Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand 9717853577, Iran.
Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran 9717113163, Iran.
Curr Oncol. 2021 Apr 6;28(2):1412-1423. doi: 10.3390/curroncol28020134.
Our aim was to investigate and evaluate the influence of metformin on cancer-related biomarkers in clinical trials.
This systematic study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Major databases, including Scopus, Web of Sciences, PubMed, Ovid-Medline, and Cochrane, were systematically reviewed by February 2020. Clinical trials investigating metformin effects on the evaluation of homeostatic models of insulin resistance (HOMA-IR), Ki-67, body mass index (BMI), fasting blood sugar (FBS), and insulin were selected for further analysis. Quality assessment was performed with version 2 of the Cochrane tool for determining the bias risk for randomized trials (RoB 2). Heterogeneity among the included studies was assessed using the Chi-square test. After quality assessment, a random effects model was performed to summarize the data related to insulin, HOMA-IR, Ki-67, and a fixed-effect model for FBS and BMI in a meta-analysis.
Nine clinical trials with 716 patients with operable breast and endometrial cancer and 331 with primary breast cancer were involved in the current systematic and meta-analysis study. Systematic findings on the nine publications indicated metformin decreased insulin levels in four studies, FBS in one, BMI in two, Ki-67 in three studies, and HOMA-IR in two study. The pooled analysis indicated that metformin had no significant effect on the following values: insulin (standardized mean differences (SMD) = -0.87, 95% confidence intervals (CI) (-1.93, 0.19), = 0.11), FBS (SMD = -0.18, 95% CI (-0.30, -0.05), = 0.004), HOMA-IR (SMD = -0.17, 95% CI (-0.52, 0.19), = 0.36), and BMI (SMD = -0.13, 95% CI (-0.28, 0.02), = 0.09). Metformin could decrease Ki-67 in patients with operable endometrial cancer versus healthy subjects (SMD = 0.47, 95% CI (-1.82, 2.75), = 30.1). According to Egger's test, no publication bias was observed for insulin, FBS, BMI, HOMA-IR, and Ki-67.
Patients with operable breast and endometrial cancer under metformin therapy showed no significant changes in the investigated metabolic biomarkers in the most of included study. It was also found that metformin could decrease Ki-67 in patients with operable endometrial cancer. In comparison to the results obtained of our meta-analysis, due to the high heterogeneity and bias of the included clinical trials, the present findings could not confirm or reject the efficacy of metformin for patients with breast cancer and endometrial cancer.
本研究旨在探讨和评估二甲双胍在临床试验中对癌症相关生物标志物的影响。
本系统研究根据系统评价和荟萃分析的首选报告项目（PRISMA）指南进行。主要数据库，包括 Scopus、Web of Sciences、PubMed、Ovid-Medline 和 Cochrane，于 2020 年 2 月进行了系统审查。选择了评估二甲双胍对稳态模型胰岛素抵抗（HOMA-IR）、Ki-67、体重指数（BMI）、空腹血糖（FBS）和胰岛素评估影响的临床试验进行进一步分析。使用 Cochrane 工具版本 2 对随机试验的偏倚风险（RoB 2）进行了质量评估。使用卡方检验评估纳入研究的异质性。在质量评估后，使用随机效应模型对与胰岛素、HOMA-IR、Ki-67 相关的数据进行汇总分析，使用固定效应模型对 FBS 和 BMI 进行汇总分析。
本系统和荟萃分析共纳入 9 项临床试验，涉及 716 例可手术乳腺癌和子宫内膜癌患者和 331 例原发性乳腺癌患者。9 项研究的系统评价结果表明，二甲双胍可降低 4 项研究中的胰岛素水平，1 项研究中的 FBS，2 项研究中的 BMI，3 项研究中的 Ki-67 和 2 项研究中的 HOMA-IR。荟萃分析结果表明，二甲双胍对以下值没有显著影响：胰岛素（标准化均数差（SMD）=-0.87，95%置信区间（CI）（-1.93，0.19），=0.11）、FBS（SMD=-0.18，95%CI（-0.30，-0.05），=0.004）、HOMA-IR（SMD=-0.17，95%CI（-0.52，0.19），=0.36）和 BMI（SMD=-0.13，95%CI（-0.28，0.02），=0.09）。二甲双胍可降低可手术子宫内膜癌患者的 Ki-67 水平，与健康受试者相比（SMD=0.47，95%CI（-1.82，2.75），=30.1）。根据 Egger 检验，胰岛素、FBS、BMI、HOMA-IR 和 Ki-67 均未发现发表偏倚。
接受二甲双胍治疗的可手术乳腺癌和子宫内膜癌患者，在大多数纳入研究中，其代谢生物标志物无明显变化。此外，还发现二甲双胍可降低可手术子宫内膜癌患者的 Ki-67 水平。与我们的荟萃分析结果相比，由于纳入的临床试验存在高度异质性和偏倚，因此目前的研究结果既不能证实也不能否定二甲双胍对乳腺癌和子宫内膜癌患者的疗效。
