We’re busy reviewing the evidence on metformin. While we’re working, we share the original summary from our predecessor website, Beyond Conventional Cancer Therapies.

Please consider supporting our update and revision to this information.

Metformin

Key Points

  • Before using this therapy, consult your oncology team about interactions with other treatments and therapies. Also make sure this therapy is safe for use with any other medical conditions you may have.
  • Metformin is a prescription drug used to control high blood glucose in type 2 diabetes.
  • BCCT is interested in metformin because reduced risk of cancer and anticancer effects in several cancers, especially in diabetics, is demonstrated in lab, animal and human studies.
  • Most of the evidence on metformin’s uses related to cancer comes from epidemiological, observational and case-control studies.
  • Many clinical trials are in progress to test metformin’s effects in preventing cancer and in supplementing other cancer treatments.
  • Metformin has low toxicity and is inexpensive, widely available and very familiar to most physicians.
  • Although generally safe, there are cautions, side effects, contraindications and drug interactions with metformin. Metformin should be used only under medical supervision.
  • Some integrative cancer care physicians use metformin off-label as a supplement to cancer treatment.

Metformin is a prescription drug used to control high blood glucose in type 2 diabetes. Evidence shows that metformin may reduce risks of some types of cancer and also may improve outcomes in people with certain cancers, especially with people with diabetes. Some integrative cancer care physicians use metformin off-label for cancer treatment. Off-label use is a drug’s application for a disease or condition that has not yet received FDA approval. Every US state allows drugs to be used off-label as long as enough evidence supports its use.

“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 the diabetic population, but also with the better outcome in cancer patients. . .Definite data on the efficacy of metformin as neoadjuvant therapy in cancer patients is lacking.”1

Highlighted Videos

Donald Abrams, MD, explains how metformin can be used as a cancer therapy in a 2014 presentation.
CanerChoices advisor Brian Bouch, MD, explores metformin for cancer care in this interview from 2018.

Treating the Cancer

Working against cancer growth or spread, improving survival, or working with other treatments or therapies to improve their anticancer action

Clinical Evidence

Clinical trials using metformin as a cancer adjuvant (supplement) to cancer treatment are in progress and are described below. Most of the evidence in humans to date is from observational, population cohort and case-control studies. Evidence from these types of studies is not strong enough to conclude that metformin is the cause of the positive effects seen. See also preliminary indications that metformin may interfere with chemoradiotherapy in Cautions below.

How It Works: Diabetes and Cancer

Evidence shows these intriguing relationships between diabetes and cancer:

  • People with diabetes show a higher incidence of certain types of cancer, such as colorectal, liver, pancreatic, endometrial, breast and bladder cancers.2
  • Postmenopausal women with diabetes are at higher risk for invasive cancer in general, as well as cancers of the colon, liver, pancreas and endometrium and non-Hodgkins lymphoma.3
  • Type 2 diabetes is associated with a poorer prognosis in people with cancer, depending on the cancer type and anti-diabetes treatment. However, diabetics on metformin have shown improved survival compared with other treatments for diabetes and in comparison with a nondiabetic population.”4

Diabetes and cancer share some common underlying pathways. For example, obesity is common in people with type 2 diabetes, and it has also been associated with certain cancers such as endometrial, esophageal, kidney, pancreatic, colon and postmenopausal breast cancer.5

However, obesity doesn’t seem to fully explain the increased cancer risk in diabetics. La Vecchia and Bosetti propose that the cancer risk is more likely linked to metabolic factors “related to insulin resistance, hyperinsulinemia, and their influence on the insulin growth factor (IGF) system, which may stimulate cell proliferation and inhibit programmed cell death (apoptosis).”6

Metabolic Factors

Strategies to manage insulin resistance and hyperinsulinemia (excess levels of insulin in blood) may prove useful in reducing risk of cancer or treating cancers associated with these metabolic factors. Evidence shows that healthy lifestyle practices related to eating well, moving more, managing stress and sleeping well all influence these metabolic factors.

These practices are a key component of an integrative cancer care plan and  a logical first step in creating a “terrain” in one’s body that is inhospitable to cancer. In addition, natural products are used in managing high glucose and insulin as well as insulin resistance. See below for a more thorough discussion of protocols using supplements and lifestyle practices in addressing these metabolic problems.

Some integrative cancer care physicians, such as BCCT advisor Dwight McKee, MD, and Raymond Chang, MD, suggest that drugs such as metformin may have a place off-label as an adjunctive (supplementary) treatment for cancer.7

Because insulin is a known growth factor for cancer, and because metformin decreases insulin levels, and because evidence indicates that metformin may reduce risks of some cancers and/or improve response to cancer treatment, using metformin in certain individuals with cancer may make sense.

Evidence shows that metformin may reduce risks of some types of cancer and also may improve outcomes in people with certain cancers, especially with people with diabetes.

Evidence of Action

Scientists have not yet determined the exact action of metformin in cancer. However, general agreement exists on the probable actions. In lab and animal experiments, metformin shows anticancer activity:

  • Direct effects on the cancer cells, such as inhibiting the AMPK/mTOR pathway, which blocks the growth effects of insulin and insulin-like growth factor (IGF-1), affecting cancer metabolism and inhibiting cancer proliferation and growth
  • Indirect effects on the tumor microenvironment, such as lowering inflammation and blood glucose8
  • Reducing the amount of circulating estrogen and testosterone, both of which can stimulate the growth of hormone-dependant tumors such as breast cancer and prostate cancer9

Cancers in General

Reduced mortality:

  • Reduced mortality in diabetic patients treated with metformin alone for diabetes, whether before or after cancer diagnosis, compared with those on other anti-diabetic medications (insulin or sulfonylurea).10
  • Reduced cancer mortality among people with diabetes who received metformin compared to the general population11
  • Better survival outcomes for people with cancer, regardless of diabetes status, compared to those not taking metformin.12

Brain and Nervous System Cancers

Glioma

  • Improved survival in patients with type 2 diabetes.13
  • Improved survival with grade 3 glioma but not grade 4.14

Glioblastoma

  • Prolonged progression-free survival among people with glioblastoma undergoing radiation therapy15

Breast Cancer

Improved survival:

  • Substantially improved overall survival and cancer-specific survival in cancer patients with diabetes, including after adjusting for hormone receptor expression16
  • No significant improved survival or progression-free survival in randomized controlled trials17
  • Longer estimated disease-free survival among breast cancer patients using metformin at the time of diagnosis18
  • No improved survival when used during adjuvant therapy for triple negative breast cancer in patients with diabetes19

Decreased metastases:

  • Decreased numbers of metastatic cases after six months of hormone therapy in nondiabetic women20
  • A nonsignificant trend for decreased risk of developing distant metastasis among people with triple negative breast cancer and diabetes compared with non-diabetics.21

Greater response to treatment:

  • Greater response (pathologic complete response rates) among people with diabetes and breast cancer22

Cervical Cancer

  • Improved disease-free survival but not overall survival in patients with type 2 diabetes one study,23 but not another study after adjusting for patient demographics and tumor characteristics24

Colorectal Cancer

Improved survival:

  • Improved overall survival, also with improved colorectal cancer-specific mortality in some studies of people with diabetes25 but not others26
  • May improve overall survival in colorectal cancer patients with metabolic syndrome27
  • No improved overall or relapse‐free survival in patients with resected colon cancer treated with adjuvant fluoropyrimidine‐oxaliplatin chemotherapy28

Reduced disease progression:

  • Increased disease control rate at week 12 when combined with irinotecan29 or at week 8 with 5-fluorouracil (both are chemotherapy drugs)30 in patients with measurable metastatic colorectal cancer
  • Reversed the enhanced proliferation of colorectal cancer cells with d-(+)-glucose administration

Improved response to treatment:

  • Considerably increased sensitivity to the chemotherapy drug oxaliplatin31
  • Increased phosphorylation of AMPKα and decline in tumor markers with use with non-diabetic patients during chemotherapy32
  • May be a useful adjuvant (supplemental therapy), especially in colorectal cancer patients receiving radical radiotherapy.33

Kidney Cancer

  • Improved overall survival and cancer-specific survival in patients with diabetes in a meta-analysis,34 but not with metastatic disease35 and not in all studies36

Liver Cancer

  • Improved survival of diabetic patients using metformin37

Lung Cancer

  • Improved overall survival and disease-free survival among lung cancer patients with diabetes:38
    • With both small cell lung cancer and non-small cell lung cancer, in patients receiving chemotherapy but not chemoradiotherapy39
    • Among people with diabetes and with inoperable non-small cell lung cancer40
    • Among people with with diabetes mellitus and EGFR-TKIs treatment41
    • Improvement in distant metastasis-free survival and progression-free survival when used with concurrent chemoradiotherapy for locally advanced non-small cell lung cancer, but no improvement in locoregional recurrence-free survival or overall survival (at two years) in patients with diabetes42 
    • No benefit in diabetic patients with non-small cell lung cancer (NSCLC) treated with concurrent metformin and definitive chemoradiation in a small study43
    • Improved overall survival in diabetic patients undergoing resection of stage I non-small cell lung cancer compared to diabetic patients not on metformin in a small study44
  • Improved survival in people with lung cancer without diabetes
    • Improved survival in patients with advanced or metastatic nonsquamous non‐small cell lung cance45
    • A non-significant trend toward improved survival when used with chemotherapy in stage IV non-small cell lung cancer46

Lymphoma

  • Improved progression-free survival in people with diffuse large B-cell lymphoma with diabetes undergoing standard chemo-immunotherapy using metformin, compared to other patients with diabetes and non-diabetic patients, and improved overall survival compared to other diabetic patients in a small study47
  • No meaningful improvement in the response rates, progression-free survival or overall survival when used during bendamustine and rituximab therapy for follicular lymphoma in the first line or relapsed/refractory setting in a small study,48 nor in patients with diffuse large B-cell lymphoma receiving chemoimmunotherapy49

Multiple Myeloma

  • Higher rates of complete response after stem cell transplant, longer progression-free survival, and a trend toward longer overall survival in multiple myeloma patients using metformin at the time of diagnosis50

Ovarian Cancer

  • Improved overall survival51
  • Reduced mortality in people treated with metformin monotherapy (treatment only with metformin) at the time of diagnosis for ovarian or endometrial cancer or for 90 days after diagnosis in an observational study52 and progression-free survival with post-diagnostic metformin use by ovarian cancer patients both with and without diabetes,53 but not in all studies54

Pancreatic Cancer

  • Improved survival, specifically in patients with resection and patients with locally advanced tumors, but not in patients with metastatic tumors in a meta-analysis55
  • Improved overall survival among people with pancreatic ductal adenocarcinoma56
  • Improved overall survival in cohort studies but not randomized controlled trials, nor for progression-free survival in a meta-analysis57 One explanation for the difference is offered: “The association between metformin and pancreatic cancer survival has been greatly exaggerated in previous cohort studies due to the wide existence of immortal time bias.”58

Prostate Cancer

  • Improved overall survival, cancer-specific survival and recurrence-free survival in some meta-analyses,59 but no improvement in all-cause mortality in another.60
  • No change in insulin resistance and metabolic syndrome related to androgen deprivation therapy in men with prostate cancer and without diabetes treated with metformin, a low-glycemic-index diet and an exercise program in a small RCT.61
  • No effect on further progression and no meaningful clinical benefit among men with metastatic castration-resistant prostate cancer and prostate-specific antigen progression receiving abiraterone therapy compared to baseline in a small study62

Uterine/Endometrial Cancer

  • Improved overall survival and and progression-free survival among patients with diabetes63
  • Greater reduction in tumor or tumor markers among women without diabetes with atypical endometrial hyperplasia or endometrial cancer when given before surgery in small RCTs64

Lab and Animal Evidence

Click or tap to open.

Managing Side Effects and Promoting Wellness

Managing or relieving side effects or symptoms, reducing treatment toxicity, supporting quality of life or promoting general well-being

Clinical Evidence

  • Reduced grade 3/4 neutropenia among people with metastatic breast cancer80
  • Lower rate of grade 2 and 3 neuropathy, lower pain scores and lower markers of oxidative stress and heightened sensitivity to pain (hyperalgesia) among patients with colorectal cancer81
  • Reduced nausea in people with lung cancer without diabetes82

Animal Evidence

Click or tap to open.

Reducing Risk

Reducing the risk of developing cancer or the risk of recurrence

Clinical Evidence

Clinical trials using metformin as a cancer preventive are in progress.

Cancer in General
  • Significantly reduced overall cancer incidence in two meta-analyses,85 with one also finding a trend toward improved recurrence-free survival.86
  • Reduced cancer incidence in people with type 2 diabetes.87
Breast Cancer
  • Lower incidence of grade 3 tumors among breast cancer patients using metformin at the time of diagnosis; however, results for incidence of various types of breast cancer (triple negative, ER positive, PR positive) were mixed.88
  • No reduced risk in some reviews89 , but the Women’s Health Initiative clinical trials found reduced risk of invasive breast cancer in postmenopausal women only90
Colorectal Cancer
  • Reduced risk with use in some but not all analyses,91 including in those with type 2 diabetes92
  • Decreased risk of colorectal adenoma recurrence93 and reduced aberrant crypt foci (a pre-cancerous condition) in patients at high risk of adenoma recurrence94
  • Reduced incidence of colon neoplasia,colon cancer and colon polyps among metformin users.95
  • Preventing metachronous (secondary) colorectal adenomas or polyps when compared with placebo96
Liver Cancer

Reduced incidence of hepatocellular carcinoma (HCC, a liver cancer) with metformin use, but HCC incidence increased with sulfonylurea or insulin use to control diabetes; however post hoc analysis of randomized control trials didn’t show a significant link between antidiabetic medications and risk of HCC.97

Lung Cancer

Mixed results:

  • Reduced risk of lung cancer if using metformin and/or one of the thiazolidinediones (TZDs).98 
  • No reduced risk of lung cancer99 See Cautions below.
Pancreatic Cancer
  • Reduced risk of cancer of the pancreas among people with diabetes,100 but increased risk with insulin or insulin secretagogues (drugs that stimulate relesase of insulin)101
Prostate Cancer

Mixed results:

  • Reduced risk of prostate cancer in a 2014 meta-analysis of epidemiological observational studies, but not of biochemical recurrence.102
  • No lower risk of prostate cancer in other reviews and meta-analyses103

Uterine Cancers (Endometrial and Sarcoma)

  • Reduced risk of recurrence, but not significantly lower risk of endometrial cancer104
  • Reversion of atypical endometrial hyperplasia to a normal endometrial histology105 
  • Anti-estrogenic effect on endometrial histology inducing endometrial atrophy among women with disordered proliferative endometrium or simple endometrial hyperplasia in a small RCT106

Lab and Animal Evidence

Click or tap to open.

Optimizing Your Terrain

Creating an environment within your body that does not support cancer development, growth or spread

  • Anti-inflammatory108
  • Reduced blood glucose (glycemia);109 elevated levels are a risk factor for colorectal cancer110 and are associated with poorer survival in some reports111
  • Reduced levels of insulin, fasting glucose, CRP, HOMA, leptin, BMI, and Ki-67 in breast cancer patients receiving metformin as treatment for diabetes112
  • Increased phosphorylation of AMPKα113
  • Physical activity and metformin both led to weight loss as well as significant changes in insulin and other biomarkers in colorectal cancer and breast cancer survivors.114 
  • Decrease in insulin resistance and metabolic syndrome related to androgen deprivation therapy in men without diabetes who received metformin and made lifestyle changes.115
  • Did not affect expression of markers of the PI3K–Akt–mTOR or insulin signaling pathways, and did not result in weight loss among women with atypical hyperplasia or endometrioid endometrial cancer116

Access

Metformin is available with a prescription in oral form at pharmacies.

Cautions

Cautions Specific to Cancer Treatments and Outcomes
  • A small study of people without diabetes who have locally advanced non–small cell lung cancer found that use of metformin during chemoradiotherapy was linked to worse treatment efficacy and increased toxic effects compared to chemoradiotherapy alone. The proportion of patients who experienced a failure event within one year (locoregional disease progression, distant metastases, death, or withdrawal) was 69.2% in the metformin arm versus 42.9% in the control arm.117
  • Gastrointestinal toxicity is noted for prostate cancer patients receiving abiraterone therapy in a small study.118
  • A 2012 study found that diabetics who developed lung cancer while receiving metformin were more likely to present with metastatic disease, had reduced survival, and had a different histology distribution (microscopic tissue characteristics) than those who were not receiving metformin.119 However, Yin et al. provided context that “the study by Mazzone et al. is the only study showing a significantly increased risk for death associated with metformin treatment whereas most of the studies in our data pool . . . favor a protective effect of metformin.”120
Common Side Effects/Adverse Events

Side effects common in first few days of taking metformin:

  • Nausea and vomiting
  • Stomach upset
  • Diarrhea
  • Weakness
  • Metallic taste in the mouth

If any of these effects persist or worsen, tell your doctor or pharmacist promptly. Stomach symptoms occurring after the first days of treatment may be signs of lactic acidosis, described below.

Other mild to moderate side effects and their related recommendations:121

  • Malabsorption of vitamin B12 in up to 30 percent of patients; recommend checking vitamin B12 levels once to twice per year
  • Thyroid hormone abnormalities; recommend checking thyroid hormone levels once or twice per year
  • Reduced testosterone levels; recommend checking once or twice per year

Serious side effects:

  • Hypoglycemia (very rare)
  • Lactic acidosis (buildup of lactic acid in the bloodstream); those with poor renal function are at greater risk: symptoms include unusual fatigue, dizziness, severe drowsiness, chills, blue/cold skin, muscle pain, fast/difficult breathing, slow/irregular heartbeat, stomach pain with nausea, vomiting or diarrhea. Seek treatment immediately.
  • Serious allergic reaction (rare)
  • According to Vecchia and Bosetti. “Of specific concern is a recent report of an association between metformin use and poor cognitive function . . . Thus, metformin may exert a favorable effect on cancer, but an unfavorable one on cognitive function, this being in line with the inverse relationship observed between Alzheimer’s disease and cancer on a population level. This issue is, however, too preliminary for any assessment and risk quantification.”122
  • High-dose metformin (500-2000 mg/day) was associated with higher risk of developing lactic acidosis (buildup of lactic acid in the bloodstream) and adverse gastrointestinal effects such as diarrhea.123
  • Metformin use is linked to deficiencies of vitamin B12124 and folate,125 which could lead to elevated homocysteine levels. Preliminary evidence shows can be corrected with supplements.126
Precautions

Numerous precautions are involved in taking metformin, and patients must notify their doctors of certain conditions that will increase their risk of developing serious problems from taking metformin. For a listing of these precautions, see: WebMD: Metformin HCL: Precautions.

Metformin is not recommended in patients with abnormal renal or hepatic function, nor should it be prescribed in patients with heart failure.127

Interactions

Numerous potential drug interactions are associated with metformin. Consult with your pharmacist for interactions, and discuss using metformin with your doctor. For a listing of these interactions see WebMD: Metformin HCL: Interactions.

Dosing

CancerChoices does not recommend therapies or doses, but only provides information for patients and providers to consider as part of a complete treatment plan. Patients should discuss therapies with their physicians, as contraindications, interactions and side effects must be evaluated.

“Most of the cancer clinical trials of metformin use the same doses typically used to treat diabetes.” These are typically trials of cancer prevention. Some suggest higher doses may be more effective in the adjuvant cancer treatment setting, but safety and effectiveness of higher doses has not yet been established in clinical trials.128

Dosage information and recommendations are available from these sources:

Integrative Programs, Protocols and Medical Systems

For more information about programs and protocols, see our Integrative Programs and Protocols page.

Programs and protocols

  • Block program129
    • Pharmaceutical glycemia terrain modifier
  • Chang strategies130
  • McKinney protocols131
  • Breast cancer
  • Carcinoid/neuroendocrine cancer
  • Lymphoma
  • Melanoma
  • Pancreatic cancer
  • Prostate cancer
  • Sarcoma
  • Thyroid cancer

Commentary

“We found that metformin was associated with benefit regardless of cancer treatments.”

Margel et al.

From a 2013 article by Margel et al: “There are several clinical implications of our findings. First, consistent with current guidelines, metformin should be considered first-line therapy among patients with prostate cancer and diabetes, not only for diabetes control but possibly to improve cancer prognosis. Second, we found that metformin was associated with benefit regardless of cancer treatments. These results suggest that metformin may further improve survival as an adjunct therapy, even among those already receiving optimal cancer treatments. Finally, metformin may be ideal for secondary prevention because it is inexpensive, safe, and well tolerated.132

From a 2013 article by Yin et al.: “Patients with type 2 diabetes have increased cancer risk and cancer-related mortality, which can be reduced by metformin treatment. However, it is unclear whether metformin can also modulate clinical outcomes in patients with cancer and concurrent type 2 diabetes. Our meta-analysis provided evidence that there was a relative survival benefit associated with metformin treatment compared with treatment with other glucose-lowering medications. Our results suggest that metformin is the drug of choice in the treatment of patients with cancer and concurrent type 2 diabetes..133

From a 2014 article by Yu et al: Any conclusions without a large-scale prospective randomized study should be cautious. However, “considering the high prevalence of prostate cancer in Western countries and its rising incidence in the world, [and} the low cost and favorable toxicity of metformin, the applicability of metformin use as recommendation for prevention or treatment of prostate cancer may suit multiple populations, in people both with or without type 2 diabetes, and in both developed or developing countries.”134

From a 2013 presentation by integrative oncologist and BCCT advisor Dwight McKee, MD: “Metformin can be safely given as an off-label adjunctive treatment in cancer patients, especially breast, ovarian, colorectal, prostate, pancreas and perhaps in glioma patients who have type 2 diabetes, metabolic syndrome, elevated circulating insulin levels, or are obese, or even simply those who cannot or do not adhere to a low-carb, low-fat diet.”135

From a 2009 book by integrative oncologist and BCCT advisor Keith Block, MD: If you are taking glycemic support supplements or terrain modifiers and they are not correcting your glycemic imbalance, Keith Block, MD, suggests talking with your physician about increasing the doses of these, and/or considering using metformin. “Metformin . . . is approved for insulin resistance, reduces the liver’s ability to release glucose and so may be helpful for patients whose glucose imbalance results from this mechanism.”136

Integrative physician and BCCT advisor Barry Elson, MD, February 18, 2021: Observational studies find benefit in those with insulin resistance and/or obesity, perhaps because metformin stimulates the tumor suppressor AMPK. AMPK is poorly activated in obese patients, since they are generally deficient in adiponectin, an AMPK-activating hormone.

In addition to chemical stimulation of AMPK, avoiding sugar and taking other measures to curb insulin resistance can achieve some of the same impacts without the side effects of metformin. Several excellent natural remedies are available, such as these:

  • Chromium (HealthLine)
  • Alpha lipoic acid
  • Berberine (Web MD)
  • Fish oil
  • Cinnamon (HealthLine)

“Avoiding sugar and taking other measures to curb insulin resistance can achieve some of the same impacts without the side effects of metformin.”

Barry Elson, MD

Also known by these names

Brand names:

  • Fortamet
  • Glumetza
  • Glucophage
  • Glucophage XR
  • Riomet

Resources

General Information

Clinical Trials

More from Our Resources Database

References

  1. Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy. Annals of Translational Medicine. 2014;2(6):57.
  2. Yin M, Zhou J, Gorak EJ, Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist. 2013 Dec;18(12):1248-1255.
  3. Gong Z, Aragaki AK, Chlebowski RT, et al. Diabetes, metformin and incidence of and death from invasive cancer in postmenopausal women: results from the Women’s Health Initiative. International Journal of Cancer. 2016;138(8):1915-1927.
  4. Currie CJ, Poole CD et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299-304.
  5. American Cancer Society. Does body weight affect cancer risk? January 4, 2018. Viewed January 18, 2018.
  6. La Vecchia C, Bosetti C. Metformin: are potential benefits on cancer risk extended to cancer survival? The Oncologist. 2013 Dec;18(12):1245-1247.
  7. Chang R. Beyond the Magic Bullet: The Anti-Cancer Cocktail. New York: Square One Publishers. 2012. p. 93.
  8. Coyle C, Cafferty FH, Vale C, Langley RE. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Annals of Oncology. 2016;27(12):2184-2195; Li D, Yeung S-CJ, Hassan MM, Konopleva M, Abbruzzese JL. Anti-diabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137(2):482-488; Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy. Annals of Translational Medicine. 2014;2(6):57.
  9. Lawenda, BD. Metformin Supplementation and Cancer Treatment. Integrative Oncology Essentials. February 19, 2013. Viewed January 18, 2018.
  10. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006; 29: 254-258; Currie CJ, Poole CD et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299-304; Yin M, Zhou J, Gorak EJ, Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist. 2013 Dec;18(12):1248-1255; Currie CJ, Poole CD et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299-304; Gong Z, Aragaki AK, Chlebowski RT, et al. Diabetes, metformin and incidence of and death from invasive cancer in postmenopausal women: results from the Women’s Health Initiative. International Journal of Cancer. 2016;138(8):1915-1927.
  11. Currie CJ, Poole CD et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299-304; Currie CJ, Poole CD et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299-304.
  12. Yin M, Zhou J, Gorak EJ, Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist. 2013 Dec;18(12):1248-1255.
  13. Elmaci I, Altinoz MA. A metabolic inhibitory cocktail for grave cancers: metformin, pioglitazone and lithium combination in treatment of pancreatic cancer and glioblastoma multiforme. Biochemical Genetics. 2016 Oct;54(5):573-618.
  14. Seliger C, Luber C et al. Use of metformin and survival of patients with high-grade glioma. International Journal of Cancer. 2019 Jan;144(2):273-280.
  15. Adeberg S, Bernhardt D et al. Metformin influences progression in diabetic glioblastoma patients. Strahlentherapie und Onkologie. 2015 Dec;191(12):928-35.
  16. Xu H, Chen K et al. Metformin use is associated with better survival of breast cancer patients with diabetes: a meta-analysis. The Oncologist. 2015 Nov;20(11):1236-44; Zhang P, Li H, Tan X, Chen L, Wang S. Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer Epidemiology. 2013 Jun;37(3):207-18.
  17. Zhang ZJ, Yuan J, Bi Y, Wang C, Liu Y. The effect of metformin on biomarkers and survivals for breast cancer- a systematic review and meta-analysis of randomized clinical trials. Pharmacological Research. 2019 Mar;141:551-555; Nanni O, Amadori D et al. Metformin plus chemotherapy versus chemotherapy alone in the first-line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial. Breast Cancer Research and Treatment. 2019 Apr;174(2):433-442; Coyle C, Cafferty FH, Vale C, Langley RE. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Annals of Oncology. 2016 Dec;27(12):2184-2195.
  18. Aksoy S, Sendur MA, Altundag K. Demographic and clinico-pathological characteristics in patients with invasive breast cancer receiving metformin. Medical Oncology. 2013;30(2):590.
  19. Bayraktar S, Hernadez-Aya LF et al. Effect of metformin on survival outcomes in diabetic patients with triple receptor–negative breast cancer. Cancer. 2012;118(5):1202-1211.
  20. El-Haggar SM, El-Shitany NA, Mostafa MF, El-Bassiouny NA. Metformin may protect nondiabetic breast cancer women from metastasis. Clinical & Experimental Metastasis. 2016 Apr;33(4):339-57.
  21. Bayraktar S, Hernadez-Aya LF et al. Effect of metformin on survival outcomes in diabetic patients with triple receptor–negative breast cancer. Cancer. 2012;118(5):1202-1211.
  22. Jiralerspong S, Palla SL et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. Journal of Clinical Oncology. 2009;27(20):3297-3302; Jiralerspong S, Palla SL et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. Journal of Clinical Oncology. 2009 Jul 10;27(20):3297-302..
  23. Hanprasertpong J, Jiamset I et al. The effect of metformin on oncological outcomes in patients with cervical cancer with type 2 diabetes mellitus. International Journal of Gynecological Cancer: Official Journal of the International Gynecological Cancer Society. 2017 Jan;27(1):131-137.
  24. Takiuchi T, Machida H et al. Association of metformin use and survival outcome in women with cervical cancer. International Journal of Gynecological Cancer: Official Journal of the International Gynecological Cancer Society. 2017 Sep;27(7):1455-1463.
  25. Coyle C, Cafferty FH, Vale C, Langley RE. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Annals of Oncology. 2016;27(12):2184-2195; Lee JH, Kim TI et al. The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. International Journal of Cancer. 2012;131:752–759; Yang IP, Miao ZF et al. High blood sugar levels but not diabetes mellitus significantly enhance oxaliplatin chemoresistance in patients with stage III colorectal cancer receiving adjuvant FOLFOX6 chemotherapy. Therapeutic Advanced in Medical Oncology. 2019 Aug 20;11:1758835919866964; Mei ZB, Zhang ZJ et al. Survival benefits of metformin for colorectal cancer patients with diabetes: a systematic review and meta-analysis. PLoS One. 2014 Mar;9(3):e91818; Henderson D, Frieson D, Zuber J, Solomon SS. Metformin has positive therapeutic effects in colon cancer and lung cancer. American Journal of the Medical Science. 2017 Sep;354(3):246-251.
  26. Tian S, Lei HB, Liu YL, Chen Y, Dong WG. The association between metformin use and colorectal cancer survival among patients with diabetes mellitus: an updated meta-analysis. Chronic Diseases and Translational Medicine. 2017 Sep;3(3):169-175. 
  27. Mafiana RN, Al-Kindi MS, Mafiana N, Al Lawati AS, Al Moundhri M. Impact of Metabolic syndrome diagnosis and its treatment on survival of colorectal cancer patients. Journal of Cancer Epidemiology. 2019 Apr 21;2019:6527457.] or diabetes[Gash KJ, Chambers AC, Cotton DE, Williams AC, Thomas MG. Potentiating the effects of radiotherapy in rectal cancer: the role of aspirin, statins and metformin as adjuncts to therapy. British Journal of Cancer. 2017 Jul 11;117(2):210-219.
  28. Vernieri C, Galli F et al. Impact of metformin use and diabetic status during adjuvant fluoropyrimidine-oxaliplatin chemotherapy on the outcome of patients with resected colon cancer: a TOSCA study subanalysis. The Oncologist. 2019 Mar;24(3):385-393.
  29. Bragagnoli A, Araujo R et al. Final results of a phase II of metformin plus irinotecan for refractory colorectal cancer. Journal of Clinical Oncology. 2018;36(15_suppl):e15527-e15527.
  30. Miranda VC, Braghiroli MI et al. Phase 2 trial of metformin combined with 5-fluorouracil in patients with refractory metastatic colorectal cancer. Clinical Colorectal Cancer. 2016 Dec;15(4):321-328.e1.
  31. Yang IP, Miao ZF et al. High blood sugar levels but not diabetes mellitus significantly enhance oxaliplatin chemoresistance in patients with stage III colorectal cancer receiving adjuvant FOLFOX6 chemotherapy. Therapeutic Advanced in Medical Oncology. 2019 Aug 20;11:1758835919866964.
  32. Godara A, Siddiqui NS, Hachem H, Martell RE, Saif WM. First prospective study evaluating effect of metformin (M) on disease control (DC) and activation of AMP-activated protein kinase (AMPKα) in patients (pts) with GI malignancies. Journal of Clinical Oncology. 2018 Feb;36(4): 264–264.
  33. Coyle C, Cafferty FH, Vale C, Langley RE. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Annals of Oncology. 2016;27(12):2184-2195.
  34. Li Y, Hu L, Xia Q, Yuan Y, Mi Y. The impact of metformin use on survival in kidney cancer patients with diabetes: a meta-analysis. International Urology and Nephrology. 2017 Jun;49(6):975-981.
  35. Cheng JJS, Li H et al. Metformin use in relation with survival outcomes of patients with renal cell carcinoma. Clinical Genitourinary Cancer. 2016 Apr;14(2):168–175.
  36. Nayan M, Finelli A et al. Metformin use and kidney cancer outcomes in patients with diabetes: a propensity score analysis. Clinical Genitourinary Cancer. 2017 Apr;15(2): 300–305.
  37. Currie CJ, Poole CD et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299-304; Chen TM, Lin CC, Huang PT, Wen CF. (2011). Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation. Journal of Gastroenterology and Hepatology. 2011 May; 26(5):858–865.
  38. Xin WX, Fang L et al. Effect of hypoglycemic agents on survival outcomes of lung cancer patients with diabetes mellitus: a meta-analysis. Medicine (Baltimore). 2018 Mar;97(9):e0035; Henderson D, Frieson D, Zuber J, Solomon SS. Metformin has positive therapeutic effects in colon cancer and lung cancer. American Journal of the Medical Science. 2017 Sep;354(3):246-251.
  39. Wan G, Yu X et al. Metformin therapy associated with survival benefit in lung cancer patients with diabetes. Oncotarget. 2016 Jun;7(23):35437–35445.
  40. Chuang MC, Yang YH et al. Survival benefit associated with metformin use in inoperable non-small cell lung cancer patients with diabetes: a population-based retrospective cohort study. PLoS One. 2018 Jan 12;13(1):e0191129.
  41. Hung MS, Chuang MC, Tsai YH, Yang YH. Metformin improves survival in lung cancer patients receiving EGFR-TKIs therapy. European Respiratory Journal. 2018;52(suppl62):2856.
  42. Wink KCJ, Belderbos JSA et al. Improved progression free survival for patients with diabetes and locally advanced non-small cell lung cancer (NSCLC) using metformin during concurrent chemoradiotherapy. Radiotherapy and Oncology: The Journal of the European Society for Therapeutic Radiology and Oncology. 2016 Mar;118(3):453-9.
  43. Ahmed I, Ferro A et al. Impact of metformin use on survival in locally-advanced, inoperable non-small cell lung cancer treated with definitive chemoradiation. Journal of Thoracic Disease. 2015 Mar;7(3): 346–355.
  44. Dhillon SS, Groman A et al. Metformin and not diabetes influences the survival of resected early stage NSCLC patients. Journal of Cancer Science & Therapy. 2014 Jul;6(7):217-222.
  45. Marrone KA, Zhou X et al. A randomized phase II study of metformin plus paclitaxel/carboplatin/bevacizumab in patients with chemotherapy‐naïve advanced or metastatic nonsquamous non‐small cell lung cancer. The Oncologist. 2018 Jul;23(7):859–865.
  46. Sayed R, Saad AS, El Wakeel L, Elkholy E, Badary O. Metformin addition to chemotherapy in stage IV non-small cell lung cancer: an open label randomized controlled study. Asian Pacific Journal of Cancer Prevention: APJCP. 2016 Mar;118(3):453-9.
  47. Singh A, Gu J, Yanamadala V, Czuczman MS, Hernandez-Ilizaliturri FJ. Metformin lowers the mitochondrial potential of lymphoma cells and its use during front-line rituximab-based chemo-immunotherapy improves the clinical outcome of diffuse large B-cell lymphoma. Blood. 2013 Nov;122(21):1825-1825.
  48. Hicks AM, Singh A et al. Therapeutic effects of metformin in follicular lymphoma (FL) treated with rituximab in combination with bendamustine. Blood. 2017 Dec;130(suppl1):5152–5152.
  49. Koo YX, Tan DSW et al. Effect of concomitant statin, metformin, or aspirin on rituximab treatment for diffuse large B-cell lymphoma. Leukemia & Lymphoma. 2011 Aug;52(8):1509-16.
  50. Duma N, Vera Aguilera J et al. Impact of metformin use in the outcomes of multiple myeloma patients post stem cell transplant. Journal of Clinical Oncology. 2017 May;35(15suppl):8034–8034.
  51. Kumar S, Meuter A et al. Metformin intake is associated with better survival in ovarian cancer: a case-control study. Cancer. 2013;119:555–562.
  52. Currie CJ, Poole CD et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299-304.
  53. Gong TT, Wu QJ et al. Observational studies on the association between post-diagnostic metformin use and survival in ovarian cancer: a systematic review and meta-analysis. Frontiers in Oncology. 2019 May 29;9:458.
  54. Wang Y, Liu X et al. No effect of metformin on ovarian cancer survival: a systematic review and meta-analysis of cohort studies. Current Pharmaceutical Design. 2019;25(23):2595-2601.
  55. Li X, Li T, Liu Z, Gou S, Wang C. The effect of metformin on survival of patients with pancreatic cancer: a meta-analysis. Scientific Reports. 2017 Jul 19;7(1):5825. 
  56. Kozak MM, Anderson EM, von Eyben R, Pai JS, Poultsides GA, Visser BC, Norton JA, Koong AC, Chang DT. Statin and metformin use prolongs survival in patients with resectable pancreatic cancer. Pancreas. 2016 Jan;45(1):64-70.
  57. Zhou DC, Gong H, Tan CQ, Luo JQ. Prognostic significance of anti-diabetic medications in pancreatic cancer: a meta-analysis. Oncotarget. 2017 Sep 5; 8(37): 62349–62357.
  58. Wei M, Liu Y, Bi Y, Zhang Z. Metformin and pancreatic cancer survival: real effect or immortal time bias? International Journal of Cancer. 2019 Mar;145(7):1822-1828.
  59. He K, Hu H et al. (2019). The effect of metformin therapy on incidence and prognosis in prostate cancer: a systematic review and meta-analysis. Scientific Reports. 2019 Feb 18;9(1):2218; Coyle C, Cafferty FH, Vale C, Langley RE. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Annals of Oncology. 2016;27(12):2184-2195.
  60. Yu H, Yin L et al. Effect of metformin on cancer risk and treatment outcome of prostate cancer: a meta-analysis of epidemiological observational studies. PLoS ONE. 2014;9(12):e116327.
  61. Nobes JP, Langley SE, Klopper T, Russell-Jones D, Laing RW. A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. BJU International. 2012 May;109(10):1495-502.
  62. Mark M, Klingbiel D et al. Impact of addition of metformin to abiraterone in metastatic castration-resistant prostate cancer patients with disease progressing while receiving abiraterone treatment (MetAb-Pro): Phase 2 pilot study. Clinical Genitourinary Cancer. 2019 Apr;17(2):e323-e328.
  63. Currie CJ, Poole CD et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299-304; Chu D, Wu J et al. Effect of metformin use on the risk and prognosis of endometrial cancer: a systematic review and meta-analysis. BMC Cancer. 2018 Apr 18;18(1):438; Meireles CG, Pereira SA et al. Effects of metformin on endometrial cancer: systematic review and meta-analysis. Gynecologic Oncology. 2017 Oct;147(1):167-180; Xie W, Li T et al. Metformin use and survival outcomes in endometrial cancer: a systematic review and meta-analysis. Oncotarget. 2017 Aug 22;8(42):73079-73086.
  64. Sivalingam VN, Kitson S et al. Measuring the biological effect of presurgical metformin treatment in endometrial cancer. British Journal of Cancer. 2016 Feb 2;114(3):281-9; Laskov I, Drudi L et al. Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer. Gynecologic Oncology. 2014 Sep;134(3):607-14. 
  65. Yin M, Zhou J, Gorak EJ, Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist. 2013 Dec;18(12):1248-1255.
  66. Song CW, Lee H et al. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Scientific Reports. 2012;2:362.
  67. Ding L, Liang G et al. Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages. Oncotarget. 2015 Nov 3;6(34):36441-55.
  68. Hanna RK, Zhou C et al. Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. Gynecologic Oncology. 2012 May;125(2):458-69125 (2012) 458–469.
  69. Cha JH, Yang WH et al. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Molecular Cell. 2018 Aug 16;71(4):606-620.e7.
  70. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Research. 2006 Nov 1;66(21):10269-73.
  71. Eikawa S, Nishida M et al. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proceedings of the National Academy of Sciences of the United States of America. 2015 Feb 10;112(6):1809-14.
  72. Davies G, Lobanova L et al. Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer. PLoS One. 2017 Dec 6;12(12):e0187191.
  73. Rico M, Baglioni M et al. Metformin and propranolol combination prevents cancer progression and metastasis in different breast cancer models. Oncotarget. 2017 Jan 10;8(2):2874-2889.
  74. Eikawa S, Nishida M et al. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proceedings of the National Academy of Sciences of the United States of America. 2015 Feb 10;112(6):1809-14.
  75. Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunology Research. 2017 Jan;5(1):9-16.
  76. Mert I, Chhina J et al. Synergistic effect of MEK inhibitor and metformin combination in low grade serous ovarian cancer. Gynecologic Oncology. 2017 Aug;146(2):319-326.
  77. Lengyel E, Litchfield LM et al. Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models. American Journal of Obstetrics and Gynecology. 2015 Apr;212(4):479.e1-479.e10.
  78. Hijaz M, Chhina J et al. Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer. Gynecologic Oncology. 2016 Aug;142(2):323-31.
  79. Li B1, Li X et al. Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells. Oncotarget. 2016 Sep 13;7(37):59458-59470.
  80. Nanni O, Amadori D et al. Metformin plus chemotherapy versus chemotherapy alone in the first-line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial. Breast Cancer Research and Treatment. 2019 Apr;174(2):433-442.
  81. El-Fatatry BM, Ibrahim OM, Hussien FZ, Mostafa TM. Role of metformin in oxaliplatin-induced peripheral neuropathy in patients with stage III colorectal cancer: randomized, controlled study. International Journal of Colorectal Disease. 2018 Dec;33(12):1675-1683.
  82. Sayed R, Saad AS, El Wakeel L, Elkholy E, Badary O. Metformin addition to chemotherapy in stage IV non-small cell lung cancer: an open label randomized controlled study. Asian Pacific Journal of Cancer Prevention: APJCP. 2016 Mar;118(3):453-9.
  83. Patterson S. Metformin may have broad utility in cancer. MD Anderson Cancer Center. November-December 2014. Viewed January 19, 2018.
  84. Zhou W, Kavelaars A, Heijnen CJ. Metformin prevents cisplatin-induced cognitive impairment and brain damage in mice. PLoS ONE. 2016;11(3):e0151890.
  85. Coyle C, Cafferty FH, Vale C, Langley RE. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Annals of Oncology. 2016;27(12):2184-2195; Zhang P, Li H, Tan X, Chen L, Wang S. Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer Epidemiology. 2013 Jun;37(3):207-18.
  86. Coyle C, Cafferty FH, Vale C, Langley RE. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Annals of Oncology. 2016 Dec;27(12):2184-2195.
  87. Yin M, Zhou J, Gorak EJ, Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist. 2013 Dec;18(12):1248-1255; Evans JMM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330:1304–5.
  88. Aksoy S, Sendur MA, Altundag K. Demographic and clinico-pathological characteristics in patients with invasive breast cancer receiving metformin. Medical Oncology. 2013;30(2):590.
  89. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009 Sep;52(9):1766-77; Calip GS, Yu O, Elmore JG, Boudreau DM. Comparative safety of diabetes medications and risk of incident invasive breast cancer: a population-based cohort study. Cancer Causes & Control. 2016 May;27(5):709-20.
  90. Chlebowski RT, McTiernan A et al. Diabetes, metformin, and breast cancer in postmenopausal women. Journal of Clinical Oncology. 2012 Aug 10;30(23):2844-52.
  91. Song M, Chan AT. Environmental factors, gut microbiota, and colorectal cancer prevention. Clinical Gastroenterology and Hepatology. 2019 Jan;17(2):275-289; Katona BW, Weiss JM. Chemoprevention of colorectal cancer. Gastroenterology. 2019 Sep 26. pii: S0016-5085(19)41364-4; Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009 Sep;52(9):1766-77; Jung YS, Park CH, Eun CS, Park DI, Han DS. Metformin use and the risk of colorectal adenoma: a systematic review and meta-analysis. Journal of Gastroenterology and Hepatology. 2017 May;32(5):957-965.
  92. Joo MK, Park JJ, Chun HJ. Additional benefits of routine drugs on gastrointestinal cancer: statins, metformin, and proton pump inhibitors. Digestive Diseases. 2018;36(1):1-14; Rokkas T, Portincasa P. Colon neoplasia in patients with type 2 diabetes on metformin: a meta-analysis. European Journal of Internal Medicine. 2016 Sep;33:60-6; Krstic MN, Mijac DD, Popovic DD, Pavlovic Markovic A, Milosavljević T. General aspects of primary cancer prevention. Digestive Diseases. 2019;37(5):406-415; Katona BW, Weiss JM. Chemoprevention of colorectal cancer. Gastroenterology. 2019 Sep 26. pii: S0016-5085(19)41364-4; Krstic MN, Mijac DD, Popovic DD, Pavlovic Markovic A, Milosavljević T. General aspects of primary cancer prevention. Digestive Diseases. 2019;37(5):406–415; Smiechowski B, Azoulay L, Yin H, Pollak MN, Suissa S. The use of metformin and colorectal cancer incidence in patients with type II diabetes mellitus. Cancer Epidemiology, Biomarkers & Prevention. 2013 Oct;22(10):1877-83.
  93. Paleari L, Burhenne J et al. High accumulation of metformin in colonic tissue of subjects with diabetes or the metabolic syndrome. Gastroenterology. 2018 Apr;154(5):1543-1545; Umezawa S, Higurashi T et al. Chemoprevention of colorectal cancer: past, present, and future. Cancer Science. 2019 Oct;110(10):3018-3026; Higurashi T, Hosono K et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncology. 2016 Apr;17(4):475-483.
  94. Higurashi T, Nakajima A. Metformin and colorectal cancer. Frontiers in Endocrinology (Lausanne). 2018 Oct 23;9:622.
  95. Rokkas T, Portincasa P. Colon neoplasia in patients with type 2 diabetes on metformin: a meta-analysis. European Journal of Internal Medicine. 2016 Sep;33:60-6.
  96. La Vecchia C, Bosetti C. Metformin: are potential benefits on cancer risk extended to cancer survival? The Oncologist. 2013 Dec;18(12):1245-1247.
  97. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. American Journal of Gastroenterology. 2013 Jun;108(6):881-91; quiz 892.
  98. Mazzone PJ, Rai H et al. The effect of metformin and thiazolidinedione use on lung cancer in diabetics. BMC Cancer. 2012 Sep 14;12:410.
  99. Bodmer M, Becker C, Jick SS, Meier CR. Metformin does not alter the risk of lung cancer: a case–control analysis. Lung Cancer. November 2012; 78; 2; 133–137.
  100. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009 Sep;52(9):1766-77.
  101. Li D, Yeung S-CJ, Hassan MM, Konopleva M, Abbruzzese JL. Anti-diabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137(2):482-488.
  102. Yu H, Yin L et al. Effect of metformin on cancer risk and treatment outcome of prostate cancer: a meta-analysis of epidemiological observational studies. PLoS ONE. 2014;9(12):e116327.
  103. He K, Hu H et al. (2019). The effect of metformin therapy on incidence and prognosis in prostate cancer: a systematic review and meta-analysis. Scientific Reports. 2019 Feb 18;9(1):2218; Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009 Sep;52(9):1766-77.
  104. Chu D, Wu J et al. Effect of metformin use on the risk and prognosis of endometrial cancer: a systematic review and meta-analysis. BMC Cancer. 2018 Apr 18;18(1):438.
  105. Meireles CG, Pereira SA et al. Effects of metformin on endometrial cancer: systematic review and meta-analysis. Gynecologic Oncology. 2017 Oct;147(1):167-180.
  106. Tabrizi AD, Melli MS, Foroughi M, Ghojazadeh M, Bidadi S. Antiproliferative effect of metformin on the endometrium—a clinical trial. Asian Pacific Journal of Cancer Prevention. 2014;15(23):10067-70. 
  107. McCloskey CW, Cook DP et al. Metformin abrogates age-associated ovarian fibrosis. Clinical Cancer Research. 2019 Oct 9. pii: clincanres.0603.2019.
  108. Joo MK, Park JJ, Chun HJ. Additional benefits of routine drugs on gastrointestinal cancer: statins, metformin, and proton pump inhibitors. Digestive Diseases. 2018;36(1):1-14.
  109. Umezawa S, Higurashi T et al. Chemoprevention of colorectal cancer: past, present, and future. Cancer Science. 2019 Oct;110(10):3018-3026.
  110. Cui G, Zhang T et al. High blood glucose levels correlate with tumor malignancy in colorectal cancer patients. Medical Science Monitor. 2015 Dec 8;21:3825-33; Perrigue MM, Drewnowski A et al. Randomized trial testing the effects of eating frequency on two hormonal biomarkers of metabolism and energy balance. Nutrition and Cancer. 2017 Jan;69(1):56-63.
  111. Wolpin BM, Meyerhardt JA et al. Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer. Journal of Clinical Oncology. 2009 Jan 10;27(2):176-85; Sax AT, Jenkins DG et al. The insulin-like growth factor axis: a biological mechanism linking physical activity to colorectal cancer survival. Cancer Epidemiology. 2014 Aug;38(4):455-9; Yuan C, Bao Y et al. Influence of dietary insulin scores on survival in colorectal cancer patients. British Journal of Cancer. 2017 Sep 26;117(7):1079-1087.
  112. Rahmani J, Manzari N et al. The effect of metformin on biomarkers associated with breast cancer outcomes: a systematic review, meta-analysis, and dose–response of randomized clinical trials. Clinical & Translational Oncology. 2020 Jan;22(1):37-49.
  113. Godara A, Siddiqui NS, Hachem H, Martell RE, Saif WM. First prospective study evaluating effect of metformin (M) on disease control (DC) and activation of AMP-activated protein kinase (AMPKα) in patients (pts) with GI malignancies. Journal of Clinical Oncology. 2018 Feb;36(4): 264–264.
  114. Meyerhardt JA, Irwin ML et al. Multicenter, randomized phase II trial of physical activity (PA), metformin (Met), or the combination on metabolic biomarkers in stage I-III colorectal (CRC) and breast cancer (BC) survivors. Journal of Clinical Oncology. 2017 May;35(15):10059-10059.
  115. Margel D, Urbach DR et al. Metformin use and all-cause and prostate cancer–specific mortality among men with diabetes. Journal of Clinical Oncology. 2013 31:25, 3069-3075.
  116. Kitson SJ, Maskell Z et al. Pre-surgical metformin in uterine malignancy (PREMIUM): a multi-center, randomized double-blind, placebo-controlled phase III trial. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2019 Apr 15;25(8):2424-2432.
  117. Tsakiridis T, Pond GR et al. Metformin in combination with chemoradiotherapy in locally advanced non-small cell lung cancer: the OCOG-ALMERA randomized clinical trial. JAMA Oncology. 2021 Jul 29.
  118. Mark M, Klingbiel D et al. Impact of addition of metformin to abiraterone in metastatic castration-resistant prostate cancer patients with disease progressing while receiving abiraterone treatment (MetAb-Pro): Phase 2 pilot study. Clinical Genitourinary Cancer. 2019 Apr;17(2):e323-e328.
  119. Mazzone PJ, Rai H, Beukemann M, et al. The effect of metformin and thiazolidinedione use on lung cancer in diabetics. BMC Cancer. 2012;12:410.
  120. Yin M, Zhou J, Gorak EJ, Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist. 2013 Dec;18(12):1248-1255.
  121. Lawenda, BD. Metformin Supplementation and Cancer Treatment. Integrative Oncology Essentials. February 19, 2013. Viewed January 18, 2018.
  122. La Vecchia C, Bosetti C. Metformin: are potential benefits on cancer risk extended to cancer survival? The Oncologist. 2013 Dec;18(12):1245-1247.
  123. Higurashi T, Nakajima A. Metformin and colorectal cancer. Frontiers in Endocrinology (Lausanne). 2018 Oct 23;9:622.
  124. Nervo M, Lubini A et al. Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil. Revista da Associação Médica Brasileira. (1992). 2011 Jan-Feb;57(1):46-9; Calvo Romero JM, Ramiro Lozano JM. Vitamin B(12) in type 2 diabetic patients treated with metformin. Endocrinología y Nutrición. 2012 Oct;59(8):487-90; Kos E, Liszek MJ, Emanuele MA, Durazo-Arvizu R, Camacho P. Effect of metformin therapy on vitamin D and vitamin B₁₂ levels in patients with type 2 diabetes mellitus. Endocrine Practice. 2012 Mar-Apr;18(2):179-84; Leung S, Mattman A, Snyder F, Kassam R, Meneilly G, Nexo E. Metformin induces reductions in plasma cobalamin and haptocorrin bound cobalamin levels in elderly diabetic patients. Clinical Biochemistry. 2010 Jun;43(9):759-60; Jawa AA, Akram J, Sultan M, Humayoun MA, Raza R. Nutrition-related vitamin B12 deficiency in patients in Pakistan with type 2 diabetes mellitus not taking metformin. Endocrine Practice. 2010 Mar-Apr;16(2):205-8.
  125. Zhang Q, Li S et al. Metformin treatment and homocysteine: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2016 Dec 9;8(12):798.
  126. Nervo M, Lubini A et al. Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil. Revista da Associação Médica Brasileira. (1992). 2011 Jan-Feb;57(1):46-9; Jawa AA, Akram J, Sultan M, Humayoun MA, Raza R. Nutrition-related vitamin B12 deficiency in patients in Pakistan with type 2 diabetes mellitus not taking metformin. Endocrine Practice. 2010 Mar-Apr;16(2):205-8; Zhang Q, Li S et al. Metformin treatment and homocysteine: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2016 Dec 9;8(12):798.
  127. Patterson S. Metformin may have broad utility in cancer. MD Anderson Cancer Center, November-December 2014. Viewed January 19, 2018.
  128. National Cancer Institute. Metformin: Can a Diabetes Drug Help Prevent Cancer? April 15, 2013. Viewed January 19, 2018.
  129. Block KI. Life over Cancer: The Block Center Program for Integrative Cancer Treatment. New York: Bantam Dell. 2009.
  130. Chang R. Beyond the Magic Bullet: The Anti-Cancer Cocktail. New York: Square One Publishers. 2012.
  131. McKinney N. Naturopathic Oncology, 3rd Edition. Victoria, BC, Canada: Liaison Press. 2016.
  132. Margel D, Urbach DR et al. Metformin use and all-cause and prostate cancer–specific mortality among men with diabetes. Journal of Clinical Oncology. 2013 31:25, 3069-3075.
  133. Yin M, Zhou J, Gorak EJ, Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist. 2013 Dec;18(12):1248-1255.
  134. Yu H, Yin L et al. Effect of metformin on cancer risk and treatment outcome of prostate cancer: a meta-analysis of epidemiological observational studies. PLoS ONE. 2014;9(12):e116327.
  135. McKee D; Lecture: Off label pharmaceutical ‘cocktails’ for cancer treatment. Presentation at A4M Integrative Cancer Therapies, Module 6. June 6-8, 2013. Used with permission of Dwight McKee and Raymond Chang. Slides are available on request.
  136. Block KI. Life over Cancer: The Block Center Program for Integrative Cancer Care. New York: Bantam Dell. 2009. p. 404.
  137. Nestler J. Metformin for the treatment of the polycystic ovary syndrome. New England Journal of Medicine. 2008; 358:47-54; Lashen H. Role of metformin in the management of polycystic ovary syndrome. Therapeutic Advances in Endocrinology and Metabolism. 2010;1(3):117-128.
  138. Marchesini G, Natale S, Manini R, Agostini F. Review article: the treatment of fatty liver disease associated with the metabolic syndrome. Alimentary Pharmacology and Therapeutics. 2015 Nov;22(2):37-39.
  139. Apolzan JW, Venditti EM et al. Long-term weight loss with metformin or lifestyle intervention in the Diabetes Prevention Program Outcomes Study. Annals of Internal Medicine. 2019 Apr 23.