Cancer and Metformin

Metformin: Can a Diabetes Drug Help Prevent Cancer?

Photo of French lilacs.

Metformin originates from compounds derived from the French lilac (Galega officinalis). The plant has been used since the Middle Ages to relieve the symptoms of diabetes.

Credit: Epibase, Göteborg, Sweden

In 1957, the first results from a clinical trial of the diabetes drug metformin in patients were published. Yet, it would take nearly 40 years for the drug to be approved in the United States as a treatment for type 2 diabetes.

Now researchers want to know whether this decades-old drug may have additional uses in another disease—cancer. Based on findings from a number of large epidemiologic studies and extensive laboratory research, metformin is being tested in clinical trials not only as a treatment for cancer, but as a way to prevent it in people at increased risk, including cancer survivors who have a higher risk of a second primary cancer.

Numerous early-stage clinical trials are currently under way to investigate metformin’s potential to prevent an array of cancers, including colorectal, prostate, endometrial, and breast cancer. Several of these trials are being funded by NCI’s Consortia for Early Phase Prevention Trials. And NCI is collaborating with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to study participants from the landmark clinical trial, the Diabetes Prevention Program (DPP), to investigate metformin’s impact on cancer incidence.

Some of the early-phase prevention trials of metformin are enrolling participants who are at increased risk for cancer and who are obese, have elevated glucose or insulin levels, or have other conditions that put them at risk for diabetes.

“With the obesity epidemic, these studies are applicable to a substantial portion of the U.S. population and, increasingly, of the world population,” said Brandy Heckman-Stoddard, PhD, MPH, of NCI’s Division of Cancer Prevention.

Expanding the Data Pool

Much of the human data on metformin and cancer has come from epidemiologic studies of people with diabetes. In many, though not all, of these studies, people with diabetes who were assigned to take metformin had a lower incidence of cancer than those taking other diabetes drugs.

Completed in 2002, the original DPP enrolled more than 3,200 people at increased risk of developing diabetes and randomly assigned them to one of three groups: one group received metformin, one took part in an intensive diet and physical activity program, and one received a placebo. Participants in the metformin arm had a substantially lower risk of developing diabetes than the general population; participants in the exercise and diet regimen fared even better.

With NCI’s involvement, the program’s extension, called the DPP Outcomes Study, will allow investigators to document cancer incidence and death among study participants. Those observations should provide some of the strongest data available to date on metformin’s anticancer effects in people without diabetes, explained Dr. Heckman-Stoddard. The first data on cancer outcomes in study participants, which will be based on 15 years of follow-up, should be available in 2014.

“Once we have that data, there are a host of other questions we can ask,” she said. For example, Dr. Heckman-Stoddard and her colleagues plan to study metformin’s impact on certain blood biomarkers that studies have suggested are associated with cancer risk. They will also study the drug’s mechanism of action—that is, how metformin may work to prevent changes in cells that can lead to cancer.

For Prevention, Small Biomarker-Driven Trials

The smaller prevention trials being conducted are very different from the DPP Outcomes Study. These trials are not designed to determine whether metformin prevents cancer. Prevention trials must generally have a large number of participants and span many years to show whether a drug or some other intervention reduces the risk of cancer.

Instead, these short, 3- to 6-month trials are investigating whether the drug has an effect on specific proteins and/or signaling pathways that have been implicated in cancer development and that laboratory studies have shown are affected by metformin.

At the University of California, Irvine Chao Family Comprehensive Cancer Center, for example, Jason Zell, DO, MPH, is leading an early-phase clinical trial that is testing metformin’s effect on the mTOR signaling pathway in obese people who have previously had precancerous growths removed from their colons.

Numerous studies have implicated the mTOR pathway as an integral hub in cancer development and progression, and laboratory studies have consistently shown that metformin can blunt mTOR signaling.

“The key point of the trial is to get at the mechanisms of action … to see if metformin is behaving in the expected manner” based on the lab findings, Dr. Zell explained.

Numerous early-stage clinical trials are currently under way to investigate metformin’s potential to prevent an array of cancers, including colorectal, prostate, endometrial, and breast cancer.

Dr. Zell and his colleagues chose to study obese patients “because of the interesting side-effect profile of metformin, which can include weight loss,” meaning it may not be suitable for underweight, nondiabetic individuals, he continued.

If this first trial shows that metformin is having the expected effects on mTOR signaling, the next trial would be similar but would measure a clinical outcome, such as whether metformin decreases the number of colorectal polyps that return.

A phase II trial at the University of California, San Diego Moores Cancer Center is testing metformin’s effects on a host of biomarkers in postmenopausal breast cancer survivors who are obese.

Funded by NCI’s Transdisciplinary Research on Energetics and Cancer (TREC) program, the trial, called Reach for Health, will involve treatment with metformin alone and in combination with an exercise program. The study will examine the effect of 6 months of metformin treatment, with or without exercise, on a host of biomarkers associated with cancer risk. The change in biomarker measurements before and after treatment will be compiled into a score that predicts the risk of dying from breast cancer.

This is all part of the trial’s novel “biomarker bridge” design, the lead investigator, Ruth Patterson, PhD, explained. The biomarkers and the risk score are being derived from an analysis of tissue samples collected as part of an NCI-supported phase III trial called the Women’s Healthy Eating and Living (WHEL) study. This study found that a diet low in fat and high in fruits and vegetables did not reduce the risk of cancer returning in survivors of early-stage breast cancer compared with survivors who maintained their normal diet. Researchers have continued to follow the health of WHEL participants to document their health outcomes, including death from breast cancer.

“The WHEL trial is over, and we have a freezer full of blood samples, and we know participants’ breast cancer recurrences, mortality, and other outcomes,” Dr. Patterson said. “So we’re hooking together a short-term trial with a long-term cohort study by means of blood biomarkers.”

The Dose Is the Question

Most of the cancer clinical trials of metformin use the same doses typically used to treat diabetes. That makes sense, because all of the epidemiologic data suggesting a cancer benefit came from studies that used those doses, said Michael Pollak, MD, of McGill University in Montreal, who has extensively studied metformin and its anticancer potential.

“We already know that those doses are safe, so why not study them?” Dr. Pollak continued. “But then you have to realize that virtually all of the lab studies [of metformin] have been done using drug concentrations that are as much as 100-fold higher than those found in the serum of diabetic patients. So the lab studies do not directly justify the clinical trials that are using conventional antidiabetic doses.”

With the obesity epidemic, these studies are applicable to a substantial portion of the U.S. population and, increasingly, of the world population.

—Dr. Brandy Heckman-Stoddard

Although laboratory studies suggest that larger doses of metformin “deserve study” for cancer treatment, Dr. Pollak noted that “for cancer prevention, we can only consider the hypothesis that the antidiabetic dose, or even lower doses, will be clinically useful.”

Dr. Zell agreed. “In the realm of cancer prevention, where side effects are less acceptable than they are in the realm of cancer treatment, the conventional dose for treating diabetes or something close to it may be the limit.

“I don’t imagine that prevention researchers will be looking to use [significantly larger] doses of metformin,” he continued. “In a healthy population, even a low risk of side effects could be extraordinary when applied to a larger population…. That’s why trials like ours are important. At the end of this 12-week intervention, we’ll have a good idea of whether the standard dose of metformin can affect cancer signaling pathways.”

Early Days

It’s still far too early to tell whether there is any future for metformin as a means of preventing or treating cancer, several researchers said.

Despite the very strong epidemiological evidence, there’s a chance that, even if metformin has some ability to prevent cancer, its efficacy may be limited to just several cancer types, Dr. Pollak noted. For example, metformin is not absorbed very well by the body and is absorbed differently by different tissues, he explained, which could limit how effective it might be against particular cancers.

Although the drug in its current form has certain limitations, some investigators are working on developing more potent derivatives of metformin. At the 2012 San Antonio Breast Cancer Symposium, for example, Italian and U.S. researchers reported that several metformin derivatives they had developed potently blocked the growth of breast cancer cells in the laboratory, including cell lines of triple-negative breast cancer, and caused the cells to die.

To be used for cancer prevention, any metformin derivative would have to be safe, with few side effects, Dr. Heckman-Stoddard stressed. As for the original metformin formulation, she added, current trials should help to map the way forward for its use in prevention.

“It’s important that we identify the right populations in which this is most likely to be an effective agent,” said Dr. Heckman-Stoddard. “We need to look at the evidence from all of these early-phase trials as a whole,” she continued, including examining the population groups exhibiting the strongest suggestions of efficacy “so we can design efficient phase III trials.”

Examples of Clinical Trials Testing Metformin for Cancer Prevention
Trial Phase Measured Endpoints Sponsor
Exercise and Metformin in Colorectal Cancer Survivors


Insulin levels and other biomarkers Dana-Farber Cancer Institute
An Endometrial Cancer Chemoprevention Study of Metformin [and Lifestyle Intervention]


Biomarkers in the endometrium and insulin levels University of Texas MD Anderson Cancer Center
Metformin as a Chemoprevention Agent in Non-Small Cell Lung Cancer


Progression of potentially precancerous bronchial lesions (secondary endpoint) in patients who have undergone surgery for lung cancer Mayo Clinic
Prostate Cancer Active Surveillance Metformin Trial


Progression of prostate cancer in men undergoing active surveillance for low-risk disease University Health Network, Toronto
Metformin Hydrochloride as Chemoprevention in Patients with Barrett Esophagus


Changes in the levels of the signaling pathway protein pS6K1, thought to play important role in progression to esophageal cancer Mayo Clinic
  • Posted: April 15, 2013

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PMCID: PMC4200668

Metformin in cancer prevention and therapy


The prevalence of diabetes is dramatically increasing worldwide. The results of numerous epidemiological studies indicate that diabetic population is not only at increased risk of cardiovascular complications, but also at substantially higher risk of many forms of malignancies. The use of metformin, the most commonly prescribed drug for type 2 diabetes, was repeatedly associated with the decreased risk of the occurrence of various types of cancers, especially of pancreas and colon and hepatocellular carcinoma. This observation was also confirmed by the results of numerous meta-analyses. There are however, several unanswered questions regarding the exact mechanism of the anticancer effect of metformin as well as its activity against various types of cancer both in diabetic and nondiabetic populations. In the present work we discuss the proposed mechanism(s) of anticancer effect of metformin and preclinical and clinical data suggesting its anticancer effect in different populations.

Keywords: Metformin, cancer, molecular action, clinical evidence

The prevalence of diabetes is dramatically increasing worldwide reaching epidemic proportion. Landmark of diabetes, chronic hyperglycemia leads to the development and progression of life-treating complications, predominantly cardiovascular. The results of several studies indicate that people with diabetes (mainly type 2, T2DM) are also at substantially higher risk of cancer of the pancreas, liver, endometrium, breast, colon, rectum and urinary bladder compared to individuals without this chronic disease (1). However, the incidence of other types of cancer (e.g., lung, kidney, non-Hodgkin lymphomas) does not seem to be strongly associated with diabetes or the evidence is inconclusive (2). Interestingly enough, it has been suggested that diabetes is associated with a lower risk for prostate cancer (2,3). According to the American Diabetes Association and the American Cancer Society consensus report the relative risks imparted by diabetes are greatest (about two fold or higher) for cancers of the liver, pancreas, and endometrium, and lesser (about 1.2-1.5 fold) for cancers of the colon and rectum, breast, and bladder (2). Clinical observations indicate that the prevalence of diabetes in newly diagnosed cancer patients ranges from 8% to 18%, suggesting bidirectional association between these two disease (4,5). The association of diabetes and cancer was first reported as an incidental finding in 1932 (6). Nowadays, this coexistence is well recognized, however in spite of the intensive studies its mechanism still remains unclear. There is a general agreement that T2DM and cancer share several common potential risk factors (e.g., aging, sex, obesity, physical inactivity, diet, alcohol, and smoking). In T2DM, insulin resistance and hyperinsulinemia (either endogenous due to insulin resistance or induced by administration of exogenous insulin formulations) are considered to be independent risk factors for cancer development (1,2). In addition, hyperglycemia-related oxidative stress, accumulation of advances glycation end products as well as low-grade inflammation may also enhance the risk of malignant transformation (7,8). Recent publications have also suggested the link between hypoglycemic medications and cancer (811). The results of numerous preclinical, epidemiological and clinical studies suggested that metformin use is associated with inhibition of cancer cell growth and proliferation and reduction in all-cancer incidents in comparison with users of other hypoglycemic drugs. In the present work we discuss the proposed mechanism(s) of anticancer effect of metformin as well as preclinical and clinical data suggesting this beneficial effect.

Molecular action of metformin in cancer cell

The current proposed anticancer molecular action of metformin is mainly associated with the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). The mTOR pathway plays a pivotal role in metabolism, growth and proliferation of cancer cell (12). Metformin is thought to inhibit mTORC1 pathway (Figure 1).

Figure 1

Proposed molecular action of metformin in cancer cells. Abbreviations: Akt, protein kinase B; AMPK, AMP-activated protein kinase; Atg13, autophy-related protein 13; 4EBP1, eIF4E binding ptotein, eIF4E, eukaryotic translation initiation factor 4E; PI3K,

It is believed that systemic effect of metformin manifested by the reduction of circulating level of insulin and insulin-like growth factor 1 (IGF-1) might be associated with anticancer action (13). Insulin/IGF-1 is involved not only in regulation of glucose uptake but also in carcinogenesis through upregulation of insulin/IGF receptor signaling pathway (14). The excessive food consumption (insulin) leads to increased liver production of IGF-1 that binds to IGF-1 receptor and insulin receptor. Then, through insulin receptor substrate (IRS) the signal is transmitted to phosphoinositide 3-kinase (PI3K), and Akt/protein kinase B (PKB) that indirectly activates (not phosphorylates) mTORC1. Additionally, insulin receptor through growth factor receptor-bound protein 2 (GRB2) propagates signal to Ras/Raf/ERK pathway that drives cell growth. Evidences indicate that these pathways play important role in changes of cellular metabolism that are typical feature of tumor cells (15). Increased levels of circulating insulin/IGF1 and upregulation of insulin/IGF receptor signaling pathways were demonstrated to be involved in the formation of many types of cancer. Metformin was found to reduce insulin level, inhibit insulin/IGF signaling pathways, and modify cellular metabolism in normal and cancer cells (16).

Evidences suggest that the inhibition of mTOR pathway by metformin proceeds dependent and independent on AMP-activated protein kinase (AMPK) activation. AMPK phosphorylates tuberous sclerosis complex protein 2 (TSC2) that inhibits mTORC1 leading to decrease in protein synthesis and cell growth (17). Among the first studies that showed the participation of AMPK activation in antitumor action of metformin were researches performed on breast cancer cells (18,19). Dowling et al. showed that compound C, an inhibitor of AMPK, reversed inhibition of initiation of translation evoked by metformin (18). More recently, Mohammed et al. showed reduction of carcinoma spread in pancreas of transgenic mice fed with metformin (20). Additionally, pancreatic tissue of mice fed with metformin revealed a significant inhibition of mTOR, and an increase of phosphorylated AMPK and TSC2 (20). However, Gwinn el al. demonstrated that inhibition of mTOR could be independent on TSC2, since AMPK directly phosphorylates the rotor compartment of mTOR (21).

Several studies identified that liver kinase B1 (LKB1), a major upstream kinase of AMPK, may be involved in anticancer action of metfromin associated with inhibition of mTOR. In vitro and in vivo studies revealed that deletion of LKB1 function accelerated proliferation of tumor cell and sensitized them to activators of AMPK such as biguanide (2224). Due to the fact that p53 expression and phosphorylation is regulated by AMPK and p53 is involved in cell metabolism and control of cell cycle its participation in metformin action is discussed. Growing evidences from in vivo and in vitro studies of various cancers revealed that metformin blocked cell cycle in G0/G1 phase with a significant decrease expression of G1 cyclins (including cyclin D1) without changes in p53 status (2527). However, others researches indicated that inhibitory effect on cancer cell growth of metformin was associated with p53 activity (2831). Taking together the results of preclinical studies are inconclusive whether antitumor action of metformin is associated with p53. Some investigators hypothesize that the dose of metformin may determine the effect of metformin. Yi et al. demonstrated on hepatoma cells that low concentration of metformin induced p53-dependent senescence, whereas higher doses induced apoptotic cell death (32).

Inhibition of mTOR by metformin independent on AMPK activation was demonstrated by Memmott et al. in mice lung cancer cells (16). Metformin evoked inhibition of mTOR pathway with accompanied decreasing activation of IGF-1/insulin receptor, Akt, extracellular signal-regulated kinase (ERK) without AMPK activation (16). Kalender et al. demonstrated in Drosophilla cells that inhibition of mTOR signaling induced by metformin occurred in the absence of AMPK. They reveal the existence of an alternative TSC1/2-mTOR AMPK-independent pathway mediated by RAG GTPase (33). Metformin was found to inhibit breast carcinoma cell growth through decreasing level of epidermal growth factor receptor 2 (HER2). This effect was mediated by inhibition of the mTOR effector, p70S6K1 (34). p70S6K is responsible for the phosphorylation of S6 ribosomal protein and thereby protein synthesis at the ribosome (35). Antiproliferative action of metformin related to enhancement of DNA-damage-inducible transcript 4 protein (DDIT4, REDD1) expression, a negative regulator of mTOR, was reported in prostate cancer cells by Ben Sahra et al. (36). This effect of metformin was also independent on AMPK activation (36).

The results of preclinical studies undoubtedly confirm the efficacy of metformin to inhibit cancer cell growth in vitro and to reduce tumor spread in animal models of various cancers. However, it should be stressed that molecular action of metformin is still investigated and seems to be affected by the type of tumor cell line.

Metformin and the risk of cancer

Metformin is the most commonly prescribed drug for T2DM. Its use in diabetes was shown to prevent macrovascular complications to the better extent than other oral hypoglycemic drugs as well as insulin (37,38). Additionally, the results of numerous epidemiologic studies repeatedly indicated that T2DM patients receiving metformin, compared to those taking other antidiabetic medications, had a decreased risk of the occurrence of various types of cancers (39). This observation was also confirmed by numerous meta-analyses that confirmed that metformin reduces cancer incidence by 30-50%.

Bowker et al. used databases from Saskatchewan Health (Canada) to examine the association between different therapeutic schedules of diabetes and cancer mortality in T2DM patients (10). It was observed that in T2DM patients using sulfonylureas (SU) or insulin the risk of cancer-related mortality was significantly increased compared to metformin users. A similar difference in cancer incidence in metformin users compared with SU was also reported by Evans et al. (40). The researchers used databases developed in Tayside (Scotland) to assess the influence of metformin therapy on the risk of cancer in patients with T2DM (40). They observed that metformin reduced the risk of cancer in patients with T2DM, both before and after adjusting for BMI. Additionally, they suggested the existence of the inverse relation between the dose of metformin and the risk of cancer.

Currie et al. performed a retrospective cohort study in 62,809 people older than 40 years, treated in U.K. by general practioners (41). Patients were on oral antidiabetic drugs and/or insulin. For the analysis the cohort was subdivided into four groups: metformin monotherapy, sulfonylurea monotherapy, combination therapy with metformin and sulfonylurea, or insulin. Insulin users were further subdivided into glargine, long-acting human insulin, biphasic analogue or human biphasic insulin. The observed risk of cancer in patients treated with basal human insulin alone vs. glargine alone was 1.24. Insulin therapy was associated with an increased risk for colorectal (HR =1.69) and pancreatic cancers (HR =4.63). However, when compared with metformin, this relation was not seen for breast and prostate cancers.

Franciosi et al. selected randomized studies comparing metformin and other hypoglycaemic agents as well as observational studies assessing the relation between exposure to metformin and cancer (42). Altogether, 12 randomized controlled trials and 41 observational studies met the inclusion criteria. They noted that in observational studies there was a significant association of exposure to metformin with the risk of cancer death, all malignancies, liver, colorectal, pancreas, stomach, and esophagus. Interestingly, such a relationship was not seen in randomized trials, what stresses the need for randomized trials to evaluate the efficacy of metformin as an anticancer agent.

Another meta-analysis of seventeen observational studies investigated the risk of all cancers and site-specific cancers in people with T2DM (43). Soranna et al. compared metformin with SU users. The meta-analysis showed that therapy with metformin use was associated with decreased risk for all cancer. Furthermore, except for colorectal cancer, metformin was not associated with any significant effect on the incidence of other cancers, for example, prostate and breast cancers.

In a large population-based study, a lower risk of cancer cancers was observed in patients treated with metformin in comparison with those received SU (44). The duration of diabetes was similar in both groups, but unfortunately the cause of death was not identified. That is why the researchers could not compare the association of the cancer-related mortality between metformin and SU users.

Chlebowski et al. assessed the association between diabetes, metformin use, and breast cancer among 68,019 postmenopausal women participating in Women’s Health Initiative clinical trials (45). Compared with women without diabetes, in diabetic woman the incidence of breast cancer was related to diabetes therapy. Diabetic women not treated with metformin had a slightly higher incidence of breast cancer. The association was observed for cancers positive for both estrogen receptor and progesterone receptor as well as those negative for HER2.

Home et al. (46) collected data for malignancies in Diabetes Outcome Progression Trial (ADOPT) and Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) studies. The results did not reveal significant differences in cancer incidence between metformin and rosiglitazone, however the incidence of cancer was slightly higher in SU group. One should remember that the number of malignancies was small in both trials.

Zhang et al. pooled the currently available data to examine the association between metformin therapy and colorectal cancer among patients with T2DM (47). More than 108,161 patients with T2DM were included into analysis, and once again they noted that metformin treatment was associated with a significantly lowest risk of colorectal cancer.

Noto et al. calculated pooled risk ratios (RRs) for overall cancer mortality and cancer incidence in 21,195 diabetic patients (48). Similarly to the results of other trials they noted that the use of metformin in diabetic patients was associated with significantly lower risks of both cancer incidence and mortality.

The positive correlation between metformin use and incidence of various type cancers was not universally noted by all investigators. Mamtani et al. analysed data from 87,600 patients with T2DM (49). They assessed the incidence of bladder cancer in new users of metformin and SU and did not see any association between metformin use and this type cancer.

It is still uncertain, whether the observed increased risk of cancer mortality in diabetic patients are related to a protective effect of metformin or negative effects of other therapies including SU and insulin (40). Again, if the difference in cancer-related mortality is related to the antidiabetic drugs, it may be associated with either the slower development of the cancer or better response to anticancer therapy. Additionally, one should also remember, that there are important differences in the characteristics of patients treated with metformin compared with other antidiabetic agents. These differences may be responsible for the observed differences in cancer incidence. In the United Kingdom metformin users had a higher BMI, a younger age, a lower systolic blood pressure, a lower prevalence of cardiovascular disease, and a higher proportion of aspirin and NSAID use as compared with second-generation SU users at the beginning of therapy (50,51).

Clinical evidence with metformin in cancer prevention and treatment

Biguanides were used in oncology more than 40 years ago as “metabolic rehabilitation” in breast, colorectal, or gastric cancers patients (52). The therapy with biguanides used with caloric restriction resulted in diminished tumor development and lower incidence of metastases (53). However, until now we do not have conclusive data on the role of metformin neither in cancer prevention nor the therapy both in diabetic and non-diabetic populations.

Several studies assessed the influence of metformin on metabolic status in cancer patients with and without diabetes. It was observed in nondiabetic woman that in the early stage breast cancer metformin reduced fasting insulin by 22% and improved several metabolic parameters (54). In a randomized study in woman with breast cancer, Campagnoli et al. observed that doses of metformin used routinely in diabetes decreased testosterone and insulin levels as well as several indices of insulin resistance (55). In another study in non-diabetic women with breast cancer the therapy with metformin resulted not only in reduced number of Ki67-positive cancer cells but also in changes in gene expression of molecules involved in the mTOR and AMPK pathways (56). In a randomized study, Hosono et al. showed that compared to control group metformin in small doses (250 mg/day) reduced colorectal aberrant crypt foci (regarded as surrogate marker for colorectal cancer) by 40% in non-diabetic patients (57).

Jiralerspong et al. observed 2,529 females with breast cancer. They noted increased incidence of complete response rates in metformin group, both in patients with and without diabetes (58). However, despite the increased incidence of complete response rates, metformin did not significantly improve survival. Margel et al. assessed the relation between duration of metformin therapy after prostate cancer diagnosis and mortality in patients with diabetes (59). The data were obtained from several databases in Ontario (Canada). In the cohort consisting of 3,837 patients, they noted that the longer duration of metformin treatment after diagnosis of prostate cancer was associated with a significant decrease not only in the risk of cancer-specific but also in all-cause mortality.

Metformin was also used as adjuvant therapy in cancer patients, and most of the cancer clinical trials of metformin use the same doses typically used to treat diabetes.


Preclinical evidence suggests that metformin appears to inhibit the proliferation and growth of certain types of cancer. Results of numerous clinical studies, although inconclusive, indicate that metformin use, and possibly cumulative duration of therapy and cumulative dose, is associated not only with decreased incidence of cancer in diabetic population, but also with the better outcome in cancer patients. Considering the possible variations in response to metformin in cancer patients it seems crucial to identify target populations for its use. However, factors contributing to better outcome in metformin users, such as genetic polymorphisms, are still to be elucidated (60). The definite data on the efficacy of metformin as neoadjuvant therapy in cancer patients is lacking. There are numerous trials underway in prostate cancer patients receiving androgen deprivation therapy as well as in patients with small benign thyroid nodules and insulin resistance (61,62). Altogether, there are currently more than 100 ongoing or upcoming clinical studies assessing the role of metformin in the therapy cancer (Tables 1 and and2).2). The vast majority of current trials assess the usefulness of metformin in cancer treatment, while several trials evaluate metformin in cancer prevention. Their results will permit to assess the place of metformin in cancer prevention and therapy, and define the target populations in the nearest future.

Table 1

The ongoing and upcoming clinical trials with metformin in cancer prevention (63)
Table 2

The ongoing and upcoming clinical trials with metformin in cancer therapy (63)


Disclosure: The authors declare no conflict of interest.


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Use of Metformin

commonly used as the front-line treatment for type 2 diabetes — improves survival for some breast cancer patients, and shows promise as a treatment for patients diagnosed with endometrial hyperplasia, according to the results of two new studies presented by researchers from the Perelman School of Medicine at the University of Pennsylvania at the American Society of Clinical Oncology (ASCO) Annual Meeting.

In one study (abstract 1569), the first to examine the effect of metformin on survival rates for breast cancer patients, researchers examined clinical outcomes for 1,215 patients who were diagnosed and underwent surgical treatment for breast cancer between 1997 and 2013. Ninety-seven patients examined reported using metformin before their diagnosis, and 97 reported use of the drug after diagnosis.

Results of the study showed that patients who used metformin before being diagnosed with breast cancer were more than twice as likely to die than patients who never used the drug, while patients who began using metformin after their cancer diagnosis were almost 50 percent more likely to survive than non-users.

“Using metformin as a cancer prevention strategy has been controversial and results have been inconsistent, but our analysis reveals that use of the drug is time-dependent, which may explain the disparity. While use of the drug may have a survival benefit for some breast cancer patients, those who developed breast cancer while already using Metformin may have more aggressive cancer subtypes,” said lead author Yun Rose Li, MD, PhD, a clinical research fellow in the division of Endocrine and Oncologic Surgery at the Perelman School of Medicine at the University of Pennsylvania, who will present the results. “Our study also illustrates the complex interaction between underlying metabolic risks and breast cancer outcomes, and underscore the importance of a multi-system approach to cancer treatment.”

Additional results of the study showed that patients who used metformin were more likely to be over the age of 50 at diagnosis and to be African-American. While tumor size and disease progression were similar across all groups, the patients who began using the drug after their diagnosis were more likely to have ER/PR positive tumors while the patients who used it prior to their diagnosis had higher rates of Her2+ and Triple Negative tumors

Since this work is among the first to examine the effects of long-standing metformin use in the context of when patients start using it as it relates to breast cancer diagnosis, the authors say that further investigations are necessary to examine the impact of metformin use on cancer recurrence. Nonetheless, the authors say there is compelling biological evidence suggesting that the differences observed in breast cancer tumor markers may be due to mechanistic differences in cancer initiation in patients who develop cancer while taking metformin.

The results will be presented at the Cancer Prevention, Genetics, and Epidemiology poster session on Monday, June 6.

In the second study (abstract 5592), researchers examined the effectiveness of using metformin as a treatment for women newly diagnosed with endometrial hyperplasia, a condition that occurs when there is a hormonally related unbalanced overgrowth of the uterine lining. If left untreated, patients are at a significantly higher risk of developing uterine cancer.

Eighteen participants were enrolled in a multi-institutional trial and treated with metformin for three months. Results showed 56 percent of patients responded to treatment, defined as complete resolution of the hyperplasia. The effect was seen especially in women with simple hyperplasia without additional complications or irregularities.

Typically, women with endometrial hyperplasia are treated with progesterone-based therapies via depot injections, intrauterine devices, or oral medications. Progesterone works by counteracting the effects of estrogen and thinning the uterine lining. While effective in up to 80 percent of cases, progesterone therapies have been shown to cause significant side effects such as weight gain, mood changes, and gastrointestinal distress. Hysterectomy (surgical removal of the uterus) is also an alternative therapy for women who are post-menopausal, or have completed child-bearing.

“The results of our study may present an alternative treatment for particular forms of endometrial hyperplasia, in contrast to standard progesterone-based therapies or hysterectomy,” said Emily Ko, MD, MSCR, an assistant professor of Obstetrics and Gynecology at the Perelman School of Medicine at the University of Pennsylvania, and lead author of the study. “Future prospective studies may better identify women for which metformin may be most beneficial, as well as the most effective dosing regimens.”

University of Pennsylvania School of Medicine. “Diabetes drug metformin holds promise for cancer treatment and prevention: Results show survival benefit for some breast cancer patients and potential treatment option for patients with endometrial hyperplasia.” ScienceDaily. ScienceDaily, 4 June 2016. <>.
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