Metformin

Metformin, a prescription drug used to manage diabetes, has shown some benefits in lower risks of cancer and better survival, mostly among people with diabetes or high blood sugar.

Safety and precautions

Interactions with other therapies and effects on cancer outcomes

Some evidence shows toxicity during chemotherapy, higher mortality among people with liver cancer, and worse cancer outcomes among people with lung cancer. No matter which cancer type or chemotherapy you are using, your oncologist and pharmacist need to know if you are taking metformin. Always rely on your medical professional to confirm there are no concerning interactions before taking metformin alongside other treatments. Use metformin only as directed by your licensed physician.

CT/PET scans

Metformin should be stopped after any scan that uses contrast medium, such as CT or PET-CT scans.¹Lan M, Wojtan E. Stopping Metformin after Getting Contrast Medium. University Health Network. 2020. Viewed February 24, 2023.

Effects on cancer outcomes

Side effects or adverse events

Common side effects

These side effects are common in the first few days of taking metformin.¹¹Side effects of metformin. National Health Service. 24 March 2022. Viewed August 11, 2022; 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.

Tell your doctor or pharmacist promptly if any of these effects persist or worsen after a few days. Stomach symptoms occurring after the first days of treatment may be signs of lactic acidosis, described in “serious side effects” below.

Other mild to moderate side effects and their related recommendations:

• Anemia and low folate/vitamin B₁₂ levels can be a more serious side effect among people with cancer who are already anemic. Anemia due to malabsorption and deficiencies of vitamin B₁₂ or folate are seen in up to 30% of people.¹²Nervo M, Lubini A et al. Vitamin B₁₂ in metformin-treated diabetic patients: a cross-sectional study in Brazil. Revista da Associação Médica Brasileira. 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 et al. Metformin induces reductions in plasma cobalamin and haptocorrin bound cobalamin levels in elderly diabetic patients. Clinical Biochemistry. 2010 Jun;43(9):759-60; 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. Low folate/B₁₂ levels can contribute to high homocysteine levels (hyperhomocysteinemia), which can lead to arterial damage, blood clots, and other serious medical conditions.¹³High Homocysteine Level (Hyperhomocysteinemia). Healthline. January 2, 2018. Viewed February 24, 2023. Recommendations include checking vitamin B₁₂ levels once to twice per year¹⁴Lawenda, BD. Metformin Supplementation and Cancer Treatment. Integrative Oncology Essentials. February 19, 2013. Viewed August 11, 2022. and supplementing as indicated.¹⁵Lohmann AE, Liebman MF et al; From the CCTG, Alliance, SWOG, ECOG, NSABP Cooperative Groups. Effects of metformin versus placebo on vitamin B12 metabolism in non-diabetic breast cancer patients in CCTG MA.32. Breast Cancer Research and Treatment. 2017 Jul;164(2):371-378; Liu Q, Li S, Quan H, Li J. Vitamin B12 status in metformin treated patients: systematic review. PLoS One. 2014 Jun 24;9(6):e100379; Yang W, Cai X, Wu H, Ji L. Associations between metformin use and vitamin B12 levels, anemia, and neuropathy in patients with diabetes: a meta-analysis. Journal of Diabetes. 2019 Sep;11(9):729-743; Aroda VR, Edelstein SL et al; Diabetes Prevention Program Research Group. Long-term metformin use and vitamin B₁₂ deficiency in the Diabetes Prevention Program Outcomes Study. Journal of Clinical Endocrinology and Metabolism. 2016 Apr;101(4):1754-61. Preliminary evidence shows deficiencies can be corrected with vitamin B₁₂ and folate supplements.¹⁶Nervo 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. Also see the story below.
• Thyroid hormone abnormalities; recommend checking thyroid hormone levels once or twice per year¹⁷Lawenda, BD. Metformin Supplementation and Cancer Treatment. Integrative Oncology Essentials. February 19, 2013. Viewed August 11, 2022; Wang J, Gao J, Fan Q, Li H, Di Y. The effect of metformin on thyroid-associated serum hormone levels and physiological indexes: a meta-analysis. Current Pharmaceutical Design. 2019;25(30):3257-3265.
• Reduced testosterone levels; recommend checking levels once or twice per year¹⁸Lawenda, BD. Metformin Supplementation and Cancer Treatment. Integrative Oncology Essentials. February 19, 2013. Viewed August 11, 2022.

Serious side effects

A buildup of lactic acid in the bloodstream (lactic acidosis) is a serious condition: seek treatment immediately. People with poor renal function are at greater risk, and using high doses of metformin may also increase risk.¹⁹Higurashi T, Nakajima A. Metformin and colorectal cancer. Frontiers in Endocrinology (Lausanne). 2018 Oct 23;9:622. Symptoms:

Other serious side effects of metformin use:

• Low blood sugar (hypoglycemia) (very rare)
• Serious allergic reaction (rare)
• Poor cognitive function²⁰(La Vecchia C, Bosetti C. Metformin: are potential benefits on cancer risk extended to cancer survival? The Oncologist. 2013 Dec;18(12):1245-1247.

Effects on pregnancy or offspring

Similar rates of pregnancy but a weak trendan apparent change due to a therapy, close to but not achieving full statistical significance (this is the CancerChoices definition; other researchers and studies may define this differently toward lower rate of live birth among reproductive-aged women with atypical endometrial hyperplasia or early endometrial cancer (not specific to diabetes) treated with progestin and metformin compared to progestin alone in meta-analysesa statistical analysis that combines the results of two or more research studies; the results of smaller research studies addressing the same or similar questions can be analyzed as though they are one bigger, more powerful study of 1 observationala type of study in which individuals are observed or certain outcomes are measured, but no attempt is made to affect the outcome (for example, no treatment is given); an example is a study that records people’s diets, but doesn’t try to alter their diets, and looks for patterns of disease or other outcomes related to different foods study and 1 RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects of moderate quality²¹Chae-Kim J, Garg G et al. Outcomes of women treated with progestin and metformin for atypical endometrial hyperplasia and early endometrial cancer: a systematic review and meta-analysis. International Journal of Gynecological Cancer. 2021 Dec;31(12):1499-1505.

Higher body weight among children exposed to metformin before birth compared to no metformin or to insulin in a meta-analysis of 11 RCTs²²Xu Q, Xie Q. Long-term effects of prenatal exposure to metformin on the health of children based on follow-up studies of randomized controlled trials: a systematic review and meta-analysis. Archives of Gynecology and Obstetrics. 2019 May;299(5):1295-1303. 

Higher risk of birth defects, especially genital defects among male children, among children whose fathers were treated with metformin during the development of fertilizing sperm compared to no metformin in a very large observational study²³Wensink MJ, Lu Y et al. Preconception antidiabetic drugs in men and birth defects in offspring: a nationwide cohort study. Annals of Internal Medicine. 2022 Mar 29.

Do not use (contraindications)

Metformin is not recommended in people with abnormal kidney²⁴Orloff J, Min JY, Mushlin A, Flory J. Safety and effectiveness of metformin in patients with reduced renal function: A systematic review. Diabetes, Obesity & Metabolism. 2021 Sep;23(9):2035-2047. or liver function.²⁵Side effects of metformin. National Health Service. 24 March 2022. Viewed August 11, 2022.

Drug interactions

Many potential drug interactions are associated with metformin. Consult your pharmacist for interactions, and discuss any cautions with your doctor.

Personal story

CancerChoices Senior Clinical Consultant Laura Pole, RN, MSN, OCNS: My colleague, a medical advocate, and I navigated a 50-year-old woman with breast cancer and type 2 diabetes. She takes metformin for her diabetes. She had completed chemotherapy and radiation therapy over a year before working with us, yet still experienced marked fatigue affecting her work and personal life. My colleague ordered a test of her vitamin B₁₂ level, and it came back low. He prescribed B₁₂ injections for her, and within a week her energy came back to pre-chemo levels. For over a year and half her fatigue was blamed on the chemo, when its persistence was likely due to metformin’s effect on her B₁₂ levels.

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