|
 
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| REVIEW ARTICLE |
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| Year : 2023 | Volume
: 14
| Issue : 1 | Page : 90 |
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The relationship between metformin consumption and cancer risk: An updated umbrella review of systematic reviews and meta-analyses
Farid Najafi1, Fatemeh Rajati1, Diana Sarokhani2, Maryam Bavandpour2, Mehdi Moradinazar1
1 Research Center for Environmental Determinants of Health, School of Public Health, Kermanshah University of Medical Sciences; Behavioral Disease Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
2 Behavioral Disease Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| Date of Submission | 12-Feb-2021 |
| Date of Acceptance | 15-Jun-2022 |
| Date of Web Publication | 15-Jul-2023 |
Correspondence Address:
Mehdi Moradinazar
Research Center for Environmental Determinants of Health, School of Public Health, Kermanshah University of Medical Sciences, Kermanshah
Iran
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijpvm.ijpvm_62_21
Background: Considering that metformin is widely used in the treatment of diabetes, and its protective role against various malignancies, the strength and validity of the available evidence from related systematic reviews and meta-analysis were evaluated. Methods: Scopus, PubMed, Embase, Cochrane, Web of science databases, and Google Scholar and manual screening of retrieved references were systematically searched from their inception dates to 24 March 2020 by extracting the effect size (Odds ratios (OR) and relative risk (RR) in each study. To present the forest plot of effect of metformin on each cancer, Stata version 14.2 was used. Results: This study included 36 meta-analysis studies and 620 original research studies (26 randomized control trials studies and 594 observational studies (cohort, case–control)) covering 15 different cancers. Overall, metformin medication prevented different cancers, including ovarian cancer (OR = 0.76, 95% CI: 0.62,0.93), cervical cancer (OR = 0.60, 95% CI: 0.43, 0.83), endometrial cancer (OR = 1.05, 95% CI: 0.82,1.35), liver cancer (OR = 0.59, 95% CI: 0.47,0.74), pancreatic cancer (OR = 0.59, 95%CI 0.50,0.69), head and neck cancer (OR = 0.71, 95% CI: 0.61,0.83), stomach cancer (OR = 0.72, 95% CI: 0.26,1.99), colorectal cancer (OR = 0.73, 95% CI: 0.59,0.91), colorectal adenoma cancer (OR = 0.75, 95% CI: 0.65,0.86), colon cancer (OR = 0.79, 95% CI: 0.69,0.91), esophagus cancer (OR = 0.90, 95% CI: 0.83,0.98), lung cancer (OR = 0.92, CI95%:0.85,0.99), breast cancer (OR = 0.93, 95% CI: 0.84,1.02), prostate cancer (OR = 0.94, 95% CI: 0.85-1.04), and bladder cancer (OR = 0.94 95% CI: 0.64,1.38). Conclusions: Treatment with metformin can significantly decrease the chance of all cancers with larger preventive effect on hepatocellular carcinoma and smaller preventive effect on lung and breast cancers.
Keywords: Diabetes mellitus, meta-analysis, metformin, neoplasms, review
How to cite this article:
Najafi F, Rajati F, Sarokhani D, Bavandpour M, Moradinazar M. The relationship between metformin consumption and cancer risk: An updated umbrella review of systematic reviews and meta-analyses. Int J Prev Med 2023;14:90 |
How to cite this URL:
Najafi F, Rajati F, Sarokhani D, Bavandpour M, Moradinazar M. The relationship between metformin consumption and cancer risk: An updated umbrella review of systematic reviews and meta-analyses. Int J Prev Med [serial online] 2023 [cited 2023 Sep 30];14:90. Available from: https://www.ijpvmjournal.net/text.asp?2023/14/1/90/381726 |
| Introduction | |  |
Diabetes comprises a major component of the global burden of disease.[1] Diabetes mellitus is a risk factor for cardiovascular diseases, retinopathy, chronic kidney disease, and neuropathy and causes other adverse health effects. Findings from a number of population-based studies have also shown that diabetic patients face an increased risk of various types of malignant tumors.[2] Therefore, physicians are interested in prescribing antidiuretic drugs for diabetic patients to reduce the risk of cancer.
The role of insulin resistance has recently been proved as a risk factor for cancer in diabetes.[3] Metformin is a biguanide drug that is mainly used as first-line drug to treat type II diabetes for improving insulin resistance.[4] The effect of anti-diabetic drugs on reducing the risk of cancer has recently attracted researchers' attention. Some documents show metformin medication may reduce the incidence of cancer, progression, and even cancer-related mortality.[5]
Cancer is the second leading cause of death across both developing and developed countries, approximately 9.6 million death was recorded because of cancer worldwide in 2018.[6] The cancer-related burden is expected to rise worldwide because of aging of population.[7]
The major anti-cancer mechanism of metformin relates to its ability to activate Liver Kinase B/AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) that blocks the tumor growth because of decreased circulating insulin levels.[8] Recent studies show that metformin can reduce the risk of various cancers in diabetic population, such as thyroid cancer,[9] oral cancer,[10] gastric cancer,[11] bladder cancer,[12] prostate cancer,[13] breast cancer,[14] endometrial cancer,[15] ovarian cancer,[16] and cervical cancer.[17]
An initial meta-analysis of studies in diabetic patients showed that compared to other diabetes treatments, the metformin medication can reduce the risk of all metformin-related cancers up to 30%.[18] Systematic review and meta-analyses on the effects of the metformin medication on incidence of various cancers have been carried out. Furthermore, a published umbrella review of the systematic review and meta-analyses has been searched up to 2018. However, some systematic review and meta-analysis studies after this date are controversial,[19],[20] and in some cases, studies have reviewed a new outcome, such as colorectal adenoma[21] and cervical cancers.[22] In addition, in case of finding more than one meta-analysis regarding a certain cancer, authors selected the meta-analysis that has the most number of the original article. It is possible that the meta-analysis study that we exclude has several basic studies that are not present in the largest existing meta-analysis, and we miss those studies. Therefore, for a more precise estimation, the umbrella review needs to be updated.
| Methods | | |
Protocol and registration
This is an updated umbrella review study investigating meta-analyses that have examined the relationship between metformin consumption to treat diabetes and the risk of developing cancers. Our report follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes protocol (www.prisma-statement.org).[23] The protocol for this study has been registered at PROSPERO (ID: 124229, Date: 02-02-2019).
Eligibility criteria
The following studies were excluded from this umbrella review: studies that examined (a) the effect of combination of metformin and another antidiabetic drug, (b) the effect of metformin on the mortality rate of cancer patients, (c) the effect of metformin on cancer recurrence among patients with history of cancer, and (d) the effect of metformin on the prognosis of cancer patients.
In this study, to achieve targeted studies, eligible meta-analyzes based on cancer site were separated. If there was only one meta-analysis study for a particular cancer site, then the same study was chosen as the most comprehensive study. Whenever more than one meta-analysis study examined the relationship between metformin consumption and the risk of a particular cancer, a meta-analysis that was more up-to-date and comprehensive than other meta-analysis studies was chosen. In this case, three conditions were considered for selecting the most comprehensive and up-to-date meta-analysis. In the first step, the timeframe of meta-analysis studies to find out which meta-analysis study is more up-to-date and has covered more years was compared. Second, the number of included studies of each meta-analysis was compared. In the third step, the quality of meta-analysis studies were examined using the AMSTAR checklist If a meta-analysis was found to meet all three conditions (more comprehensive timeframe, number of more basic studies, and higher quality level), that meta-analysis was chosen. But whenever more than one eligible meta-analysis study was selected for each cancer site, the remaining studies were re-analyzed by integrating each of those meta-analyzes and eliminating overlapping (duplicate) cases and a new meta-analysis was carried out in these cases,
Search strategy
Different databases were systematically searched: Scopus, PubMed, Embase, Cochrane, Web of Science and Google Scholar from inception by 24 March 2020. Limited the search to humans and no language or time restrictions were applied. Supplementary [Table S1] in the appendix shows the search strategy. The References list of the eligible reviews were also reviewed.
Main keywords or corresponding MeSH terms were as follows: cancer, carcinoma, neoplasia, tumor, neoplasm, Meta-analysis, Meta-analyses, Systematic review, Metformin, Diabetes Mellitus, and Malignancy. A manual search was also done for references cited in the selected articles, in selected reviews, or books.
Methodological quality assessment
Using the online version of assessing the Methodological Quality of Systematic Reviews (AMSTAR) (https://amstar.ca) the systematic reviews and meta-analyses graded into three levels of quality: “high,” “moderate,” and “low.” AMSTAR is an 11-item assessment tool that has been validated and is being increasingly used by health care policy makers, health technology assessment agencies, and some authors and journal editors.[24]
Data extraction
Two investigators carried out data extraction independently and then, the extracted data were compared and discrepancies were resolved with discussion. A third investigator arbitrated on any remaining differences. For each eligible article, the first author, year of publication, study design, cancer site, number of studies (by study design), and OR/RR with its confidence interval were extracted [Table 1].
Statistical analysis
To evaluate the effect of metformin on the risk of cancer, the odds ratio (OR) and Relative Risk (RR) were used. To present the forest plot for the effect of metformin for each cancer, Stata version 14.2 (Stata Corp, College Station, Texas) was used.
| Results | | |
Description of meta-analyses
Using the search strategy outlined in the Materials and Methods Section, a total number of 814 articles were found in the reviewed databases. According to inclusion and exclusion criteria, 36 meta-analysis articles remained eligible that included a total of 620 articles (26 randomized control trial – RCT studies and 594 observational studies (cohort, case–control)) [Figure 1]. The largest sample size belonged to a meta-analysis by Lang Wu et al,[43] (sample size = 7,600,000, number of study = 265) and the smallest meta-analysis carried out by Hui Zhang et al.[40] (sample size = 16,549, number of study = 7) [Table 1]. | Figure 1: Diagram of selection of studies for inclusion in umbrella review
Click here to view |
In all studies, taking metformin prevents the development of cancers (RR <1, OR <1) with the exception of four studies [Table 1].[20],[30],[51],[53] Thakkar et al.[30] reviewed clinical trials (RCT) investigating the association between metformin consumption and cancers and concluded that metformin consumption increased the risk of cancer (RR >1); however, the result was not statistically significant. On the other hand, the same article had reported the protective effect of metformin consumption in cohort, case–control studies (RR <1), indicating that metformin consumption prevented the risk of cancer. Christopher B. Chen et al.[20] investigated the relationship between prostate cancer and metformin consumption in 26 included studies with no statistically and clinically important effect. Overall, in this study, out of all the reviewed articles, only 12 articles[20],[29],[30],[37],[42],[45],[46],[48],[51],[52],[53],[56] indicated that metformin consumption had no statistically significant effect on cancer risk (with 77.6 of heterogeneity), but the effect of metformin consumption on cancer prevention was significant in other meta-analyses [Table 1].
In this umbrella review study, some studies focused on one specific type of cancer.[33],[42],[45] Others have investigated the association between metformin consumption and the risk of several different cancers that were reported by type of cancer.[26],[29] To eliminate overlap between studies, the remaining 36 meta-analyses were separated by site of cancer. Of all reported meta-analyses on different sites of cancers, the most comprehensive and updated meta-analysis were retained. Finally, there were 15 different site of cancer [Table 2] and [Figure 2]. | Figure 2: Relationship between metformin use and the risk of cancer worldwide. The midpoint of each segment estimates the odds ratio and length of the segment, showing the 95% confidence interval in each study
Click here to view |
 | Table 2: The effect of metformin on the risk of cancers by type of cancer
Click here to view |
Diabetic patients who received metformin medication had a lower risk for liver cancer, pancreatic cancer, cervical cancer, head and neck cancer, colorectal cancer, colorectal adenoma cancer, colon cancer, ovarian cancer, esophageal cancer, and lung cancer. Furthermore, a protective role also (but not significant) between metformin medication and incidence of prostate cancer, bladder cancer, gastric cancer, and breast cancer was observed. The largest protective effect of metformin was related to liver and pancreatic cancers and the least to lung cancer. However, metformin was a risk factor for incidence of endometrial cancer. Some of the meta-analyses evaluated all cancer incidence. They also revealed a protective role of the metformin [Table 2].
| Discussion | | |
This umbrella review showed that diabetic patients who received metformin treatment had a lower risk of cancer compared to diabetic patients who did not use metformin, with a non-significant effect on endometrial cancer. Metformin as an AMPK inhibitor exerts its anticancer effect by activating mTOR pathway. Metformin inhibits cancer cell mitosis by inducing activation of the activated protein kinase-adenosine monophosphate and consequently reducing growth factor signaling. Inhibition of GTPase and microRNA222 suppression induced by metformin administration leads to increased levels of p27 and p57 molecules and consequently disrupts cell cycle in tumor cells. Other possible mechanisms underlying the metformin potential anti-neoplasm effect could be the following: antagonizing effect on obesity or via the reduction of inflammation,[57] p-53 activation,[58] down regulation of cyclin D1,[59] and killing of cancer stem cells.[60]
Metformin consumption plays a protective role on cancer incidence, although it was not statistically significant in some meta-analyzes.[18],[26] Previous studies have shown that metformin at lower doses can block HER2 activity. In addition, metformin can prevent drug resistance to targeted HER2 chemotherapy with drugs such as trastuzumab and lapatinib. Therefore, treatment with both metformin and HER2 may have a synergistic effect. These results confirmed that the risk of invasive breast cancer in metformin-treated diabetics is lower than in recipients of other antidiabetic drugs. There was also a significant effect of metformin treatment on reducing risk of both ovarian and cervical cancer, supported by high quality meta-analyses according to AMSTAR 2.
So far, two meta-analyses have been conducted to investigate the relationship between metformin consumption and colon cancer risk, both of them showed a protective effect on colon cancer, which was statistically significant in study by Rokkas et al.[34] [RR: 0.79 (95% CI: 0.69–0.91)]. Such protective effect of metformin consumption was not statistically significant in the study by Decensi et al.[18] Clinical and laboratory studies have shown that metformin inhibits cell growth in colorectal cancer. Results of a meta-analysis reviewing five studies (total sample size = 108,161 diabetic patients) showed that metformin significantly reduces the risk of colorectal cancer. This study reported that metformin reduced the relative risk of colorectal cancer by 39%. The same meta-analysis examined the effects of insulin and thiazolidinediones, both of them were shown to be unable to reduce the mortality rate of colorectal cancer.[25]
The results of six studies that examined the relationship between metformin and colorectal cancer showed that metformin consumption reduced the risk of colorectal cancer and this relationship was statistically significant [Table 2]. Metformin consumption had no effect on the risk of colorectal cancer in the meta-analysis performed on RCT studies by Franciosi et al.[29] [RR: 1.02 (95% CI: 0.41-2.50]. In contrast, analysis performed on observational studies had a preventive effect.
All five meta-analyses on the association between metformin consumption and prostate cancer showed no statistically significant association. However, three studies by Noto et al.,[26] Ghiasi et al.,[45] and Feng et al.[48] indicated its protective role. Low sex hormone-binding globulin levels may facilitate conversion of testosterone to estradiol, which in turn may increase the risk of hormone-dependent breast cancer. The duration of metformin treatment in diabetic patients was associated with a decrease in mortality from prostate cancer.[61]
Nie et al.[42] reported that metformin consumption had no effect on the risk of lung cancer (OR= 0.99 (95% CI: 0.87–1.12)). However, Zhang et al. showed metformin consumption reduced significantly the relative risk of lung cancer (RR= 0.71 (95% CI: 0.55–0.95)).[31] Noto et al.[26] also found that metformin consumption significantly reduced the risk of lung cancer (RR = 0.67, 95% CI: 0.45–0.99).
Studies have shown the protective role of metformin consumption against pancreatic cancer, although the effect was not statistically significant in some studies.[26],[29],[37],[41] Metformin probably reduces inflammation and fibrosis, which is the most common cause of pancreatic cancer. Findings of cellular and animal models as well as in tumor specimens suggest that this positive effect may be observed in obese or overweight patients more frequently.[62]
In fact, metformin can reduce desmoplasia, an accumulation of dense connective tissue, and tumor-associated immune cells, and a key feature of pancreatic cancer. This function is accomplished by inhibiting the activity of pancreatic stellate cell (PaSCs). PaSCs produce extracellular matrix and reprogram immune cells to reduce inflammation. These effects are only visible in tumors found in obese and overweight people, as these tumors seem to be more fibrous in nature.
Review of previous studies showed that four meta-analyses were performed on the association between metformin consumption and the risk of hepatocellular cancer. All studies revealed that metformin consumption had a preventive effect on hepatocellular cancer and this relationship was statistically significant (Siddharth Singh,[38] RR = 0.50 (95% CI: 0.34–0.73), Hiroshi Noto[26] (RR = 0.20 (95% CI: 0.07–0.59), Ping Wang[36] (RR = 0.31 (95% CI: 0.19–0.49), and Hui Zhang[40] (RR = 0.24 (95% CI: 0.13–0.46).
Metformin not only inhibited proliferation and colony formation ability via (AMPK) in hepatocellular carcinoma cell[63] but also as an anti-hyperglycemic agent, it inhibited hepatic gluconeogenesis,[64] decreased serum concentrations of insulin and insulin growth factor,[65] improved the HbA1c levels, and reduced inflammatory response.[66] This process reduces the aggressive behavior of cancer cells. All previous relevant studies have shown that metformin consumption can prevent hepatocellular cancer.
Only three associations (between metformin and colon, ovarian, and cervical cancer) were supported by both high quality and statistically significant relationship. Patients who received metformin treatment have odds of 0.21, 0.24, and 0.40 to develop colon, ovarian, and cervical cancer, respectively.
Some of the reviews showed nonsignificant protective effect with a moderate to high quality. The possible reasons for the statistically insignificant results can be different, including the inadequate sample size and the study designs of included meta-analyses.
This study is an update of previous meta-analyses and umbrella reviews covering most common cancer sites. Because most included studies did not report the relative risk of cancers on consumption of metformin by study type (cohort, clinical trial, case–control, etc.), this report failed to perform analyses stratified by study type. In addition, some meta-analysis studies were based on medical or insurance data that are not specifically designed to evaluate the impact of metformin therapy on cancer. There were incomplete details on dose, duration, changes occurring in treatment over time, and potential confounders.
In fact, considerable heterogeneity among included studies in terms of population of the studies, diversity of the disease duration, type of cancer, and study design did not allow to pool the data for estimating an effect size. Unadjusted measures and some possible confounding factors in the original studies may have rendered the results of this study less valid. Overestimation of the effect of metformin may have occurred. In some studies, the characteristics of comparison group has been defined as “Non-metformin consumer,” which in turn may have received other glucose lowering drugs with synergistic effect with other medications, affecting the likelihood of cancer. The most commonly used drugs are insulin and sulfonylurea, which are associated with hyperinsulinemia which is associated with an increased risk of cancer. Therefore, hyperinsulinemia in comparison groups might overestimate the effect of metformin. On the other hand, the synergistic effect of metformin with some common medications in diabetic patients may have led to an overestimation of the effect of metformin on cancer.[67] Confounding by treatment indication such as using metformin medication in younger age with a lower risk of cancer also might overestimate the effect of metformin.
| Conclusions | | |
Metformin therapy in diabetic patients may be a reasonable prescription for the prevention of cancers if it has not been clinically contraindicated. Such effect was higher in hepatocellular carcinoma and lower in lung and breast cancers; however, it had no significant effect on some cancers, including prostate cancer, bladder cancer, endometrial cancer, gastric cancer, and breast cancer.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]
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