible time-dependent confounding.
Observational studies on metformin and cancer varied in design, and the majority were at risk of a range of biases. The studies least likely to be affected by bias did not support a causal effect of metformin on cancer risk.
现有观察性研究对于二甲双胍使用对2型糖尿病患者癌症风险的因果效应提供了相互矛盾的证据，并且人们担心一些研究存在偏倚。
使用MEDLINE检索观察性研究，以调查二甲双胍与2型糖尿病患者总体或特定部位癌症之间的关联。进行了系统的数据提取和偏倚评估，根据预定义标准评估八个偏倚领域（结局、暴露、对照选择、基线混杂、时间依赖性混杂、不朽时间、缺失数据、删失方法）的风险，并将其评为不太可能、低、中或高。
在识别出的46项研究中，21项评估了二甲双胍对所有癌症的影响。报告的相对风险范围为0.23至1.22，21项中有12项报告了具有统计学意义的保护作用，无一报告有害作用。特定部位癌症的估计范围相似；46项研究中有3项在所有领域的偏倚风险被评为低或不太可能。其中两项的结果表明二甲双胍无作用；一项总体观察到中度保护作用，但进一步分析后作者得出结论认为这与因果关系不一致。然而，46项研究中有28项因暴露定义存在偏倚风险，22项因基线调整不足存在偏倚风险，35项因可能存在时间依赖性混杂存在偏倚风险。
关于二甲双胍与癌症的观察性研究在设计上各不相同，并且大多数存在一系列偏倚风险。最不可能受偏倚影响的研究不支持二甲双胍对癌症风险有因果效应。
