Metformin Reduces the Incidence of Cancer in Type 2 Diabetes Patients: an Update Meta Analysis

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January 01, 2018.   doi:10.12123/npcd201801004

BIOWED January 01, 2018

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Dan Zhang, Jiaru Luo, Yunzhi Ling*

All authors are from Biowed (China) Co., Ltd.

Communication: lyz@algaemedical.com

Keywords: Metformin; type 2 diabetes; Cancer incidence risk; Meta analysis

Received: September 01,2017 Accept: November 01,2017 published:January 01,2018

ABSTRACT

To evaluate the association between metformin treatment and the incidence risk of cancer in diabetes patients. Firstly, literatures related to metformin treatment and type 2 diabetes were searched in CBM, CNKI, VIP, wanfang, Cochrane Library, PubMed and Web of science databases via computer-based retrieval and manual retrieval, the searching date was updated to April 2017. Then according to the eligibility criteria to screen literatures, and twenty-five studies were included in this study. Finally, the related data were extracted and analyzed using Revman 5.3 software. The meta results of fifteen cohort studies showed: the incidence of cancer in type 2 diabetes patients who were treated with metformin was obviously lower than that in type 2 diabetes patients without metformin treatment, and RR=0.49, 95% CI [0.34, 0.72]. The meta results of ten case-control studies showed the reduction of cancer incidence in type 2 diabetes patients is associated with the use of metformin, and OR=0.82, 95% CI [0.7, 0.95]. In conclusion, metformin treatment can effectively decrease the incidence of cancer in type 2 diabetes patients.

Introduction

Diabetes is one type of the most common chronic diseases. As the diseases progress, lesion of the large vessel and the micro vessel could be induced by long-term hyperglycemia, which would eventually lead to a variety of complications, seriously affecting the patients on their daily life. Moreover, people living with diabetes are at a higher risk of getting various diseases and tend to have higher molarity than the general population. Over the past few decades, the incidence of diabetes is gradually increasing year by year as quality of people's life improves. According to International Diabetes Federation (IDF), as of 2015, the number of people with diabetes has exceeded 450 million in the world. This figure is expected to continue growing for the following decades and would eventually reach about 642 million in 2040(1). Type 2 diabetes mellitus (T2DM), also known as adult-onset diabetes, mostly onset around age 35 to 40, which make up more than 90% of diabetic patients. In recent years, the incidence of type 2 diabetes (T2DM) kept rising and showed young trend. It not only endangers the health of patients severely but also puts the patients and their family, or even the whole society, under huge economic burden(2). Epidemiological studies have shown that T2MD is mainly caused by the factors of high-fat diet, lack of exercise and obesity, etc., and the islet cell dysfunction, decreased insulin secretion and insulin resistance are the main symptoms of most patients. A large number of studies have shown that the risk of cancer in patients with diabetes was significantly higher than the general population, in fact, it is far above the expectation, especially for T2MD patients. The incidence liver cancer, pancreatic cancer and endometrial tumor of them are 2 times higher, as for the risk of renal cancer, bladder cancer, and breast cancer are 1.2-1.5 times higher(3-5).

Metformin, a biguanide drug, which is a preferred early treatment for T2MD due to its effectiveness, safety, and affordable price. It is used since it is successfully developed from the 50s of 20th century. According the 2017 edition of the American "Diabetes Medical Diagnostic Criteria", released by American Diabetes Association (ADA): If no contraindications and it is tolerable, metformin should be the first choice of early treatment for patients with type 2 diabetes Metformin can treat T2MD through improving the utilization of glucose, inhibit carbohydrate absorption and gluconeogenesis, which play a similar role as insulin(6). In 2005, a retrospective study has found that T2MD patients who received metformin as treatment were found under significantly lower risk of cancer, comparing to patients who were on other medication(7). Since then, using metformin as an anti-cancer drug had become a research hotspot. Over the years, some studies have shown that with the use of metformin can reduce the risk of getting various cancers including pancreatic cancer, rectal cancer, ovarian cancer, prostate cancer, lung cancer, thyroid tumors, laryngeal cancer etc. There are also studies the risk of cancer is not related to the use of metformin. However, long-term use of metformin can increase the survival of T2MD patients with breast cancer(8). Never the less, in the study of Kowall et al(9) shows there isn't any significant protective effect on colorectal cancer, lung cancer, breast cancer and prostate cancer. In the meantime, using metformin can neither increase the survival rate of patients with pancreatic cancer nor improve the prognosis(10).

Metformin, a biguanide drug, which is a preferred early treatment for T2MD due to its effectiveness, safety, and affordable price. It is used since it is successfully developed from the 50s of 20th century. According the 2017 edition of the American "Diabetes Medical Diagnostic Criteria", released by American Diabetes Association (ADA): If no contraindications and it is tolerable, metformin should be the first choice of early treatment for patients with type 2 diabetes Metformin can treat T2MD through improving the utilization of glucose, inhibit carbohydrate absorption and gluconeogenesis, which play a similar role as insulin(6). In 2005, a retrospective study has found that T2MD patients who received metformin as treatment were found under significantly lower risk of cancer, comparing to patients who were on other medication(7). Since then, using metformin as an anti-cancer drug had become a research hotspot. Over the years, some studies have shown that with the use of metformin can reduce the risk of getting various cancers including pancreatic cancer, rectal cancer, ovarian cancer, prostate cancer, lung cancer, thyroid tumors, laryngeal cancer etc. There are also studies the risk of cancer is not related to the use of metformin. However, long-term use of metformin can increase the survival of T2MD patients with breast cancer(8). Never the less, in the study of Kowall et al(9) shows there isn't any significant protective effect on colorectal cancer, lung cancer, breast cancer and prostate cancer. In the meantime, using metformin can neither increase the survival rate of patients with pancreatic cancer nor improve the prognosis(10).

Materials and Methods

Inclusion Criteria

(1) Subjects are type 2 diabetes patients; (2) Comparison in the risk of cancer between patients receive metformin and control is performed; (3) OR value/HR value is reported in the result.

Exclusion Criteria

(1) Animal research or cytology experimental study; (2) Article type is review; (3) Cross-sectional study; (4) The results of the study did not give the adjusted value of disease risk, meanwhile, it cannot be calculated from known data; (5) Design flaws, incomplete data and incorrect statistical method exist in study.

Search Strategy

Searched in CNKI, CBM, VIP, and Wanfang using "metformin", "diabetes", "cancer" as keywords; Using keywords: "Metformin", "Diabetes Mellitus", "Neoplasms" to search in PubMed, Cochrane, Web of science. The searching date is updated to April 2017.

Data Extraction

Following the pre-design data extraction table, two researchers, one was responsible for entering the information extraction and the other make sure everything was on the right track. In case of disagreement, it could be discussed within the two researchers or judged by the third party. Lack of information should be made up by contacting with the author by phone or email. Information that were extracted including: (1) General information: title, name of author(s), date published, and resource of articles; (2) Research method; (3) The total number of patients with diabetes and the number of people with cancer within them, which region they are from, what is the diagnostic criteria, and also their sex, age, nationality, is there any interference is done etc.; (4) Outcome and time; (5) Outcome and effect indicators.

Statistical Analysis

Revman 5.3 software was used in this meta-analysis. In case-control and cohort studies, the incidence rate is represented as odds ratio (OR) and relative risk (RR), respectively. If the value of incidence rate is less than one (OR<1 or RR<1), and 95% CI does not overlap with the value of one, it suggests that metformin is a protective factor for T2MD patients. That is, taking metformin can reduce the risk of tumorigenesis; The heterogeneity was detected by I2 and Q test. If I2 < 50% and P > 0.10, then there is no heterogeneity, which means the fixed effect model should be used, otherwise, choose random effect model. If there is significant heterogeneity and the source of it cannot be determined, then no meta-analysis should be performed but using descriptive analysis instead.

Results

Characteristics of Included Studies

In this meta-analysis, total 708 related literatures were retrieved. Twenty-five of them were included in the analysis by carefully reading the title, abstract and full text, excluding those cross-sectional studies, repeated publications, animal or cytology experiments(7,11-34), and research not based on T2MD patients, etc. The literature screening process is shown in Figure 1. Subjects of all 25 studies are T2MD patients along with exact OR of the incidence rate of cancer. Within these studies, 15 of them are cohort study(14,17,18,20,24-34), and 10 of them are case-control study(7,11-13,15,16,19,21-23); Notice that Tseng, C. H.(24-32) in 2014 to 2016, has published 9 retrospective cohort study articles, respectively, on the risk of T2MD patients in colon cancer, prostate cancer, thyroid cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, oral cancer, renal cell carcinoma. Only one of them is listed in Figure 1. See more details of the articles included in the study in Table 1.

In addition, in the data extraction process of this meta-analysis, if both the pre-adjusted and post-adjusted OR are provided in the articles, the post-adjusted value is adopted due to the fact that post-adjusted value has taken the confounding factors into consideration, which makes it more precise than the pre-adjusted value. When the incidence of cancer in T2MD patients is low in case-control studies (such as studies of Azoulay, L.(11), Smiechowski, B. B.(23) and Smiechowski, B. (22)), since the effect of OR is close to RR, RR value can be used as OR value for analysis.

Meta analysis

The result of this accumulated meta-analysis which included 10 case-control studies showed that there was a significant heterogeneity (I2=81%, P<0.00001), therefore, the random effect model was adopted here. The result of the forest plot showed that: The incidence of cancer is lower in the T2MD patients who were treated with metformin, with OR=0.82, 95% CI [0.7, 0.95] (Figure 2).

Similarly, the results of the accumulated meta-analysis which included 15 cohort study showed that there is a significant heterogeneity between each study (I2=97%, P<0.00001), and random effect model was used. According to the forest plot: administration of metformin can reduce the incidence of cancer in T2MD patients, with RR=0.49, 95% CI [0.34, 0.72] (Figure 3).

Subgroup Analysis

Since the degree of heterogeneity in the accumulated meta-analysis was high, we performed a subgroup analysis based on the type of cancer furtherly. However, the type of cancer in the 10 case-control studies was all different from each other, therefore, only the 15 cohort studies are accounted for this subgroup analysis.

Within the 15 cohort studies, 3 of them have analyzed the incidence of colorectal cancer in T2MD patients and 3 have analyzed the incidence of breast cancer.

The results of the subgroup analysis for the 3 studies on colorectal cancer showed that there was no heterogeneity between the studies (I2=7%, P=0.34), and fixed effect model was used. Meanwhile, the result of forest plot suggested that taking treatment of metformin can reduce the incidence risk of colorectal cancer in T2MD patients, with RR=0.68, 95% CI [0.56, 0.84] (Figure 4A).

The results of the subgroup analysis for the 3 studies on breast cancer showed that the heterogeneity between the 3 studies was I2=57% (P=0.10), so random effect model was adopted. And the forest plot indicated that the reductionof the incidence risk of breast cancer in T2MD patients is related to metformin administration, with RR=0.69, 95% CI [0.55, 0.87] (Figure 4B).

Sensitivity Analysis

In addition, in order to assess the stability of the meta-analysis, a sensitivity analysis using a single variable sensitivity analysis was used to test: whether the study had a significant effect on the overall outcome. The results suggested the pooled ORs were statistically robust and reliable.

Figure. 1 A flow diagram of the study selection process.

Table.1 Characters of Included Studies.

Figure 2 In the 10 case-control studies, the incidence rate of cancer in T2MD patients treated with or

without metformin were compared.

Figure 3 Comparison of cancer incidence in metformin treatment group and non-metformin treatment group of T2MD patients, in the 15 cohort studies. Among that, "Tseng, C. H 2016 b" represented the total RR value which accumulated by the RR value of 9 studies published by Tseng, et al from 2014 to 2016. "XILIN YANG 2011 1" and "XILIN YANG 2011 2" represented the RR value of effects when treated with two different concentrations of metformin in YANG's study, respectively.

Discussion

Diabetes is a common chronic metabolic disorder characterized by hyperglycemia and could be induced by varies of causes, often leading to three major metabolic disorders in patients, which eventually give rise to dysfunction of multiple organs(35). Never the less, high blood sugar, insulin resistance and the other diseases that induced by metabolic disorders can easily cause the risk of a variety of cancer to increase(36,37). In recent years, as the incidence of diabetes keeps increasing and continuous research shows that type 2 diabetes is closely related to the risk of cancer. Both clinical and basic research on the relationship between diabetes medication and the incidence of cancer has become a research focus in a wide range.

Metformin as the preferred medication for treating T2MD, it can reduce the blood sugar in patients by reducing the body's resistance to insulin, which enhances the efficiency of using insulin for the body. With the widespread use of metformin in treating T2MD, some recent epidemiological studies found that metformin not only have extraordinary hypoglycemic effects but also has some significant effect on treating a variety of cancers and could be a potential anticancer drug(38). A large number of experimental studies have shown that the cell proliferation of esophageal cancer(39,40), gastric cancer(41,42), liver cancer(43,44), pancreatic cancer(45), breast lobular carcinoma(46) and another tumor cells can be inhibited in T2MD patients after metformin administration, which helps reduce the risk of incidence of cancer. In 2016, Amin et al. have analyzed 1916 diabetic patients with pancreatic cancer (PDAC) and found that the risk of death is reduced by 12% in patients who are on metformin treatment(47). In addition, in vitro cell experiments have also confirmed that metformin can activate AMPK and inhibits P13K/AKT/mTOR signaling pathways which help regulate cell cycle(48), or inhibits cancer cells from metastasis by regulating EMT expression through inhibiting the COX/PGE2/STAT3 signal pathways(49), which can also reach the goal of reducing the incidence and development of tumors (50).

Although the prevention of metformin on malignant is highly supported by many epidemiological investigations and clinical research, there still not yet has a conclusion about if metformin can really reduce the incidence rate of cancer in T2MD patients. In order to clarify this relationship, this study has quantitatively synthesized the published result of the incidence of cancer in T2MD patients and analyzed them with meta-analysis, based on the principle of evidence-based medicine, try to reduce the impact of offset on the outcome and improve the accuracy and reliability. In this study, 25related studies with high quality were included in the meta-analysis, after retrieval and screening based on the established literature exclusion and inclusion criteria. Within these studies, 15 of them are cohort study, and 10 of them are case-control study. The result of the accumulated meta-analysis of the case-control studies showed that: compared with the T2MD patients treated without metformin, the incidence of cancer is lower in the T2MD patients who treated with metformin, with OR=0.82, 95% CI=[0.7, 0.95] (I2=81%, P<0.00001). Since the result of this meta had a high heterogeneity, we checked for the heterogeneity by excluding one study each time and found that Hassan, M. M.'s study in 2010 (16) was the main source of heterogeneity. When this study was excluded, OR=0.89, 95% CI [0.80, 0.99], (I2=58%, P=0.01). The result of cohort studies of meta-analysis showed: total RR=0.49, 95% CI [0.34, 0.72] (I2=81%, P<0.00001), the heterogeneity was high and the heterogeneity had no significant change while using the exclusion method; therefore, subgroup analysis was applied, and the result showed that: metformin can effectively reduce the risk of colorectal cancer and breast cancer in T2MD patients. To ensure the robustness of the meta-analysis, we took a step further and presented the sensitivity analysis, which showed that the results of this study were relatively stable and reliable.

In summary, this study has preliminarily confirmed that metformin treatment can effectively reduce the risk of cancer in T2MD patients. However, due to the fact that most of the study on using metformin as hypoglycemic treatment are observational studies which are case-control study or cohort study. There is a certain degree of limitation in the verification, and the reliability of the results is relatively low. But notice the fact that evidence-based medicine analysis is still developing and despite the above flaws, this study has conducted a systematic evaluation to this problem, based on existing data resources. The number and the quality of the articles that were taken into account are relatively large and high, as well ascomprehensive. The conclusion can still be a guide for preventingand treating cancer in type 2 diabetes patients.

Figure 4 Subgroup analysis: (A) Comparison of colorectal cancer incidence in metformin treatment group and

non-metformin treatment group of T2MD patients; (B) Comparison of breast cancer incidence in metformin

treatment group and non-metformin treatment group of T2MD patients.

Conclusion

This study has done a meta-analysis on the data which is extracted from the selected articles and the results show that: Metformin treatment can reduce the incidence rate of cancer in type 2 diabetes patients.

Acknowledgement

All authors sincerely acknowledge the support given by Biowed (China) Co., Ltd and Guangzhou Algae Technology Information Consuitant Co., Ltd.

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