Metformin is a cornerstone treatment of diabetes mellitus. Since 2005 when it has been first reported to reduce the risk of cancer in diabetics, a large number of preclinical and clinical studies have implicated its potential role as a preventative and adjunct therapy for a broad range of cancers. Whereas preclinical studies demonstrate its actions on a multitude of molecular pathways involving nearly all aspects of cancer development including metabolism, angiogenesis, apoptosis, autophagy, immunity, epigenetics, inflammation and crosstalk with the microbiome, other studies demonstrate its synergism with a range of anticancer modalities including chemotherapy, radiotherapy, immunotherapy, and targeted therapies. Furthermore, an increasing number of clinical studies not only confirm its preventative properties against cancers but have extended its potential for a possible adjunctive role in the neoadjuvant, adjuvant, maintenance and salvage therapies of cancer. This article intends to summarize the basic science that allows us to understand the complex multiple mechanisms of action of this remarkable multitasking molecule as well as review the recent meta-analyses that have summarized the clinical studies assessing the therapeutic efficacy of metformin for various cancers.
- cancer therapy
Metformin is derived from the French lilac (also known as goat’s rue or
Given that this review is intended as a summary of current clinical evidence for the potential uses of metformin in the prevention and treatment of cancer, we will provide only a succinct synthesis of the thousands of preclinical studies on the biological mechanisms and molecular pathways that has been performed in the past two decades and focus our attention mostly on recent clinical evidence of metformin’s efficacy as demonstrated by clinical studies.
2. Pleiotropic effects of metformin against cancer
The early days of laboratory research on metformin’s anti-cancer mechanisms focused mainly on its metabolic effects on cell proliferation, which naturally follows from the initial use of metformin as a treatment for T2DM as a metabolic disorder. Eventually, it became gradually apparent that unlike modern day targeted therapies, metformin’s anti-neoplastic bioactivity is broad ranged and pleiotropic, encompassing not only its established metabolic effects, but also involving antiangiogenic, anti-inflammatory, epigenetic, apoptotic and autophagic, and immunologic actions as well as effects on the microbiome and on cancer stem cells (CSCs) that all synergistically contribute to overall cancer prevention and control. Furthermore, within each category of its bioactivity, it further exerts multiple molecular actions, and it has thus become increasingly apparent that metformin could be properly conceived of as a multi-faceted multi-tasking molecule with direct and indirect actions against cancer. In summary, the anti-cancer effects of metformin is based on 1) its main action on cellular metabolism via the maintenance of plasma glucose and insulin levels, 2) targeted action against cancer cells with pleiotropic inhibitory effects on multiple pathways involved in cancer cell survival and metastasis, and 3) indirect anti-angiogenic anti-inflammatory as well as immunomodulatory effects and also its actions on the microbiome and CSCs. The complex pleiotropic nature of metformin effects on cancer is illustrated in Figure 2.
2.1 Metformin metabolic effects
To understand the metabolic impact of metformin on cancer, we must first recognize the intimate relationship between glucose energy metabolism and cellular proliferation as well as a unique propensity of cancer cells to utilize glucose anaerobically even in the presence of oxygen in contrast to non-cancer cells which utilize oxidative phosphorylation to generate energy. This phenomenon was first noted by Otto Warburg almost a hundred years ago, and subsequently termed the “Warburg effect” . This altered energy metabolism of cancer cells may underline their proliferation, invasiveness, and chemoresistance and this altered metabolic pattern in cancer is regulated by oncogenic and tumor suppressor signals such as hypoxia inducible factor 1 (HIF-1), myelocytomatosis oncogene cellular homolog (Myc), p53, and the phosphoinositide 3 kinase (PI3K)/AKT8 virus oncogene cellular homolog (Akt)/mammalian target of rapamycin (mTOR) pathways.
Metformin’s main pharmacologic action is the reducing elevated plasma glucose is largely due to the improvement in hepatic insulin resistance leading to a reduction in hepatic glucose output from gluconeogenesis, increases glucose uptake in muscle, decreased absorption of sugar from the intestines, and improved insulin sensitivity, mainly via activation of a cellular energy sensor known as AMP-activated protein kinase (AMPK). The major downstream target of AMPK is mTOR, which is very important in cellular growth processes and cancer dynamics, and mTOR is inhibited by AMPK . Since glucose metabolism is at the center of the metabolic derangement that is a hallmark of cancer cells, and metformin chiefly targets glucose metabolism, it follows that the altered metabolic pathway may be a target by metformin for cancer prevention or therapy.
It is through its main effects above on metabolism and cellular energetics that metformin can attenuate cancer cell proliferation (See Figure 3). Furthermore, these metabolic effects in turn impact the immune system, epigenetics, inflammation, cellular apoptotic and autophagic pathways as well as the microbiome and CSCs which all play a role in cancer development..
2.2 Metformin immuno-modulatory effects
The immune system participates broadly in the prevention and control of cancer and interacts with biological pathways of metabolism and inflammation, and metformin again acts in a multifaceted fashion to bolster immunity against cancer with effects on almost every aspect of the immune system, especially with reference to cancer immunty (Figure 4). One of metformin’s actions is the enhancement of CD8+ T lymphocytes and rescues them from exhaustion. CD8+ T cells which is one of the key components in cellular immunity against tumors, as these cells can expand and transform into effector cytotoxic T lymphocytes (CTL) which targets cancer. This phenomenon of the rescue of exhausted CD8+ T lymphocytes has been confirmed
2.3 Metformin effects on the microbiome
Whereas science has become increasingly aware of the central role the gut microbiome plays in health and diseases including cancer, particularly via its effects on the immune system , metformin’s beneficial role on host metabolism has also been found to be in part related to the microflora in the gut. The microbiome modulates our immune system and inflammatory response and both of these are key factors in determining cancer development and are associated with inflammatory immune response  highlights the crosstalk between metformin effects on metabolism, immunity, inflammation and the microbiome, which in turn can modulate cancer biodyamanics, and part of the mechanisms involved in this complex interplay is illustrated in Figure 5 below.
2.4 Metformin anti-inflammatory effects
Inflammation effects on cancer promotion is well known. In 1863, Rudolf Virchow first proposed the role of inflammation in cancer based on the observation of leukocytes in cancerous tissue. Subsequently, accumulated evidence has identified inflammation both as a cause and result of malignancy , with numerous studies in past decades implicating chronic inflammation in the promotion of malignancy  (Figure 6). Not surprisingly then, given the T2DM’s known association with chronic low-grade subclinical inflammation which is part and parcel of its the insulin resistance that is its hallmark , and metformin’s effects on the immune and metabolic systems, that metformin must also modulate the inflammatory response. This connection has been well demonstrated by animal experiments where metformin treated rodents reveal dampened pro-inflammatory pathways nuclear factor k B (NF-k) and Jun N-terminal kinase (JNK) and increased anti-inflammatory cytokine IL-10 .
2.5 Metformin epigenetic effects
Epigenetics is the genomic mechanism that reversibly modulates gene expression independent of DNA sequences. Epigenetic processes which allow for the gene modulatory effect involve DNA methylation, histone modification, the readout of these modifications, chromatin remodeling and the effects of noncoding RNA all of which affects cellular activities such as growth and differentiation. Thus, epigenetics can in one sense be conceived of as a master switch of cancer biological processes. Recently, there has been growing interest in epigenetic targeting as a promising therapeutic option for cancer . And since cellular metabolism is tightly linked to epigenetic modifications, it is again not surprising that metformin as a modulator of cellular metabolism may also possess significant epigenetic effects mainly via histone modification (Figure 7), which in turn is another avenue whereby metformin may exert its anti-cancer effects .
2.6 Metformin apoptotic and autophagic effects
Both apoptosis or programmed cell death and autophagy are important catabolic and tumor-suppressive pathways that control cell survival and cell death and are thus increasingly important therapeutic targets in cancer . While apoptosis involves cellular suicide and cell death pathways, autophagy involves recycling and degradation of cellular waste which if maladapted and excessive can also lead to cell death and there is significant cross-talk between these two pathways . In cancer biology, autophagy is cancer suppressive as it facilitates the degradation of oncogenic molecules thus pre-empting the development of cancers, while apoptosis leads to cellular suicide and limits the survival of cancer cells. As a result, defective or inadequate autophagy or apoptosis can both lead to cancer. The complexity of the crosstalk between the apoptosis and autophagy is illustrated in Figure 8.
In the case of these pathways, metformin has been shown to promote apoptosis in a variety of cancers via various biological pathways  while also promoting autophagy  as two other dimensions of its anti-cancer bioactivity.
2.7 Metformin effects on cancer stem cells
CSCs were only identified in the 1990s, and they have been hypothesized to persist in tumors as a distinct cell population capable of self-renewal and maybe responsible for cancer relapse and metastasis by giving rise to new tumors. These CSCs are also believed to be resistant to traditional chemotherapy and radiation. A complex regulatory network consisting of microRNAs and Wnt/β-catenin, Notch, and Hedgehog signaling pathways control the properties of CSCs. Therefore, the development of specific therapies targeting and its regulatory pathways is another avenue for improved cancer treatments to prevent relapse and metastases, and improve survival . In this regard, metformin has been reported to target CSCs perhaps via blunting of the Warburg effect and consequently down-regulates their growth. In animal studies, it has been found that metformin exposure was associated with a ~ 2-fold reduction in ovarian CSCs and increased in chemotherapy response and translational studies completed as part of a multi-center phase 2 clinical trial was able to demonstrate a 2.4-fold CSC reduction as well as improved survival in ovarian cancer patients .
2.8 Metformin’s antiangiogenic effects
Angiogenesis is the process where a tumor can induce its own blood supply via neovascularization to enhance its own nutrient source as well as increase its propensity to metastasize. It follows that antiangiogenesis which involves the suppression of vascular supply to tumors may be an effective method of cancer control as initially proposed by Folkman . In this regard, preclinical studies with metformin have reported that it indirectly modulates tumor angiogenesis most likely via metabolic pathways affecting proangiogenic signals. As an example, metformin is known to decrease HIF-1α stability in cancer cells, reducing the expression of HIF-1 targeted genes and thus resulting in smaller tumor vessel size, reduced microvessel density and slower tumor growth . Another murine experiment analyzing angiogenesis in a matrigel plug model found that metformin treatment lead to a decrease in angiogenesis .
3. Deployment strategies for metformin in cancer
Metformin can be used tactically under various scenarios against cancer. It can be used as standalone or in combination with other agents for the primary or secondary prevention of cancer , as neoadjuvant or adjuvant cancer therapy , as maintenance therapy or salvage therapy, or to reduce chemoresistance or enhance radiosensitivity  as well as for the reduction of side-effects or complications . Notably, metformin is usually deployed as an adjunct but not as a sole agent except in the case of primary prevention. Since it has such low toxicity and multi-faceted mechanisms of actions, it is usually integrated with other treatment agents and modalities under other scenarios besides primary prevention. The key feature of metformin that allows this combinatorial deployment is its low toxicity and its synergism with various other agents and modalities, as it has been demonstrated both
3.1 Metformin synergies with other anticancer agents and modalities
Notably, synergisms with metformin has been reported with numerous anticancer agents and modalities including chemotherapy , targeted drugs , and radiotherapy . In the past ten years alone, metformin synergism with chemotherapies pemetrexed , temozolomide , cisplatin , gemcitabine , paclitaxel , 5FU , vincristine  with targeted agents erlotinib against non-small cell lung cancer , imatinib against colon cancer , gefitinib against bladder cancer , trastuzumab against human epidermal growth factor receptor 2 (HER2) positive breast cancer , celecoxib against NSCLC , regorafenib against liver cancer , with everolimus as neuroendocrine cancers ; and other anticancer agents such as with nelfinavir against cervical cancer , propranolol against breast cancer , 2-deoxyglucose against ovarian cancer , arsenic trioxide against cholangiocarcinoma , and with natural compounds epigallocatechin-3-gallate , curcumin , berberine , resveratrol .
What is interesting is that different biological mechanisms may be responsible for the efficacy of metformin’s combinatorial effects depending on the specific combination. For example, regulation of lipid synthesis may underlie metformin enhancement of taxanes, pro-apoptotic mechanisms could account for its synergy with cisplatin, AMPK/mTOR signaling maybe significant when combined with hormonal drugs, and suppression of HIF-1, P glycoprotein (p-gp) and multidrug resistance-associated protein 1 (MRP1) expression is thought to be responsible for metformin’s synergy with anti-metabolites . In the case of targeted agents such as the epidermal growth factor receptor (EGFR) inhibitor gefitinib against NSCLC where a Chinese study on diabetic NSCLC patients on gefitinib demonstrated significantly improved response rate, disease control rate, median progression free survival (PFS) and median overall survival (OS) compared with patients controls (70.5% vs. 45.7%,
The use of metformin under various scenarios against cancer has been best studied clinically for primary prevention and in the neoadjuvant setting and some of the relevant data is summarized below.
3.2 Metformin for primary prevention of cancer
Cancer prevention is the earliest role that metformin was hypothesized to play in the disease as it was Evans’ original 2005 retrospective case–control study demonstrating metformin’s involvement in reducing cancer risk in T2DM that highlighted its potential for cancer . Subsequently, a confirmative cohort study of T2DM with metformin followed in which the frequency of cancer was significantly lower in patients receiving metformin versus controls who had never received metformin, after adjusting for body mass index, hemoglobin A1C, smoking and the use of other drugs , a finding that was subsequently repeatedly confirmed. Indeed, meta-analyses have demonstrated that metformin is associated with a decreased risk of breast, colon, liver, pancreas, prostate, endometrium and lung cancer across meta-analyses  suggesting that people with T2DM receiving metformin demonstrate a lower risk and improved outcomes with most common cancers; more specifically one meta-analysis found that metformin-treated T2DM patients had a 31% reduction in the incidence of cancer and a 34% reduction in cancer mortality after adjusting for body mass index .
3.3 Metformin in neoadjuvant treatment
Neoadjuvant effects of metformin in combination or alone has been clinically explored in several cancers types. In one study of two hundred eighty-five patients with esophageal adenocarcinoma treated with concurrent chemoradiation followed by esophagectomy, complete remission (CR) was higher in T2DM patients taking metformin (34.5%) compared to those who are not (4.8%,
4. Systematic reviews and meta-analyses on metformin clinical outcomes in various cancers
Since metformin is so versatile and has been studied in a wide variety of settings from the laboratory to bedside, and since this review is intended to focus on the clinical deployment of metformin, it is thus useful to have a summary perspective of its potential usefulness in cancer by reviewing clinical results as recently meta-analyzed for various cancers.
4.1 Bladder cancer
A review of 9 retrospective cohort studies with 1,270,179 patients did not reveal a benefit from metformin in preventing bladder cancer (Hazard ratio (HR) = 0.82, 95% CI = 0.61–1.09;
4.2 Breast cancer
There have been a number of studies relating to metformin’s effect on biomarkers in breast cancer patients and it has been shown that metformin therapy reduced the levels of insulin, sex hormones and sex hormone-binding globulin, Ki67, caspase-3, p-Akt, obesity, CRP, blood glucose and lipid profile overall . More, in a clinical trial to examine the clinical and biological effects of neoadjuvant metformin on patients with breast cancer, non-diabetic women with untreated breast cancer given 500 mg of metformin three times daily for ≥2 weeks exhibited decreased insulin receptor expression (
4.3 Colon cancer
Ng et al. from Singapore found 58 studies that provided incidences of colorectal adenoma and cancer and cancer survival outcomes and found that metformin significantly lowered the risk of colorectal adenoma (RR 0.77, CI 0.67–0.88,
4.4 Endometrial cancer
In 19 studies reviewed in 2017, metformin used reversed atypical endometrial hyperplasia to normal, and decreased cell proliferation from 51.94% (CI = 36.23% to 67.46%) to 34.47% (CI = 18.55% to 52.43%) , while separately, a review of seven studies showed that metformin could significantly improve overall survival of in endometrial cancer (HR = 0.61, 95% CI 0.48–0.77, P < 0.05) and reduce their recurrence risk (OR = 0.50, 95% CI 0.28–0.92,
4.5 Lung cancer
An analysis of 13 observational studies found lung cancer incidence to be reduced in diabetic patients on metformin vs. no metformin (RR = 0.89; 95% CI, 0.83–0.96;
4.6 Pancreas cancer
A review of seventeen studies involving 36791 participants study has evidenced a significant association of metformin adjuvant treatment in pancreas cancer with overall survival benefit (HR = 0.88, 95% CI = 0.80–0.97) especially in Asians, those with early stage disease and those undertaking surgery . In terms of overall survival with metformin use in pancreas cancer, a study of 8 retrospective cohort studies and 2 randomized clinical trials representing 3,042 patients revealed overall survival to be improved with metformin (meta-HR = 0.79; 95% CI: 0.70, 0.92,
4.7 Prostate cancer
In a systematic review involving eleven studies with 877,058 patients, the odds ratio of metformin use for reducing prostate cancer was estimated at 0.89 (95%CI: 0.67–1.17) and it was concluded that metformin consumption reduced the risk of prostate cancer, although the result was not statistically significant . Separately, a review of eight studies on diabetic patients with prostate cancer found no metformin use was associated with an increased risk of cancer recurrence (RR, 1.20; 95%CI, 1.00–1.44) , which concurs with another review of eight retrospective cohort studies and one nested-case–control study, metformin was found to be associated with a reduced risk of biochemical recurrence (pHR: 0.82, 95% CI 0.67, 1.01,
4.8 Ovarian cancer
4.9 Other cancers
Metformin is also increasingly studied or planned in less common cancers, such as glioblastoma, thyroid cancer, and non-Hodgkin’s lymphoma. The recent study on newly diagnosed glioblastoma showed that temozolomide plus memantine, mefloquine, and metformin are feasible as an adjuvant therapy . One planned phase 1b/2 clinical trial of metformin and chloroquine was recruiting patients with IDH1-mutated or IDH2-mutated solid tumors, including glioma . In another recent retrospective study from Korea, cancer preventative effects of metformin on thyroid cancer were observed in individuals with T2DM on long duration or higher doses of the drug . Separately, a trial in head and neck squamous cell cancer patients revealed metformin to inhibit cancer by enhancing apoptosis, and increasing cellular immune infiltration of the cancer . In non-Hodgkin’s lymphoma, a retrospective analysis of looking at T2DM patients treated with standard therapy found improved progression-free survival and overall survival compared to control not taking metformin .
Any discussion of a therapeutic agent is incomplete without covering its toxicity, side-effects and drug interactions. In this regard, metformin is probably one of the safest drugs in use, especially when compared with standard anti-cancer agents in its context as a potential cancer preventative or therapeutic. With its long history of widespread use, its pharmacokinetics and toxicity profile are well established. The most common side-effect is mild to moderate gastrointestinal discomfort or diarrhea which is usually self-limited and can be minimized if metformin is taken with food, while its most serious side-effect of lactic acidosis usually due to overdose is relatively rare, occurring once per 100,000 years of use or 3 case per 1,000,000 after long term treatment . As in the case of all medications, it should be dispensed carefully in elderly patients and in those with impaired renal, cardiac, and hepatic function. For practical purposes, it needs to be emphasized that metformin as an antidiabetic and as monotherapy does not cause hypoglycemia or weight gain, unlike insulin or sulfonylureas. For cancer, because of its very common use in diabetics, it has practically seen combined use with most oncologic agents in the diabetic cancer patient and remarkably no serious interactions with standard cancer anti-cancer agents have been reported. The minimum toxic dose of metformin is not well defined, but rare case reports of severe toxicity has only been reported after ingestion of 25 to 35 grams of metformin by adults.
A treatment for any condition is ideal if it relatively non-toxic and scientifically well evidenced, as well as low in cost and convenient to administer. Metformin fits all the above criteria. It is apparent from our review that metformin has ample scientific evidence from bench to the bedside as a repurposed drug for cancer. In fact, it is safe to say that it is currently the most well evidenced repurposed drug for cancer. Also, its wide-spread and decades of experience of clinical use and low observed toxicities alone or in combination with other agents, as well as very low cost also marks it as an optimal therapeutic agent. Finally, the versatility it possesses against various cancers and its applicability from prevention to treatment further distinguishes it as an ideal or model repurposed drug for cancer.
Of course, there remains limitations and challenges to metformin’s use as an anticancer. The first obstacle we have in translating
As an old repurposed drug, metformin is inexpensive and generic and its research is thus carried out usually without industry support. Despite such challenges, it is heartening that overall preclinical and clinical results is overwhelmingly suggestive of a protective effect from metformin against various stages of a wide spectrum of cancers. Moreover, there are over three hundred registered clinical trials on metformin and cancer internationally as of mid-2020, of which approximately one third are actively recruiting. The trials involve metformin for pre-cancers, early stage as well as metastatic solid tumors, alone or in combination with other interventions including chemotherapy, radiotherapy, hormone therapy, immunotherapy (ICIs), targeted agents, statins, aspirin, doxycycline, nelfinavir, melatonin, disulfiram, vitamin C, diet in diabetics and non-diabetics. We thus look forward for the further establishment of metformin as an ideal repurposed agent for cancer prevention and treatment.
Acronyms and abbreviations
AKT8 virus oncogene cellular homolog AMP-activated protein kinase confidence interval complete remission cancer stem cell cytotoxic T lymphocytes epidermal growth factor receptor glycerol-3-phosphate dehydrogenase human epidermal growth factor receptor 2 hypoxia inducible factor; HR: hazard ratio C-reactive protein immune checkpoint inhibitor Jun N-terminal kinase mammalian target of rapamycin multidrug resistance-associated protein 1 myelocytomatosis oncogene cellular homolog nicotinamide adenine dinucleotide (oxidized)/nicotinamide adenine dinucleotide + hydrogen nuclear factor k B non-small cell lung cancer overall survival programmed cell death protein 1 programmed death-ligand 1 P glycoprotein phosphoinositide 3 kinase progression free survival type 2 diabetes mellitus regulatory T cell
AKT8 virus oncogene cellular homolog
AMP-activated protein kinase
cancer stem cell
cytotoxic T lymphocytes
epidermal growth factor receptor
human epidermal growth factor receptor 2
hypoxia inducible factor; HR: hazard ratio
immune checkpoint inhibitor
Jun N-terminal kinase
mammalian target of rapamycin
multidrug resistance-associated protein 1
myelocytomatosis oncogene cellular homolog
nicotinamide adenine dinucleotide (oxidized)/nicotinamide adenine dinucleotide + hydrogen
nuclear factor k B
non-small cell lung cancer
programmed cell death protein 1
programmed death-ligand 1
phosphoinositide 3 kinase
progression free survival
type 2 diabetes mellitus
regulatory T cell