Background
Endometrial cancer (EC), a tumor originating from the endometrium, is a major cause of morbidity and mortality in women. Hyperplastic endometrium may be a result of exposure to unopposed estrogen, leading to the progression of cancer. It is the most common malignancy of the female genital tract in the United States, with approximately 54,870 new cases and 10,170 related deaths in 2015 [
1]. The incidence of EC is lower in developing countries compared with developed countries. However, EC was associated with higher cancer mortality and poor prognosis in developing countries [
1‐
3]. Further, despite advances in the treatment of EC, the prognosis for stages III–IV EC remains poor [
4].
Various adjuvant medications have been suggested for preventing and treating EC, including aromatase inhibitors [
5], aspirin [
6], statins [
7], hormone therapy [
8], and metformin [
9,
10]. Metformin has several advantages in addition to its anticancer activity. First, it is a first-line pharmacologic treatment for patients with type 2 diabetes mellitus [
11]. Second, in addition to metformin use for diabetes, it is also safely prescribed for various nondiabetic conditions, including polycystic ovarian syndrome [
12], primary prevention of type 2 diabetes mellitus and cardiovascular diseases [
13,
14], and obesity control [
15]. Finally, metformin is readily available worldwide at low cost.
Type 2 diabetes mellitus is a well-established risk factor for EC [
16,
17]. Insulin resistance has been suggested to be one of the critical biological processes that contribute to EC [
18,
19]. Approximately 30% of patients with EC have type 2 diabetes mellitus, and up to 36% have undiagnosed insulin resistance [
20]. Metformin use could reduce the risk of type 2 diabetes mellitus and delay its progression. It reduces insulin resistance by increasing insulin receptor tyrosine kinase activity, enhancing glycogen synthesis, and promoting the recruitment and increasing the activity of glucose transporter type 4 [
21]. Moreover, it affects endometrial maturation, proliferation, and implantation process [
22‐
24]. Finally, the risk of EC is increased in women who have higher endogenous estrogen levels [
25], and metformin has been reported to hinder estrogen-mediated endometrial proliferation [
26].
Several studies have reported that metformin is a promising intervention for preventing and treating EC. However, these studies had conflicting results, and no relevant meta-analyses have been conducted. Therefore, this systematic review and meta-analysis was performed to evaluate the effectiveness of metformin for the risk and survival outcomes in patients with EC.
Discussion
This meta-analysis on the prevention of EC with metformin included 7 studies and a total of 5,293,039 participants. The pooled data suggested that the use of metformin could not substantially prevent the development of EC. When analyzing the subgroup of patients with diabetes, who were at a higher risk of EC, a significant protective effect of metformin against EC still could not be detected compared with patients with diabetes treated with other antidiabetic therapies. Differences in the duration of use and dose of metformin might have limited the statistical power of this study. The protective effects of metformin might be time and dose dependent [
47]. However, most included studies failed to conduct dose-escalation analyses. Further, this meta-analysis also comprised 7 studies with a total of 3923 patients with EC who were treated with metformin. It was found that metformin could substantially improve the OS and reduce the risk of recurrence. The benefit for OS remained significant for the subgroup of patients with diabetes.
A previous meta-analysis based on 19 studies and illustrated effects of metformin on reversal of atypical endometrial hyperplasia, cellular proliferation biomarkers expression and overall survival. Further, they point out metformin could reverse atypical endometrial hyperplasia to normal endometrial histology, reduction of cell proliferation biomarkers, and improvement of OS. However, mostly investigated outcomes focused on precancerous indicators, while the risk of certain cancer was not evaluated [
48]. The study conducted by Perez-Lopez et al. suggested metformin therapy was associated with a reduced risk of overall mortality in T2DM women with EC. Whereas this study focused on patients with T2DM and the preventive effect of metformin on EC risk was not illustrated [
49]. Tang et al. conducted a meta-analysis based on 11 studies and indicated metformin therapy are significantly improvement EC risk and prognosis of EC. However, this study with incomplete electronic searches and the result of recurrence of EC were not calculated [
50]. This novel meta-analysis of metformin use for preventing and treating EC analyzed both risk and survival scenarios. The most comprehensive up-to-date relevant studies were included. The sample sizes of most studies were sufficiently large, and the studies were of high quality. The inclusion of participants from all parts of the world meant that the present study results should be generalizable to the general population. Most studies sufficiently adjusted for various clinicopathological confounding factors. Moreover, the role of metformin was specifically assessed among patients with diabetes.
Abundant preclinical in vitro and in vivo studies have reported the anticancer effect of metformin on various malignancies. Nevertheless, the exact molecular mechanisms remain unknown. Metformin may inhibit cancer stem cell–like subpopulations in cases of intraepithelial neoplasia [
51]. Metformin may also prevent the conversion of epithelial cells into mesenchymal cells [
52]. Several studies have reported that metformin can reverse endometrial hyperplasia [
53,
54]. Thus, metformin may have multiple functions mediated through direct and indirect mechanisms [
51]. The indirect effect is insulin dependent. Metformin helps control the circulating glucose level and improve insulin sensitivity. The direct effect is insulin independent. Metformin exerts its effects on tumor cells primarily through the adenosine 5′-monophosphate–activated protein kinase and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathways [
55]. Notably, these molecular targets are similar to the targets of current drugs, such as sorafenib and everolimus. A phase I clinical trial of 21 cases, including 4 patients with advanced EC, showed that the combination of temsirolimus and metformin was a promising treatment [
56]. Metformin is nontoxic and may be extremely useful for enhancing the treatment efficacy of the targeted drugs [
51]. Since metformin has been used for more than 50 years, its safety profile has been well established. Although it can cause potentially dangerous toxicity from lactic acidosis, the risk is mainly confined to patients aged more than 80 years, patients with alcohol abuse, or those who have comorbidities of renal, hepatic, or cardiac insufficiency [
57].
This meta-analysis had several limitations. It only identified a small number of studies exploring the role of metformin for prevention and treatment. Further, stratified results according to individuals characteristics were not reported. Therefore, a subgroup or meta-regression analysis could not identify the sources of heterogeneity. Many of the included studies were retrospectively designed, which might have led to recall and selection bias, and those study are associated with low level of evidence. Furthermore, whether patients had taken different antidiabetic drugs before metformin administration could not be determined. Their glycemic control might also be inadequate. Moreover, this meta-analysis was based on observational data, which was associated with higher indication bias. Such as, more “healthier patients” always receive the best treatment. No randomized controlled trial has been conducted on patients with EC. Interestingly, a previous large randomized controlled trial that enrolled patients with gastrointestinal malignancies showed that metformin was helpful for the chemoprevention of colorectal cancer [
58], but did not significantly improve the OS of patients with pancreatic cancer [
59]. Most of the studies included in this meta-analysis did not report the effect of metformin dose or duration. Although most of the studies performed sufficient adjustment of variables, little information was available to evaluate the potential influence of other drugs such as aspirin or statins. Moreover, stratified analyses were not conducted based on study design and other patient characteristics, since a smaller number of cohorts were included. Therefore, this comprehensive meta-analysis just provided relative results on metformin use for EC prevention and treatment.