Liu Ping, Xiao Junqi, Xiao Jinghuang, Zhou Jumei
Department of Radiation Oncology and Hunan Key Laboratory of Translational Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, HunanCancer Hospital, Changsha, China.
Cancer center, The Second Affiliated Hospital, Hengyang Medical School, University of South China, No.35 of Jiefang Avenue, Hengyang City, P. R. China.
Diabetol Metab Syndr. 2025 Jan 7;17(1):6. doi: 10.1186/s13098-024-01573-9.
Observational studies suggest that metformin may reduce the risk of malignant tumors of the digestive system (MTDS), but these findings are often confounded by bias and unmeasured variables. Recent meta-analyses have questioned these associations, emphasizing the need for robust causal inference.
Mendelian randomization (MR) was used to evaluate the causal relationship between metformin and MTDS. Genetic variants associated with metformin's molecular targets were selected from GTEx, eQTLGen, and UK Biobank and validated using genetic colocalization to ensure instrument validity. GWAS summary statistics for MTDS, encompassing up to 314,193 controls and 6,847 colorectal cancer cases, were obtained from FinnGen and EBI. The primary analysis employed the inverse-variance weighted (IVW) method, supplemented by MR-Egger, weighted median, and weighted mode analyses. Bonferroni correction was applied to adjust for multiple testing across 14 cancer types.
Genetically proxied metformin use was associated with an increased risk of colorectal cancer (OR = 2.38, 95%CI = 1.38-4.09, P = 0.0018) and related subtypes. No causal relationship was found for hepatocellular carcinoma, gastric cancer, pancreatic cancer, or other digestive system cancers. The robustness of these findings was supported by sensitivity analyses, which indicated no significant pleiotropy, and leave-one-out tests.
This study provides robust genetic evidence that metformin use increases the risk of colorectal cancer, challenging its role as a preventive agent for digestive cancers. These findings emphasize the need for clinicians to carefully evaluate the risks and benefits of metformin, particularly in populations at higher risk for colorectal cancer. Future research should focus on delineating the mechanisms underlying this association to optimize the use of metformin in clinical practice.
观察性研究表明，二甲双胍可能降低消化系统恶性肿瘤（MTDS）的风险，但这些发现常因偏倚和未测量变量而混淆。最近的荟萃分析对这些关联提出了质疑，强调需要进行有力的因果推断。
采用孟德尔随机化（MR）来评估二甲双胍与MTDS之间的因果关系。从GTEx、eQTLGen和英国生物银行中选择与二甲双胍分子靶点相关的基因变异，并使用基因共定位进行验证，以确保工具的有效性。从芬兰基因库（FinnGen）和欧洲生物信息学研究所（EBI）获得MTDS的全基因组关联研究（GWAS）汇总统计数据，其中包括多达314,193名对照和6,847例结直肠癌病例。主要分析采用逆方差加权（IVW）方法，并辅以MR-Egger、加权中位数和加权模式分析。应用Bonferroni校正来调整对14种癌症类型的多重检验。
遗传推断的二甲双胍使用与结直肠癌风险增加相关（OR = 2.38，95%CI = 1.38 - 4.09，P = 0.0018）以及相关亚型。未发现与肝细胞癌、胃癌、胰腺癌或其他消化系统癌症存在因果关系。敏感性分析支持了这些发现的稳健性，表明不存在显著的多效性，以及留一法检验。
本研究提供了有力的遗传学证据，表明使用二甲双胍会增加结直肠癌风险，对其作为消化系统癌症预防药物的作用提出了挑战。这些发现强调临床医生需要仔细评估二甲双胍的风险和益处，特别是在结直肠癌风险较高的人群中。未来的研究应专注于阐明这种关联背后的机制，以优化二甲双胍在临床实践中的使用。
