Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China; Center for Evidence-Based and Translational Medicine, Wuhan University, Wuhan, 430071, China.
The Second People's Hospital of Huaihua, Huaihua, Hunan, 418200, China.
Pharmacol Res. 2021 Mar;165:105425. doi: 10.1016/j.phrs.2021.105425. Epub 2021 Jan 13.
High heterogeneity has been reported among epidemiological studies exploring the relationship between metformin and the risk of gastric cancer. Immortal time bias might be one of the vital factors causing heterogeneity because of its widespread existence in pharmacological observational studies and it could severely exaggerate the drug's effectiveness. Immortal time bias could occur in an observational study if exposure status is determined based on a measurement or event that occurs after baseline. In this study, we aimed to assess whether immortal time bias is responsible for the false assumption that metformin reduces the risk of gastric cancer. We searched PubMed, Embase, Web of Science and Cochrane Library databases for relevant studies from the inception to August 9, 2020. The strength of the relationship was assessed using pooled relative risks (RRs) with corresponding 95% confidence intervals (95% CIs). Statistical analyses were carried out using a random-effects model. Pooled RR from 6 cohort studies with immortal time bias found a clear 33% reduced risk associated with metformin use (RR = 0.67, 95% CI = 0.59, 0.77; P < 0.001; I = 48.5%). However, pooled RR from 8 cohort studies without immortal time bias indicated no association between the use of metformin and gastric cancer risk (RR = 0.95, 95% CI = 0.85, 1.05; P = 0.317; I = 64.5%). From a univariate meta-regression model, the presence of immortal time bias was associated with a significant reduction of 29% in the effect estimate of metformin on gastric cancer risk (ratio of RR = 0.71, 95% CI = 0.58, 0.86; P = 0.002). This meta-analysis indicates that metformin use has no protective effect on gastric cancer risk. The relationship between metformin use and gastric cancer risk has been exaggerated as a result of the presence of immortal time bias. Further studies are required to confirm the results by controlling for immortal time bias based on appropriate study designs and statistical methods.
研究表明，探讨二甲双胍与胃癌风险之间关系的流行病学研究存在高度异质性。由于其在药理学观察性研究中广泛存在，且可能严重夸大药物的疗效，因此无事件生存时间偏倚可能是造成这种异质性的一个重要因素。如果暴露状态基于发生在基线之后的测量或事件来确定，那么在观察性研究中就可能会出现无事件生存时间偏倚。本研究旨在评估无事件生存时间偏倚是否导致了二甲双胍降低胃癌风险的错误假设。我们从建库至 2020 年 8 月 9 日，检索了 PubMed、Embase、Web of Science 和 Cochrane Library 数据库，以获取相关研究。使用合并相对风险（RR）及其相应的 95%置信区间（95%CI）评估关联强度。使用随机效应模型进行统计学分析。纳入的 6 项存在无事件生存时间偏倚的队列研究的合并 RR 显示，二甲双胍的使用与明显降低 33%的风险相关（RR=0.67，95%CI=0.59，0.77；P<0.001；I=48.5%）。然而，纳入的 8 项不存在无事件生存时间偏倚的队列研究的合并 RR 提示，二甲双胍的使用与胃癌风险之间无关联（RR=0.95，95%CI=0.85，1.05；P=0.317；I=64.5%）。从单变量荟萃回归模型可知，无事件生存时间偏倚的存在与二甲双胍对胃癌风险的效应估计值显著降低 29%有关（RR 比值=0.71，95%CI=0.58，0.86；P=0.002）。本荟萃分析表明，二甲双胍的使用对胃癌风险没有保护作用。由于无事件生存时间偏倚的存在，二甲双胍的使用与胃癌风险之间的关系被夸大了。需要进一步的研究来确认结果，这些研究需要基于适当的研究设计和统计方法，通过控制无事件生存时间偏倚来实现。
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