Department of Non Communicable Diseases Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
MRC Clinical Trials Unit at UCL, University College London, London, UK.
Int J Epidemiol. 2019 Apr 1;48(2):527-537. doi: 10.1093/ije/dyz005.
Previous studies provide conflicting evidence on whether metformin is protective against cancer. When studying time-varying exposure to metformin, covariates such as body mass index (BMI) and glycated haemoglobin (HbA1c) may act as both confounders and causal pathway variables, and so cannot be handled adequately by standard regression methods. Marginal structural models (MSMs) with inverse probability of treatment weights (IPTW) can correctly adjust for such confounders. Using this approach, the main objective of this study was to estimate the effect of metformin on cancer risk compared with risk in patients with T2DM taking no medication.
Patients with incident type 2 diabetes (T2DM) were identified in the Clinical Practice Research Datalink (CPRD), a database of electronic health records derived from primary care in the UK. Patients entered the study at diabetes diagnosis or the first point after this when they had valid HbA1c and BMI measurements, and follow-up was split into 1-month intervals. Logistic regression was used to calculate IPTW; then the effect of metformin on all cancers (including and excluding non-melanoma skin cancer) and breast, prostate, lung, colorectal and pancreatic cancers was estimated in the weighted population.
A total of 55 629 T2DM patients were alive and cancer-free at their study entry; 2530 people had incident cancer during a median follow-up time of 2.9 years [interquartile range (IQR) 1.3-5.4 years]. Using the MSM approach, the hazard ratio (HR) for all cancers, comparing treatment with metformin with no glucose-lowering treatment, was 1.02 (0.88-1.18). Results were robust to a range of sensitivity analyses and remained consistent when estimating the treatment effect by length of exposure. We also found no evidence of a protective effect of metformin on individual cancer outcomes.
We find no evidence that metformin has a causal association with cancer risk.
先前的研究提供了相互矛盾的证据，表明二甲双胍是否对癌症有保护作用。当研究二甲双胍的时变暴露时，体重指数（BMI）和糖化血红蛋白（HbA1c）等协变量既可以作为混杂因素，也可以作为因果途径变量，因此不能通过标准回归方法充分处理。具有治疗反事实权重（IPTW）的边际结构模型（MSM）可以正确调整这些混杂因素。使用这种方法，本研究的主要目的是估计与服用二甲双胍的 T2DM 患者相比，二甲双胍对癌症风险的影响。
在临床实践研究数据链（CPRD）中确定了新诊断的 2 型糖尿病（T2DM）患者，这是一个来自英国初级保健的电子健康记录数据库。患者在糖尿病诊断时或在有有效 HbA1c 和 BMI 测量值之后的第一个时间点进入研究，随访时间分为 1 个月的间隔。使用逻辑回归计算 IPTW；然后在加权人群中估计二甲双胍对所有癌症（包括和不包括非黑色素瘤皮肤癌）以及乳腺癌、前列腺癌、肺癌、结直肠癌和胰腺癌的影响。
共有 55629 名 T2DM 患者在研究入组时存活且无癌症；在中位随访时间 2.9 年（IQR 1.3-5.4 年）期间，2530 人发生了癌症。使用 MSM 方法，与无降糖治疗相比，治疗用二甲双胍的所有癌症的风险比（HR）为 1.02（0.88-1.18）。一系列敏感性分析结果稳健，当按暴露时间估计治疗效果时，结果仍然一致。我们也没有发现二甲双胍对个别癌症结局有保护作用的证据。
我们没有发现二甲双胍与癌症风险之间存在因果关系的证据。
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