metformin

Metformin is used to lower the blood glucose in those with type{{nbsp}}2 diabetes. It is also used as a second-line agent for infertility in those with polycystic ovary syndrome.{{cite journal | vauthors = Lord JM, Flight IH, Norman RJ | title = Metformin in polycystic ovary syndrome: systematic review and meta-analysis | journal = BMJ | volume = 327 | issue = 7421 | pages = 951–3 | date = October 2003 | pmid = 14576245 | pmc = 259161 | doi = 10.1136/bmj.327.7421.951 }}

The American Diabetes Association and the American College of Physicians both recommend metformin as a first-line agent to treat type{{nbsp}}2 diabetes.{{cite journal | vauthors = Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, Marinopoulos SS, Puhan MA, Ranasinghe P, Block L, Nicholson WK, Hutfless S, Bass EB, Bolen S | title = Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations | journal = Annals of Internal Medicine | volume = 154 | issue = 9 | pages = 602–13 | date = May 2011 | pmid = 21403054 | pmc = 3733115 | doi = 10.7326/0003-4819-154-9-201105030-00336 }}{{cite journal | vauthors = Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR | title = Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) | journal = Diabetes Care | volume = 35 | issue = 6 | pages = 1364–79 | date = June 2012 | pmid = 22517736 | pmc = 3357214 | doi = 10.2337/dc12-0413 }}{{cite journal | vauthors = Qaseem A, Humphrey LL, Sweet DE, Starkey M, Shekelle P | title = Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians | journal = Annals of Internal Medicine | volume = 156 | issue = 3 | pages = 218–31 | date = February 2012 | pmid = 22312141 | doi = 10.7326/0003-4819-156-3-201202070-00011 | doi-access = free | title-link = doi }} It is as effective as repaglinide and more effective than all other oral drugs for type{{nbsp}}2 diabetes.{{cite journal | vauthors = Jia Y, Lao Y, Zhu H, Li N, Leung SW | title = Is metformin still the most efficacious first-line oral hypoglycaemic drug in treating type 2 diabetes? A network meta-analysis of randomized controlled trials | journal = Obesity Reviews | volume = 20 | issue = 1 | pages = 1–12 | date = January 2019 | pmid = 30230172 | doi = 10.1111/obr.12753 | doi-access = free | title-link = doi }}

Treatment guidelines for major professional associations, including the European Association for the Study of Diabetes, the European Society for Cardiology, and the American Diabetes Association, describe evidence for the cardiovascular benefits of metformin as equivocal.{{cite journal | vauthors = Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C, Escaned J, Hammes HP, Huikuri H, Marre M, Marx N, Mellbin L, Ostergren J, Patrono C, Seferovic P, Uva MS, Taskinen MR, Tendera M, Tuomilehto J, Valensi P, Zamorano JL | title = ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD - summary | journal = Diabetes & Vascular Disease Research | volume = 11 | issue = 3 | pages = 133–73 | date = May 2014 | pmid = 24800783 | doi = 10.1177/1479164114525548 | doi-access = free | title-link = doi }} A 2020 Cochrane systematic review did not find enough evidence of reduction of cardiovascular mortality, non-fatal myocardial infarction or non-fatal stroke when comparing metformin monotherapy to other glucose-lowering drugs, behavior change interventions, placebo or no intervention.{{cite journal | vauthors = Gnesin F, Thuesen AC, Kähler LK, Madsbad S, Hemmingsen B | title = Metformin monotherapy for adults with type 2 diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 6 | pages = CD012906 | date = June 2020 | pmid = 32501595 | pmc = 7386876 | doi = 10.1002/14651858.CD012906.pub2 | collaboration = Cochrane Metabolic and Endocrine Disorders Group }}

The use of metformin reduces body weight in people with type{{nbsp}}2 diabetes in contrast to sulfonylureas, which are associated with weight gain.{{cite journal |vauthors=Johansen K |date=January 1999 |title=Efficacy of metformin in the treatment of NIDDM. Meta-analysis |journal=Diabetes Care |volume=22 |issue=1 |pages=33–7 |doi=10.2337/diacare.22.1.33 |pmid=10333900}} Some evidence shows that metformin is associated with weight loss in obesity in the absence of diabetes.{{cite journal | vauthors = Golay A | title = Metformin and body weight | journal = International Journal of Obesity | volume = 32 | issue = 1 | pages = 61–72 | date = January 2008 | pmid = 17653063 | doi = 10.1038/sj.ijo.0803695 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Mead E, Atkinson G, Richter B, Metzendorf MI, Baur L, Finer N, Corpeleijn E, O'Malley C, Ells LJ | title = Drug interventions for the treatment of obesity in children and adolescents | journal = The Cochrane Database of Systematic Reviews | volume = 11 | pages = CD012436 | date = November 2016 | issue = 11 | pmid = 27899001 | pmc = 6472619 | doi = 10.1002/14651858.CD012436 | hdl = 10149/620651 }} Metformin has a lower risk of hypoglycemia than the sulfonylureas, although hypoglycemia has uncommonly occurred during intense exercise, calorie deficit, or when used with other agents to lower blood glucose.{{cite book | vauthors = DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM |title=Pharmacotherapy: a pathophysiologic approach |publisher=McGraw-Hill |location=New York |year=2005 |isbn=978-0-07-141613-9 }}{{cite web | url = http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=18054 | title = Glucophage package insert | archive-url = https://web.archive.org/web/20210829202157/https://dailymed.nlm.nih.gov/dailymed/index.cfm | archive-date=29 August 2021 | location = Princeton, NJ | publisher = Bristol-Myers Squibb Company | date= 2009 | via = DailyMed }} Metformin modestly reduces low density lipoprotein and triglyceride levels.

In individuals with prediabetes, a 2019 systematic review comparing the effects of metformin with other interventions in the reduction of risk of developing type{{nbsp}}2 diabetes found moderate-quality evidence that metformin reduced the risk of developing type{{nbsp}}2 diabetes when compared to diet and exercise or a placebo.{{cite journal |vauthors=Madsen KS, Chi Y, Metzendorf MI, Richter B, Hemmingsen B |date=December 2019 |title=Metformin for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus |journal=The Cochrane Database of Systematic Reviews |volume=2019 |issue=12 |pages=CD008558 |doi=10.1002/14651858.CD008558.pub2 |pmc=6889926 |pmid=31794067 |collaboration=Cochrane Metabolic and Endocrine Disorders Group}} However, when comparing metformin to intensive diet or exercise, moderate-quality evidence was found that metformin did not reduce risk of developing type{{nbsp}}2 diabetes and very low-quality evidence was found that adding metformin to intensive diet or exercise did not show any advantage or disadvantage in reducing risk of type{{nbsp}}2 diabetes when compared to intensive exercise and diet alone. The same review also found one suitable trial comparing the effects of metformin and sulfonylurea in reducing the risk of developing type{{nbsp}}2 diabetes in prediabetic individuals, however, this trial did not report any patient-relevant outcomes.

In those with polycystic ovary syndrome (PCOS), tentative evidence shows that metformin use increases the rate of live births.{{cite journal | vauthors = Morley LC, Tang T, Yasmin E, Norman RJ, Balen AH | title = Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility | journal = The Cochrane Database of Systematic Reviews | volume = 11 | pages = CD003053 | date = November 2017 | issue = 2 | pmid = 29183107 | pmc = 6486196 | doi = 10.1002/14651858.CD003053.pub6 | quote = Our updated review suggests that metformin alone may be beneficial over a placebo for live birth, although the evidence quality was low. }} This includes in those who have not been able to get pregnant with clomiphene.{{cite journal | vauthors = Ghazeeri GS, Nassar AH, Younes Z, Awwad JT | title = Pregnancy outcomes and the effect of metformin treatment in women with polycystic ovary syndrome: an overview | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 91 | issue = 6 | pages = 658–78 | date = June 2012 | pmid = 22375613 | doi = 10.1111/j.1600-0412.2012.01385.x | s2cid = 41145972 | doi-access = free | title-link = doi }} Metformin does not appear to change the risk of miscarriage. A number of other benefits have also been found both during pregnancy and in nonpregnant women with PCOS.{{cite journal | vauthors = Kumar P, Khan K | title = Effects of metformin use in pregnant patients with polycystic ovary syndrome | journal = Journal of Human Reproductive Sciences | volume = 5 | issue = 2 | pages = 166–9 | date = May 2012 | pmid = 23162354 | pmc = 3493830 | doi = 10.4103/0974-1208.101012 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Tay CT, Joham AE, Hiam DS, Gadalla MA, Pundir J, Thangaratinam S, Teede HJ, Moran LJ | title = Pharmacological and surgical treatment of nonreproductive outcomes in polycystic ovary syndrome: An overview of systematic reviews | journal = Clinical Endocrinology | volume = 89 | issue = 5 | pages = 535–553 | date = November 2018 | pmid = 29846959 | doi = 10.1111/cen.13753 | doi-access = free | title-link = doi | hdl = 10536/DRO/DU:30151483 | hdl-access = free }} In an updated Cochrane (2020) review on metformin versus placebo/no treatment before or during IVF/ICSI in women with PCOS no conclusive evidence of improved live birth rates was found.{{cite journal | vauthors = Tso LO, Costello MF, Albuquerque LE, Andriolo RB, Macedo CR | title = Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | pages = CD006105 | date = December 2020 | issue = 12 | pmid = 33347618 | doi = 10.1002/14651858.CD006105.pub4 | pmc = 8171384 }} In long GnRH-agonist protocols there was uncertainty in the evidence of improved live birth rates but there could be increases in clinical pregnancy rate. In short GnRH-antagonist protocols metformin may reduce live birth rates with uncertainty on its effect on clinical pregnancy rate. Metformin may result in a reduction of OHSS but could come with a greater frequency of side effects. There was uncertainty as to metformin's impact on miscarriage. The evidence does not support general use during pregnancy for improving maternal and infant outcomes in obese women.{{cite journal | vauthors = Dodd JM, Grivell RM, Deussen AR, Hague WM | title = Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | pages = CD010564 | date = July 2018 | issue = 7 | pmid = 30039871 | pmc = 6513233 | doi = 10.1002/14651858.CD010564.pub2 }}

The United Kingdom's National Institute for Health and Clinical Excellence recommended in 2004 that women with PCOS and a body mass index above 25 be given metformin for anovulation and infertility when other therapies fail to produce results.{{cite book | author=National Collaborating Centre for Women's and Children's Health | title=Fertility: assessment and treatment for people with fertility problems | location=London | publisher=Royal College of Obstetricians and Gynaecologists | year=2004 | isbn=978-1-900364-97-3 | pages=58–59 | url=http://www.nice.org.uk/nicemedia/pdf/cg011fullguideline.pdf | url-status=live | archive-url=https://web.archive.org/web/20090711000422/http://www.nice.org.uk/nicemedia/pdf/CG011fullguideline.pdf | archive-date=11 July 2009 }} UK and international clinical practice guidelines do not recommend metformin as a first-line treatment{{cite web | vauthors = Balen A |title=Metformin therapy for the management of infertility in women with polycystic ovary syndrome |work=Scientific Advisory Committee Opinion Paper 13 |publisher=Royal College of Obstetricians and Gynaecologists |date=December 2008 |url=http://www.rcog.org.uk/files/rcog-corp/uploaded-files/SAC13metformin-minorrevision.pdf |access-date=13 December 2009 |url-status=dead |archive-url=https://www.webcitation.org/5m73m3kuM?url=http://www.rcog.org.uk/files/rcog-corp/uploaded-files/SAC13metformin-minorrevision.pdf |archive-date=18 December 2009 }} or do not recommend it at all, except for women with glucose intolerance.{{cite journal |author=The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group | title = Consensus on infertility treatment related to polycystic ovary syndrome | journal = Human Reproduction | volume = 23 | issue = 3 | pages = 462–77 | date = March 2008 | pmid = 18308833 | doi = 10.1093/humrep/dem426 | doi-access = free | title-link = doi }} The guidelines suggest clomiphene as the first medication option and emphasize lifestyle modification independently from medical treatment. Metformin treatment decreases the risk of developing type{{nbsp}}2 diabetes in women with PCOS who exhibited impaired glucose tolerance at baseline.{{cite journal | vauthors = Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Economou FN | title = Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome | journal = European Journal of Endocrinology | volume = 162 | issue = 2 | pages = 193–212 | date = February 2010 | pmid = 19841045 | doi = 10.1530/EJE-09-0733 | doi-access = free | title-link = doi }}

A total review of metformin use during pregnancy compared to insulin alone found good short-term safety for both the mother and baby, but safety in the longer term is unclear.{{cite journal | vauthors = Butalia S, Gutierrez L, Lodha A, Aitken E, Zakariasen A, Donovan L | title = Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis | journal = Diabetic Medicine | volume = 34 | issue = 1 | pages = 27–36 | date = January 2017 | pmid = 27150509 | doi = 10.1111/dme.13150 | s2cid = 3418227 }} Several observational studies and randomized controlled trials found metformin to be as effective and safe as insulin for the management of gestational diabetes.{{cite journal | vauthors = Nicholson W, Bolen S, Witkop CT, Neale D, Wilson L, Bass E | title = Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes: a systematic review | journal = Obstetrics and Gynecology | volume = 113 | issue = 1 | pages = 193–205 | date = January 2009 | pmid = 19104375 | doi = 10.1097/AOG.0b013e318190a459 | s2cid = 28115952 }}{{cite journal | vauthors = Kitwitee P, Limwattananon S, Limwattananon C, Waleekachonlert O, Ratanachotpanich T, Phimphilai M, Nguyen TV, Pongchaiyakul C | title = Metformin for the treatment of gestational diabetes: An updated meta-analysis | journal = Diabetes Research and Clinical Practice | volume = 109 | issue = 3 | pages = 521–32 | date = September 2015 | pmid = 26117686 | doi = 10.1016/j.diabres.2015.05.017 }} Nonetheless, several concerns have been raised and evidence on the long-term safety of metformin for both mother and child is lacking.{{cite journal | vauthors = Balsells M, García-Patterson A, Solà I, Roqué M, Gich I, Corcoy R | title = Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis | journal = BMJ | volume = 350 | pages = h102 | date = January 2015 | pmid = 25609400 | pmc = 4301599 | doi = 10.1136/bmj.h102 | type = Systematic Review & Meta-Analysis }} Compared with insulin, women with gestational diabetes treated with metformin gain less weight and are less likely to develop pre‐eclampsia during pregnancy.{{cite journal | vauthors = Alqudah A, McKinley MC, McNally R, Graham U, Watson CJ, Lyons TJ, McClements L | title = Risk of pre-eclampsia in women taking metformin: a systematic review and meta-analysis | journal = Diabetic Medicine | volume = 35 | issue = 2 | pages = 160–172 | date = February 2018 | pmid = 29044702 | doi = 10.1111/dme.13523 | s2cid = 40045912 | hdl = 10453/130987 | url = https://pure.qub.ac.uk/en/publications/8020376c-6e9c-4795-af4b-15441b5773bf | hdl-access = free | archive-date = 29 April 2023 | access-date = 7 April 2023 | archive-url = https://web.archive.org/web/20230429051920/https://pure.qub.ac.uk/en/publications/the-risk-of-pre-eclampsia-in-women-taking-metformin-systematic-re | url-status = live }} Babies born to women treated with metformin have less visceral fat, and this may make them less prone to insulin resistance in later life.{{cite journal | vauthors = Sivalingam VN, Myers J, Nicholas S, Balen AH, Crosbie EJ | title = Metformin in reproductive health, pregnancy and gynaecological cancer: established and emerging indications | journal = Human Reproduction Update | volume = 20 | issue = 6 | pages = 853–68 | year = 2014 | pmid = 25013215 | doi = 10.1093/humupd/dmu037 | doi-access = free | title-link = doi }} The use of metformin for gestational diabetes resulted in smaller babies compared to treatment with insulin. However, despite initially lower birth weight, children exposed to metformin during pregnancy had accelerated growth after birth, and were heavier by mid-childhood than those exposed to insulin during pregnancy. This pattern of initial low birth weight followed by catch-up growth that surpasses comparative children has been associated with long-term cardiometabolic disease.{{cite journal | vauthors = Tarry-Adkins JL, Aiken CE, Ozanne SE | title = Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis | journal = PLOS Medicine | volume = 16 | issue = 8 | pages = e1002848 | date = August 2019 | pmid = 31386659 | pmc = 6684046 | doi = 10.1371/journal.pmed.1002848 | doi-access = free | title-link = doi }}

A systematic review and meta-analysis of metformin, published in 2024, found that it is safe and effective in managing gestational diabetes or diabetes in pregnancy with no adverse impact on the mother or the child after eleven years of childbirth.{{cite journal | vauthors = Dutta D, Sharma M, Nagendra L, Bhattacharya S, Mohindra R, Yajnik CS | title = Long-Term Impact on Offspring (5 to 11 Years of Age) of Metformin Use in Pregnancy in Mothers With Diabetes: A Systematic Review and Meta-Analysis | journal = Endocrine Practice | volume = 30 | issue = 9 | pages = 854–862 | date = September 2024 | pmid = 38876183 | doi = 10.1016/j.eprac.2024.05.017 }}

Metformin use is typically associated with weight loss.{{cite journal | vauthors = Yerevanian A, Soukas AA | title = Metformin: Mechanisms in Human Obesity and Weight Loss | journal = Current Obesity Reports | volume = 8 | issue = 2 | pages = 156–164 | date = June 2019 | pmid = 30874963 | pmc = 6520185 | doi = 10.1007/s13679-019-00335-3 }} It appears to be safe and effective in counteracting the weight gain caused by the antipsychotic medications olanzapine and clozapine.{{cite journal | vauthors = Choi YJ | title = Efficacy of adjunctive treatments added to olanzapine or clozapine for weight control in patients with schizophrenia: a systematic review and meta-analysis | journal = TheScientificWorldJournal | volume = 2015 | pages = 970730 | year = 2015 | pmid = 25664341 | pmc = 4310265 | doi = 10.1155/2015/970730 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Praharaj SK, Jana AK, Goyal N, Sinha VK | title = Metformin for olanzapine-induced weight gain: a systematic review and meta-analysis | journal = British Journal of Clinical Pharmacology | volume = 71 | issue = 3 | pages = 377–82 | date = March 2011 | pmid = 21284696 | pmc = 3045546 | doi = 10.1111/j.1365-2125.2010.03783.x }}{{cite journal | vauthors = Yu O, Lu M, Lai TK, Hahn M, Agarwal SM, O'Donoghue B, Ebdrup BH, Siskind D | title = Metformin co-commencement at time of antipsychotic initiation for attenuation of weight gain: a systematic review and meta-analysis | journal = Therapeutic Advances in Psychopharmacology | volume = 14 | pages = 20451253241255476 | date = 2024 | pmid = 38827016 | doi = 10.1177/20451253241255476 | doi-access = free | pmc = 11141220 }} Although modest reversal of clozapine-associated weight gain is found with metformin, primary prevention of weight gain is more valuable.{{cite journal | vauthors = Siskind DJ, Leung J, Russell AW, Wysoczanski D, Kisely S | title = Metformin for Clozapine Associated Obesity: A Systematic Review and Meta-Analysis | journal = PLOS ONE | volume = 11 | issue = 6 | pages = e0156208 | year = 2016 | pmid = 27304831 | pmc = 4909277 | doi = 10.1371/journal.pone.0156208 | bibcode = 2016PLoSO..1156208S | doi-access = free | title-link = doi }}

Metformin may reduce the insulin requirement in type{{nbsp}}1 diabetes, albeit with an increased risk of hypoglycemia.{{cite journal | vauthors = Vella S, Buetow L, Royle P, Livingstone S, Colhoun HM, Petrie JR | title = The use of metformin in type 1 diabetes: a systematic review of efficacy | journal = Diabetologia | volume = 53 | issue = 5 | pages = 809–20 | date = May 2010 | pmid = 20057994 | doi = 10.1007/s00125-009-1636-9 | doi-access = free | title-link = doi }}

Metformin is contraindicated in people with:

• Severe renal impairment (estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m²){{cite web|date=25 February 2019|title=Metformin: medicine to treat type 2 diabetes|url=https://www.nhs.uk/medicines/metformin/|access-date=15 October 2020|website=National Health Service|archive-date=11 March 2021|archive-url=https://web.archive.org/web/20210311215750/https://www.nhs.uk/medicines/metformin/|url-status=live}}
• Known hypersensitivity to metformin
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis (from uncontrolled diabetes), with or without coma{{cite web|title=METFORMIN HYDROCHLORIDE|url=https://bnf.nice.org.uk/drug/metformin-hydrochloride.html|access-date=15 October 2020|website=NICE|archive-date=10 June 2021|archive-url=https://web.archive.org/web/20210610014142/https://www.nice.org.uk/bnf-uk-only|url-status=live}}

The most common adverse effect of metformin is gastrointestinal irritation, including diarrhea, cramps, nausea, vomiting, and increased flatulence. Metformin is more commonly associated with gastrointestinal adverse effects than most other antidiabetic medications.{{cite journal | vauthors = Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S, Wiley C, Selvin E, Wilson R, Bass EB, Brancati FL | title = Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus | journal = Annals of Internal Medicine | volume = 147 | issue = 6 | pages = 386–399 | date = September 2007 | pmid = 17638715 | doi = 10.7326/0003-4819-147-6-200709180-00178 | title-link = doi | doi-access = free }}{{cite journal | vauthors = Mohamed S | title = Metformin: Diverse molecular mechanisms, gastrointestinal effects and overcoming intolerance in type 2 Diabetes Mellitus: A review | journal = Medicine | volume = 103 | issue = 43 | pages = e40221 | date = October 2024 | pmid = 39470509 | pmc = 11521032 | doi = 10.1097/MD.0000000000040221 }} The most serious potential adverse effect of metformin is lactic acidosis; this complication is rare, and seems to be related to impaired liver or kidney function.{{cite journal | vauthors = Khurana R, Malik IS | title = Metformin: safety in cardiac patients | journal = Heart | volume = 96 | issue = 2 | pages = 99–102 | date = January 2010 | pmid = 19564648 | doi = 10.1136/hrt.2009.173773 | s2cid = 9746741 }}{{cite journal | vauthors = Ahmad R, Haque M | title = Metformin: Beyond Type 2 Diabetes Mellitus | journal = Cureus | volume = 16 | issue = 10 | pages = e71730 | date = October 2024 | pmid = 39421288 | pmc = 11486535 | doi = 10.7759/cureus.71730 | doi-access = free }} Metformin is not approved for use in those with severe kidney disease, but may still be used at lower doses in those with kidney problems.{{cite journal | vauthors = Heaf J | title = Metformin in chronic kidney disease: time for a rethink | journal = Peritoneal Dialysis International | volume = 34 | issue = 4 | pages = 353–357 | date = June 2014 | pmid = 24711640 | pmc = 4079480 | doi = 10.3747/pdi.2013.00344 }}

Gastrointestinal upset can cause severe discomfort; it is most common when metformin is first administered, or when the dose is increased.{{cite journal | vauthors = Nabrdalik K, Hendel M, Irlik K, Kwiendacz H, Łoniewski I, Bucci T, Alam U, Lip GY, Gumprecht J, Skonieczna-Żydecka K | title = Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: a systematic review and meta-analysis with meta-regression of observational studies | journal = BMC Endocrine Disorders | volume = 24 | issue = 1 | pages = 206 | date = September 2024 | pmid = 39350158 | pmc = 11440709 | doi = 10.1186/s12902-024-01727-w | doi-access = free }} The discomfort can often be avoided by beginning at a low dose (1.0 to 1.7 g/day) and increasing the dose gradually, but even with low doses, 5% of people may be unable to tolerate metformin.{{cite journal | vauthors = Fujita Y, Inagaki N | title = Metformin: New Preparations and Nonglycemic Benefits | journal = Current Diabetes Reports | volume = 17 | issue = 1 | pages = 5 | date = January 2017 | pmid = 28116648 | doi = 10.1007/s11892-017-0829-8 | s2cid = 9277684 }} Use of slow or extended-release preparations may improve tolerability.

Long-term use of metformin has been associated with increased homocysteine levels{{cite journal | vauthors = Wulffelé MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, Donker AJ, Stehouwer CD | title = Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial | journal = Journal of Internal Medicine | volume = 254 | issue = 5 | pages = 455–63 | date = November 2003 | pmid = 14535967 | doi = 10.1046/j.1365-2796.2003.01213.x | s2cid = 12507226 | doi-access = free | title-link = doi }} and malabsorption of vitamin B₁₂.{{cite journal | vauthors = Andrès E, Noel E, Goichot B | title = Metformin-associated vitamin B12 deficiency | journal = Archives of Internal Medicine | volume = 162 | issue = 19 | pages = 2251–2 | date = October 2002 | doi = 10.1001/archinte.162.19.2251-a | doi-broken-date = 17 February 2025 | pmid = 12390080 | url = https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/213629 | department = Editor's Correspondence | access-date = 22 January 2024 | archive-date = 10 June 2024 | archive-url = https://web.archive.org/web/20240610053501/https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/213629 | url-status = live }}{{cite journal | vauthors = Gilligan MA | title = Metformin and vitamin B12 deficiency | journal = Archives of Internal Medicine | volume = 162 | issue = 4 | pages = 484–5 | date = February 2002 | doi = 10.1001/archinte.162.4.484 | doi-broken-date = 10 December 2024 | pmid = 11863489 | url = https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/211187 | department = Editor's Correspondence | access-date = 22 January 2024 | archive-date = 1 December 2020 | archive-url = https://web.archive.org/web/20201201214214/https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/211187 | url-status = live }} Higher doses and prolonged use are associated with increased incidence of vitamin B₁₂ deficiency,{{cite journal | vauthors = de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJ, Stehouwer CD | title = Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial | journal = BMJ | volume = 340 | pages = c2181 | date = May 2010 | pmid = 20488910 | pmc = 2874129 | doi = 10.1136/bmj.c2181 }} and some researchers recommend screening or prevention strategies.{{cite journal | vauthors = Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM | title = Risk factors of vitamin B(12) deficiency in patients receiving metformin | journal = Archives of Internal Medicine | volume = 166 | issue = 18 | pages = 1975–9 | date = October 2006 | pmid = 17030830 | doi = 10.1001/archinte.166.18.1975 | doi-access = free | title-link = doi }}

Metformin treatment has been associated with reductions in vitamin B₁₂ in certain people.{{cite journal | vauthors = Ramzan NU, Shahjahan K, Dhillon RA, Khan NT, Hashmat MB, Anwer MU, Ahmed D, Afzal F, Tahir MM, Muzaffar A | title = Vitamin B12 Deficiency in Patients Taking Metformin: Pathogenesis and Recommendations | journal = Cureus | volume = 16 | issue = 9 | pages = e68550 | date = September 2024 | pmid = 39233729 | pmc = 11374140 | doi = 10.7759/cureus.68550 | doi-access = free }} Left untreated, vitamin B12 deficiencies can lead to serious health problems including neurological problems and anemia.{{Cite web |date=2017-10-20 |title=Vitamin B12 or folate deficiency anaemia - Symptoms |url=https://www.nhs.uk/conditions/vitamin-b12-or-folate-deficiency-anaemia/symptoms/ |access-date=2024-11-28 |website=nhs.uk |language=en |archive-date=22 November 2024 |archive-url=https://web.archive.org/web/20241122211355/https://www.nhs.uk/conditions/vitamin-b12-or-folate-deficiency-anaemia/symptoms/ |url-status=live }} Although more research is needed to understand the mechanisms of this association, it is suggested that people who take metformin monitor their vitamin B12 levels and if low, begin supplementation. In most cases of deficiencies if the person's deficiency can be corrected with exogenous administration of vitamin B12, they can continue their metformin treatment under the supervision of their doctor.

Lactic acidosis rarely occurs with metformin exposure during routine medical care.{{cite journal | vauthors = Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B | title = Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes | journal = Diabetologia | volume = 52 | issue = 1 | pages = 17–30 | date = January 2009 | pmid = 18941734 | doi = 10.1007/s00125-008-1157-y | doi-access = free | title-link = doi }} Rates of metformin-associated lactic acidosis are about nine per 100,000 persons/year, which is similar to the background rate of lactic acidosis in the general population.{{cite journal | vauthors = Stang M, Wysowski DK, Butler-Jones D | title = Incidence of lactic acidosis in metformin users | journal = Diabetes Care | volume = 22 | issue = 6 | pages = 925–7 | date = June 1999 | pmid = 10372243 | doi = 10.2337/diacare.22.6.925 }} A systematic review concluded no data exists to definitively link metformin to lactic acidosis.{{cite journal | vauthors = Salpeter SR, Greyber E, Pasternak GA, Salpeter EE | title = Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis | journal = Archives of Internal Medicine | volume = 163 | issue = 21 | pages = 2594–602 | date = November 2003 | pmid = 14638559 | doi = 10.1001/archinte.163.21.2594 | doi-access = free | title-link = doi }}

Metformin is generally safe in people with mild to moderate chronic kidney disease, with a proportional reduction of metformin dose according to severity of estimated glomerular filtration rate (eGFR) and with periodic assessment of kidney function, (e.g., periodic plasma creatinine measurement).{{cite journal | vauthors = Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK | title = Metformin in patients with type 2 diabetes and kidney disease: a systematic review | journal = JAMA | volume = 312 | issue = 24 | pages = 2668–75 | date = 2014 | pmid = 25536258 | pmc = 4427053 | doi = 10.1001/jama.2014.15298 }} The US Food and Drug Administration (FDA) recommends avoiding the use of metformin in more severe chronic kidney disease, below the eGFR cutoff of 30 mL/minute/1.73 m².{{cite web |title=FDA Drug Safety Communication: FDA revises warnings regarding the use of the diabetes medicine metformin in certain patients with reduced kidney function |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-warnings-regarding-use-diabetes-medicine-metformin-certain |website=U.S. Food and Drug Administration (FDA) |access-date=21 December 2018 |date=14 November 2017 |archive-date=25 May 2021 |archive-url=https://web.archive.org/web/20210525210522/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-warnings-regarding-use-diabetes-medicine-metformin-certain |url-status=live }} Lactate uptake by the liver is diminished with metformin use because lactate is a substrate for hepatic gluconeogenesis, a process that metformin inhibits. In healthy individuals, this slight excess is cleared by other mechanisms (including uptake by unimpaired kidneys), and no significant elevation in blood levels of lactate occurs.{{cite book |vauthors=Maharani U |veditors=Papadakis MA, McPhee SJ |chapter=Chapter 27: Diabetes Mellitus & Hypoglycemia |title=Current Medical Diagnosis and Treatment 2010 |edition=49th |publisher=McGraw-Hill Medical |year=2009 |pages=[https://archive.org/details/isbn_9780071624442/page/1092 1092–93] |isbn=978-0-07-162444-2 |url-access=registration |url=https://archive.org/details/isbn_9780071624442/page/1092 }} Given severely impaired kidney function, clearance of metformin and lactate is reduced, increasing levels of both, and possibly causing lactic acid buildup. Because metformin decreases liver uptake of lactate, any condition that may precipitate lactic acidosis is a contraindication. Common causes include alcoholism (due to depletion of NAD+ stores), heart failure, and respiratory disease (due to inadequate tissue oxygenation); the most common cause is kidney disease.{{cite book | vauthors = Shu AD, Myers MG, Shoelson SE | veditors = Golan ED, Tashjian AH, Armstrong EJ, Galanter JM, Armstrong AW, Arnaout RA, Rose HS | chapter=Chapter 29: Pharmacology of the Endocrine Pancreas |title=Principles of pharmacology: the pathophysiologic basis of drug therapy |publisher=Lippincott, Williams & Wilkins |location=Philadelphia |year=2005 |pages=540–41 |isbn=978-0-7817-4678-6}}

Metformin-associated lactate production may also take place in the large intestine, which could potentially contribute to lactic acidosis in those with risk factors.{{cite journal | vauthors = Kirpichnikov D, McFarlane SI, Sowers JR | title = Metformin: an update | journal = Annals of Internal Medicine | volume = 137 | issue = 1 | pages = 25–33 | date = July 2002 | pmid = 12093242 | doi = 10.7326/0003-4819-137-1-200207020-00009 | s2cid = 9140541 }} The clinical significance of this is unknown, though, and the risk of metformin-associated lactic acidosis is most commonly attributed to decreased hepatic uptake rather than increased intestinal production.{{cite book | vauthors = Davis SN | veditors = Brunton L, Lazo J, Parker K |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |edition=11th |year=2006 |publisher=McGraw-Hill |location=New York |isbn=978-0-07-142280-2 |chapter=Chapter 60: Insulin, Oral Hypoglycemic Agents, and the Pharmacology of the Endocrine Pancreas| title-link = Goodman & Gilman's The Pharmacological Basis of Therapeutics }}

The most common symptoms following an overdose include vomiting, diarrhea, abdominal pain, tachycardia, drowsiness, and rarely, hypoglycemia or hyperglycemia.{{cite journal | vauthors = Forrester MB | title = Adult metformin ingestions reported to Texas poison control centers, 2000-2006 | journal = Human & Experimental Toxicology | volume = 27 | issue = 7 | pages = 575–83 | date = July 2008 | pmid = 18829734 | doi = 10.1177/0960327108090589 | bibcode = 2008HETox..27..575F | s2cid = 5413561 | citeseerx = 10.1.1.1031.9486 }}{{cite journal | vauthors = Suchard JR, Grotsky TA | title = Fatal metformin overdose presenting with progressive hyperglycemia | journal = The Western Journal of Emergency Medicine | volume = 9 | issue = 3 | pages = 160–4 | date = August 2008 | pmid = 19561734 | pmc = 2672258 }} Treatment of metformin overdose is generally supportive, as no specific antidote is known. Extracorporeal treatments are recommended in severe overdoses.{{cite journal | vauthors = Calello DP, Liu KD, Wiegand TJ, Roberts DM, Lavergne V, Gosselin S, Hoffman RS, Nolin TD, Ghannoum M | title = Extracorporeal Treatment for Metformin Poisoning: Systematic Review and Recommendations From the Extracorporeal Treatments in Poisoning Workgroup | journal = Critical Care Medicine | volume = 43 | issue = 8 | pages = 1716–30 | date = August 2015 | pmid = 25860205 | doi = 10.1097/CCM.0000000000001002 | s2cid = 13861731 }} Due to metformin's low molecular weight and lack of plasma protein binding, these techniques have the benefit of removing metformin from the blood plasma, preventing further lactate overproduction.

Metformin may be quantified in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning, or assist in a forensic death investigation. Blood or plasma metformin concentrations are usually in a range of 1–4 mg/L in persons receiving therapeutic doses, 40–120 mg/L in victims of acute overdosage, and 80–200 mg/L in fatalities. Chromatographic techniques are commonly employed.{{cite journal | vauthors = Liu A, Coleman SP | title = Determination of metformin in human plasma using hydrophilic interaction liquid chromatography-tandem mass spectrometry | journal = Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences | volume = 877 | issue = 29 | pages = 3695–700 | date = November 2009 | pmid = 19783231 | doi = 10.1016/j.jchromb.2009.09.020 }}R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 939–940.

The risk of metformin-associated lactic acidosis is also increased by a massive overdose of metformin, although even quite large doses are often not fatal.{{cite journal |vauthors=Teale KF, Devine A, Stewart H, Harper NJ |date=July 1998 |title=The management of metformin overdose |journal=Anaesthesia |volume=53 |issue=7 |pages=698–701 |doi=10.1046/j.1365-2044.1998.436-az0549.x |pmid=9771180 |s2cid=45218798 | doi-access = free | title-link = doi }}

The H₂-receptor antagonist cimetidine causes an increase in the plasma concentration of metformin by reducing clearance of metformin by the kidneys;{{cite journal | vauthors = Somogyi A, Stockley C, Keal J, Rolan P, Bochner F |author-link4=Paul Rolan | title = Reduction of metformin renal tubular secretion by cimetidine in man | journal = British Journal of Clinical Pharmacology | volume = 23 | issue = 5 | pages = 545–51 | date = May 1987 | pmid = 3593625 | pmc = 1386190 | doi = 10.1111/j.1365-2125.1987.tb03090.x }} both metformin and cimetidine are cleared from the body by tubular secretion, and both, particularly the cationic (positively charged) form of cimetidine, may compete for the same transport mechanism. A small double-blind, randomized study found the antibiotic cephalexin to also increase metformin concentrations by a similar mechanism;{{cite journal | vauthors = Jayasagar G, Krishna Kumar M, Chandrasekhar K, Madhusudan Rao C, Madhusudan Rao Y | title = Effect of cephalexin on the pharmacokinetics of metformin in healthy human volunteers | journal = Drug Metabolism and Drug Interactions | volume = 19 | issue = 1 | pages = 41–8 | year = 2002 | pmid = 12222753 | doi = 10.1515/dmdi.2002.19.1.41 | s2cid = 26919498 }} theoretically, other cationic medications may produce the same effect.

Metformin also interacts with anticholinergic medications, due to their effect on gastric motility. Anticholinergic drugs reduce gastric motility, prolonging the time drugs spend in the gastrointestinal tract. This impairment may lead to more metformin being absorbed than without the presence of an anticholinergic drug, thereby increasing the concentration of metformin in the plasma and increasing the risk for adverse effects.{{cite journal | vauthors = May M, Schindler C | title = Clinically and pharmacologically relevant interactions of antidiabetic drugs | journal = Therapeutic Advances in Endocrinology and Metabolism | volume = 7 | issue = 2 | pages = 69–83 | date = April 2016 | pmid = 27092232 | pmc = 4821002 | doi = 10.1177/2042018816638050 }}

The molecular mechanism of metformin is not completely understood. Multiple potential mechanisms of action have been proposed: inhibition of the mitochondrial respiratory chain (complex I), activation of AMP-activated protein kinase (AMPK), inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP) with reduced activation of protein kinase A (PKA), complex IV–mediated inhibition of the GPD2 variant of mitochondrial glycerol-3-phosphate dehydrogenase (thereby reducing the contribution of glycerol to hepatic gluconeogenesis), and an effect on gut microbiota.{{cite journal | vauthors = Rena G, Pearson ER, Sakamoto K | title = Molecular mechanism of action of metformin: old or new insights? | journal = Diabetologia | volume = 56 | issue = 9 | pages = 1898–906 | date = September 2013 | pmid = 23835523 | pmc = 3737434 | doi = 10.1007/s00125-013-2991-0 }}{{cite journal | vauthors = Burcelin R | title = The antidiabetic gutsy role of metformin uncovered? | journal = Gut | volume = 63 | issue = 5 | pages = 706–7 | date = May 2014 | pmid = 23840042 | doi = 10.1136/gutjnl-2013-305370 | s2cid = 42142919 }}{{cite journal | vauthors = Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak MJ, Camporez JP, Lee HY, Cline GW, Samuel VT, Kibbey RG, Shulman GI | title = Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase | journal = Nature | volume = 510 | issue = 7506 | pages = 542–6 | date = June 2014 | pmid = 24847880 | pmc = 4074244 | doi = 10.1038/nature13270 | bibcode = 2014Natur.510..542M }}

Metformin exerts an anorexiant effect in most people, decreasing caloric intake. Metformin decreases gluconeogenesis (glucose production) in the liver.{{cite journal | vauthors = Triggle CR, Ding H | title = Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium | journal = Acta Physiologica | volume = 219 | issue = 1 | pages = 138–151 | date = January 2017 | pmid = 26680745 | doi = 10.1111/apha.12644 | s2cid = 312517 }} Metformin inhibits basal secretion from the pituitary gland of growth hormone, adrenocorticotropic hormone, follicle stimulating hormone, and expression of proopiomelanocortin,{{cite journal | vauthors = Vázquez-Borrego MC, Fuentes-Fayos AC, Gahete MD, Castaño JP, Kineman RD, Luque RM | title = The Pituitary Gland is a Novel Major Site of Action of Metformin in Non-Human Primates: a Potential Path to Expand and Integrate Its Metabolic Actions | journal = Cellular Physiology and Biochemistry | volume = 49 | issue = 4 | pages = 1444–1459 | date = 2018 | pmid = 30205369 | doi = 10.1159/000493448 | doi-access = free | title-link = doi }} which in part accounts for its insulin-sensitizing effect with multiple actions on tissues including the liver, skeletal muscle, endothelium, adipose tissue, and the ovaries.{{cite journal | vauthors = Diamanti-Kandarakis E, Economou F, Palimeri S, Christakou C | title = Metformin in polycystic ovary syndrome | journal = Annals of the New York Academy of Sciences | volume = 1205 | issue = 1 | pages = 192–8 | date = September 2010 | pmid = 20840272 | doi = 10.1111/j.1749-6632.2010.05679.x | s2cid = 44203632 | bibcode = 2010NYASA1205..192D }} The average patient with type{{nbsp}}2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one-third.{{cite journal | vauthors = Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, Shulman GI | title = Mechanism by which metformin reduces glucose production in type 2 diabetes | journal = Diabetes | volume = 49 | issue = 12 | pages = 2063–9 | date = December 2000 | pmid = 11118008 | pmc = 2995498 | doi = 10.2337/diabetes.49.12.2063 }}

Activation of AMPK was required for metformin's inhibitory effect on liver glucose production.{{cite journal | vauthors = Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE | title = Role of AMP-activated protein kinase in mechanism of metformin action | journal = The Journal of Clinical Investigation | volume = 108 | issue = 8 | pages = 1167–74 | date = October 2001 | pmid = 11602624 | pmc = 209533 | doi = 10.1172/JCI13505 }} AMPK is an enzyme that plays an important role in insulin signaling, whole-body energy balance, and the metabolism of glucose and fats.{{cite journal | vauthors = Towler MC, Hardie DG | title = AMP-activated protein kinase in metabolic control and insulin signaling | journal = Circulation Research | volume = 100 | issue = 3 | pages = 328–41 | date = February 2007 | pmid = 17307971 | doi = 10.1161/01.RES.0000256090.42690.05 | doi-access = free | title-link = doi }} AMPK activation is required for an increase in the expression of small heterodimer partner, which in turn inhibited the expression of the hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase and glucose 6-phosphatase.{{cite journal | vauthors = Kim YD, Park KG, Lee YS, Park YY, Kim DK, Nedumaran B, Jang WG, Cho WJ, Ha J, Lee IK, Lee CH, Choi HS | title = Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP | journal = Diabetes | volume = 57 | issue = 2 | pages = 306–14 | date = February 2008 | pmid = 17909097 | doi = 10.2337/db07-0381 | doi-access = free | title-link = doi }} Metformin is frequently used in research along with AICA ribonucleotide as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain: metformin increases the concentration of cytosolic adenosine monophosphate (AMP) (as opposed to a change in total AMP or total AMP/adenosine triphosphate) which could activate AMPK allosterically at high levels;{{cite journal | vauthors = Zhang L, He H, Balschi JA | title = Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 293 | issue = 1 | pages = H457-66 | date = July 2007 | pmid = 17369473 | doi = 10.1152/ajpheart.00002.2007 }} a newer theory involves binding to PEN-2.{{cite journal | vauthors = Ma T, Tian X, Zhang B, Li M, Wang Y, Yang C, Wu J, Wei X, Qu Q, Yu Y, Long S, Feng JW, Li C, Zhang C, Xie C, Wu Y, Xu Z, Chen J, Yu Y, Huang X, He Y, Yao L, Zhang L, Zhu M, Wang W, Wang ZC, Zhang M, Bao Y, Jia W, Lin SY, Ye Z, Piao HL, Deng X, Zhang CS, Lin SC | title = Low-dose metformin targets the lysosomal AMPK pathway through PEN2 | journal = Nature | volume = 603 | issue = 7899 | pages = 159–165 | date = March 2022 | pmid = 35197629 | pmc = 8891018 | doi = 10.1038/s41586-022-04431-8 | doi-access = free | title-link = doi | bibcode = 2022Natur.603..159M }} Metformin inhibits cyclic AMP production, blocking the action of glucagon, and thereby reducing fasting glucose levels.{{cite journal | vauthors = Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ | title = Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP | journal = Nature | volume = 494 | issue = 7436 | pages = 256–60 | date = February 2013 | pmid = 23292513 | pmc = 3573218 | doi = 10.1038/nature11808 | bibcode = 2013Natur.494..256M }} Metformin also induces a profound shift in the faecal microbial community profile in diabetic mice, and this may contribute to its mode of action possibly through an effect on glucagon-like peptide-1 secretion.

In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake (by inducing the phosphorylation of GLUT4 enhancer factor), decreases insulin-induced suppression of fatty acid oxidation,{{cite journal | vauthors = Collier CA, Bruce CR, Smith AC, Lopaschuk G, Dyck DJ | title = Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 291 | issue = 1 | pages = E182-9 | date = July 2006 | pmid = 16478780 | doi = 10.1152/ajpendo.00272.2005 }} and decreases the absorption of glucose from the gastrointestinal tract. Increased peripheral use of glucose may be due to improved insulin binding to insulin receptors.{{cite journal | vauthors = Bailey CJ, Turner RC | title = Metformin | journal = The New England Journal of Medicine | volume = 334 | issue = 9 | pages = 574–9 | date = February 1996 | pmid = 8569826 | doi = 10.1056/NEJM199602293340906 }} The increase in insulin binding after metformin treatment has also been demonstrated in patients with type{{nbsp}}2 diabetes.{{cite journal | vauthors = Fantus IG, Brosseau R | title = Mechanism of action of metformin: insulin receptor and postreceptor effects in vitro and in vivo | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 63 | issue = 4 | pages = 898–905 | date = October 1986 | pmid = 3745404 | doi = 10.1210/jcem-63-4-898 }}

AMPK probably also plays a role in increased peripheral insulin sensitivity, as metformin administration increases AMPK activity in skeletal muscle.{{cite journal | vauthors = Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ | title = Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes | journal = Diabetes | volume = 51 | issue = 7 | pages = 2074–2081 | date = July 2002 | pmid = 12086935 | doi = 10.2337/diabetes.51.7.2074 | title-link = doi | doi-access = free }} AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake.{{cite journal | vauthors = Hardie DG, Ross FA, Hawley SA | title = AMPK: a nutrient and energy sensor that maintains energy homeostasis | journal = Nature Reviews. Molecular Cell Biology | volume = 13 | issue = 4 | pages = 251–262 | date = March 2012 | pmid = 22436748 | pmc = 5726489 | doi = 10.1038/nrm3311 }} Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms, however, AMPK likely has a modest overall effect and its activity is not likely to directly decrease gluconeogenesis in the liver.

Metformin has indirect antiandrogenic effects in women with insulin resistance, such as those with PCOS, due to its beneficial effects on insulin sensitivity.{{cite journal | vauthors = Nikolakis G, Kyrgidis A, Zouboulis CC | title = Is There a Role for Antiandrogen Therapy for Hidradenitis Suppurativa? A Systematic Review of Published Data | journal = American Journal of Clinical Dermatology | volume = 20 | issue = 4 | pages = 503–513 | date = August 2019 | pmid = 31073704 | doi = 10.1007/s40257-019-00442-w | s2cid = 149443722 }} It may reduce testosterone levels in such women by as much as 50%. A Cochrane review, though, found that metformin was only slightly effective for decreasing androgen levels in women with PCOS.{{cite journal | vauthors = Luque-Ramírez M, Nattero-Chávez L, Ortiz Flores AE, Escobar-Morreale HF | title = Combined oral contraceptives and/or antiandrogens versus insulin sensitizers for polycystic ovary syndrome: a systematic review and meta-analysis | journal = Human Reproduction Update | volume = 24 | issue = 2 | pages = 225–241 | date = March 2018 | pmid = 29293982 | doi = 10.1093/humupd/dmx039 | doi-access = free | title-link = doi }}

Metformin also has significant effects on the gut microbiome, such as its effect on increasing agmatine production by gut bacteria, but the relative importance of this mechanism compared to other mechanisms is uncertain.{{cite journal | vauthors = Weersma RK, Zhernakova A, Fu J | title = Interaction between drugs and the gut microbiome | journal = Gut | volume = 69 | issue = 8 | pages = 1510–1519 | date = August 2020 | pmid = 32409589 | pmc = 7398478 | doi = 10.1136/gutjnl-2019-320204 | doi-access = free | title-link = doi }}{{cite journal | vauthors = MacNeil LT, Schertzer JD, Steinberg GR | title = Bacteria transmit metformin-associated lifespan extension | journal = Nature Reviews. Endocrinology | volume = 16 | issue = 1 | pages = 9–10 | date = January 2020 | pmid = 31645681 | doi = 10.1038/s41574-019-0278-3 | s2cid = 204836737 }}{{cite journal | vauthors = Jones GR, Molloy MP | title = Metformin, Microbiome and Protection Against Colorectal Cancer | journal = Digestive Diseases and Sciences | date = June 2020 | volume = 66 | issue = 5 | pages = 1409–1414 | pmid = 32533543 | doi = 10.1007/s10620-020-06390-4 | s2cid = 219607625 }}

Due to its effect on GLUT4 and AMPK, metformin has been described as an exercise mimetic.{{cite journal | vauthors = Guerrieri D, Moon HY, van Praag H | title = Exercise in a Pill: The Latest on Exercise-Mimetics | journal = Brain Plasticity | volume = 2 | issue = 2 | pages = 153–169 | date = March 2017 | pmid = 29765854 | pmc = 5928571 | doi = 10.3233/BPL-160043 }}{{cite journal | vauthors = Boulé NG, Robert C, Bell GJ, Johnson ST, Bell RC, Lewanczuk RZ, Gabr RQ, Brocks DR | title = Metformin and exercise in type 2 diabetes: examining treatment modality interactions | journal = Diabetes Care | volume = 34 | issue = 7 | pages = 1469–1474 | date = July 2011 | pmid = 21602430 | pmc = 3120188 | doi = 10.2337/dc10-2207 }}

Metformin has an oral bioavailability of 50–60% under fasting conditions, and is absorbed slowly.{{cite web | title=Glucophage (metformin hydrochloride) tablets, for oral use; Glucophage XR (metformin hydrochloride) extended-release tablets, for oral use Initial U.S. Approval:1995 | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=453104 | access-date=5 March 2023 | archive-date=6 March 2023 | archive-url=https://web.archive.org/web/20230306042913/https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=453104 | url-status=live }}{{cite journal | vauthors = Heller JB |title=Metformin overdose in dogs and cats |journal=Veterinary Medicine |issue=April |year=2007 |pages=231–33 |url=http://www.aspca.org/site/DocServer/vetm0407_231-234.pdf?docID=11061 |url-status=dead |archive-url=https://web.archive.org/web/20071023063354/http://www.aspca.org/site/DocServer/vetm0407_231-234.pdf?docID=11061 |archive-date=23 October 2007 }} Peak plasma concentrations (C_max) are reached within 1–3 hours of taking immediate-release metformin and 4–8 hours with extended-release formulations. The plasma protein binding of metformin is negligible, as reflected by its very high apparent volume of distribution (300–1000 L after a single dose). Steady state is usually reached in 1–2 days.

Metformin has acid dissociation constant values (pK_a) of 2.8 and 11.5, so it exists very largely as the hydrophilic cationic species at physiological pH values. The metformin pK_a values make it a stronger base than most other basic medications with less than 0.01% nonionized in blood. Furthermore, the lipid solubility of the nonionized species is slight as shown by its low logP value (log(10) of the distribution coefficient of the nonionized form between octanol and water) of −1.43. These chemical parameters indicate low lipophilicity and, consequently, rapid passive diffusion of metformin through cell membranes is unlikely. As a result of its low lipid solubility, it requires the transporter SLC22A1 for it to enter cells.{{cite journal | vauthors = Rosilio C, Ben-Sahra I, Bost F, Peyron JF | title = Metformin: a metabolic disruptor and anti-diabetic drug to target human leukemia | journal = Cancer Letters | volume = 346 | issue = 2 | pages = 188–96 | date = May 2014 | pmid = 24462823 | doi = 10.1016/j.canlet.2014.01.006 }}{{cite journal | vauthors = Pryor R, Cabreiro F | title = Repurposing metformin: an old drug with new tricks in its binding pockets | journal = The Biochemical Journal | volume = 471 | issue = 3 | pages = 307–22 | date = November 2015 | pmid = 26475449 | pmc = 4613459 | doi = 10.1042/bj20150497 }} The logP of metformin is less than that of phenformin (−0.84) because two methyl substituents on metformin impart lesser lipophilicity than the larger phenylethyl side chain in phenformin. More lipophilic derivatives of metformin are presently under investigation to produce prodrugs with superior oral absorption than metformin.{{cite journal | vauthors = Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, Williams KM | title = Clinical pharmacokinetics of metformin | journal = Clinical Pharmacokinetics | volume = 50 | issue = 2 | pages = 81–98 | date = February 2011 | pmid = 21241070 | doi = 10.2165/11534750-000000000-00000 | s2cid = 1440441 }}

Metformin is not metabolized. It is cleared from the body by tubular secretion and excreted unchanged in the urine; it is undetectable in blood plasma within 24 hours of a single oral dose. The average elimination half-life in plasma is 6.2 hours. Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours (reported as ranging from 18.5 to 31.5 hours in a single-dose study of nondiabetics).{{cite journal | vauthors = Robert F, Fendri S, Hary L, Lacroix C, Andréjak M, Lalau JD | title = Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects | journal = Diabetes & Metabolism | volume = 29 | issue = 3 | pages = 279–83 | date = June 2003 | pmid = 12909816 | doi = 10.1016/s1262-3636(07)70037-x }}

Some evidence indicates that liver concentrations of metformin in humans may be two to three times higher than plasma concentrations, due to portal vein absorption and first-pass uptake by the liver in oral administration.{{cite journal | vauthors = LaMoia TE, Shulman GI | title = Cellular and Molecular Mechanisms of Metformin Action | journal = Endocrine Reviews | volume = 42 | issue = 1 | pages = 77–96 | date = January 2021 | pmid = 32897388 | pmc = 7846086 | doi = 10.1210/endrev/bnaa023 }}

Metformin hydrochloride (1,1-dimethylbiguanide hydrochloride) is freely soluble in water, slightly soluble in ethanol, but almost insoluble in acetone, ether, or chloroform. The pK_a of metformin is 12.4.{{cite book |doi = 10.1002/0471266949.bmc198|chapter = Diabetes Drugs: Present and Emerging|title = Burger's Medicinal Chemistry and Drug Discovery|year = 2010| vauthors = Tilley J, Grimsby J, Erickson S, Berthel S |pages = 1–38|isbn = 978-0471266945}} The usual synthesis of metformin, originally described in 1922, involves the one-pot reaction of dimethylamine hydrochloride and 2-cyanoguanidine overheat.{{cite journal | vauthors = Shapiro SL, Parrino VA, Freedman L |title=Hypoglycemic Agents. I Chemical Properties of β-Phenethylbiguanide. A New Hypoglycemic Agent |journal=J Am Chem Soc |volume=81 |issue=9 |year=1959 |pages=2220–25 |doi=10.1021/ja01518a052|bibcode=1959JAChS..81.2220S }}

File:Metformin synthesis.svg

According to the procedure described in the 1975 Aron patent,{{cite journal |title=Procédé de préparation de chlorhydrate de diméthylbiguanide |journal=Patent FR 2322860|language=fr|year=1975}} and the Pharmaceutical Manufacturing Encyclopedia,{{cite book |title=Pharmaceutical Manufacturing Encyclopedia (Sittig's Pharmaceutical Manufacturing Encyclopedia) |edition=3rd |volume=3 |publisher=William Andrew |location=Norwich, NY |year=2007 |page=2208 |isbn=978-0-8155-1526-5}} equimolar amounts of dimethylamine and 2-cyanoguanidine are dissolved in toluene with cooling to make a concentrated solution, and an equimolar amount of hydrogen chloride is slowly added. The mixture begins to boil on its own, and after cooling, metformin hydrochloride precipitates with a 96% yield.

{{Anchor|impurities}}

{{See also|Ranitidine#impurities}}

In December 2019, the US Food and Drug Administration (FDA) announced that it learned that some metformin medicines manufactured outside the United States might contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA), classified as a probable human carcinogen, at low levels.{{cite web | title=Statement from Janet Woodcock, M.D., director of FDA's Center for Drug Evaluation and Research, on impurities found in diabetes drugs outside the U.S. | website=U.S. Food and Drug Administration (FDA) | date=5 December 2019 | url=http://www.fda.gov/news-events/press-announcements/statement-janet-woodcock-md-director-fdas-center-drug-evaluation-and-research-impurities-found | access-date=4 February 2020 | archive-date=18 January 2021 | archive-url=https://web.archive.org/web/20210118085409/https://www.fda.gov/news-events/press-announcements/statement-janet-woodcock-md-director-fdas-center-drug-evaluation-and-research-impurities-found | url-status=live }} {{PD-notice}} Health Canada announced that it was assessing NDMA levels in metformin.{{cite web | title=Recalls and safety alerts | website=Health Canada evaluating NDMA in metformin drugs | date=5 December 2019 | url=https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/71831a-eng.php | access-date=4 February 2020 | archive-date=17 April 2020 | archive-url=https://web.archive.org/web/20200417042128/https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/71831a-eng.php | url-status=live }}

In February 2020, the FDA found NDMA levels in some tested metformin samples that did not exceed the acceptable daily intake.{{cite web | title=Laboratory Tests - Metformin | website=U.S. Food and Drug Administration (FDA) | date=3 February 2020 | url=http://www.fda.gov/drugs/drug-safety-and-availability/laboratory-tests-metformin | access-date=4 February 2020 | archive-date=25 February 2020 | archive-url=https://web.archive.org/web/20200225004129/https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-tests-metformin | url-status=live }}{{cite web | title=FDA Updates and Press Announcements on NDMA in Metformin | website=U.S. Food and Drug Administration (FDA) | date=4 February 2020 | url=http://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-metformin | access-date=4 February 2020 | archive-date=25 February 2020 | archive-url=https://web.archive.org/web/20200225004121/https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-metformin | url-status=live }}

In February 2020, Health Canada announced a recall of Apotex immediate-release metformin,{{cite web |title=APO-Metformin (2020-02-04) |url=https://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/72281r-eng.php |publisher=Health Canada |access-date=2 June 2020 |date=4 February 2020 |archive-date=27 December 2020 |archive-url=https://web.archive.org/web/20201227043036/https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/72281r-eng.php |url-status=live }} followed in March by recalls of Ranbaxy metformin{{cite web |title=Ranbaxy Metformin Product Recall (2020-02-26) |url=https://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/72455r-eng.php/ |publisher=Health Canada |access-date=2 June 2020 |date=26 February 2020 |archive-date=26 November 2020 |archive-url=https://web.archive.org/web/20201126035657/https://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/72455r-eng.php |url-status=live }} and in March by Jamp metformin.{{cite web |title=Jamp-Metformin Product Recall (2020-03-10) |url=https://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/72565r-eng.php/ |publisher=Health Canada |access-date=2 June 2020 |date=10 March 2020 |archive-date=26 November 2020 |archive-url=https://web.archive.org/web/20201126043337/https://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/72565r-eng.php |url-status=live }}

In May 2020, the FDA asked five companies to voluntarily recall their sustained-release metformin products.{{cite press release |title=FDA Alerts Patients and Health Care Professionals to Nitrosamine Impurity Findings in Certain Metformin Extended-Release Products |url=https://www.fda.gov/news-events/press-announcements/fda-alerts-patients-and-health-care-professionals-nitrosamine-impurity-findings-certain-metformin |publisher=U.S. Food and Drug Administration (FDA) |access-date=2 June 2020 |date=28 May 2020 |archive-date=22 March 2021 |archive-url=https://web.archive.org/web/20210322105358/https://www.fda.gov/news-events/press-announcements/fda-alerts-patients-and-health-care-professionals-nitrosamine-impurity-findings-certain-metformin |url-status=live }}{{cite web | title=Questions and Answers: NDMA impurities in metformin products | website=U.S. Food and Drug Administration (FDA) | date=28 May 2020 | url=https://www.fda.gov/drugs/drug-safety-and-availability/questions-and-answers-ndma-impurities-metformin-products | access-date=5 June 2020 | archive-date=2 March 2021 | archive-url=https://web.archive.org/web/20210302090352/https://www.fda.gov/drugs/drug-safety-and-availability/questions-and-answers-ndma-impurities-metformin-products | url-status=live }}{{cite web | title=Amneal Pharmaceuticals LLC Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended Release Tablets, USP, 500 mg and 750 mg, Due to Detection of N-Nitrosodimethylamine (NDMA) Impurity | website=U.S. Food and Drug Administration (FDA) | date=29 May 2020 | url=https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/amneal-pharmaceuticals-llc-issues-voluntary-nationwide-recall-metformin-hydrochloride-extended | access-date=2 June 2020 | archive-date=16 January 2021 | archive-url=https://web.archive.org/web/20210116131122/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/amneal-pharmaceuticals-llc-issues-voluntary-nationwide-recall-metformin-hydrochloride-extended | url-status=live }}{{cite web | title=Apotex Corp. Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets 500mg Due to the Detection of N-nitrosodimethylamine (NDMA) | website=U.S. Food and Drug Administration (FDA) | date=27 May 2020 | url=https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/apotex-corp-issues-voluntary-nationwide-recall-metformin-hydrochloride-extended-release-tablets | access-date=2 June 2020 | archive-date=4 March 2021 | archive-url=https://web.archive.org/web/20210304023938/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/apotex-corp-issues-voluntary-nationwide-recall-metformin-hydrochloride-extended-release-tablets | url-status=live }}{{cite web | title=Teva Pharmaceuticals USA, Inc. Initiates Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets USP 500 mg and 750 mg Due to Detection of N-Nitrosodimethylamine (NDMA) | website=U.S. Food and Drug Administration (FDA) | date=2 June 2020 | url=https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/teva-pharmaceuticals-usa-inc-initiates-voluntary-nationwide-recall-metformin-hydrochloride-extended | access-date=5 June 2020 | archive-date=21 January 2021 | archive-url=https://web.archive.org/web/20210121160530/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/teva-pharmaceuticals-usa-inc-initiates-voluntary-nationwide-recall-metformin-hydrochloride-extended | url-status=live }}{{cite web | title=Marksans Pharma Limited Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets, USP 500mg, Due to the Detection of N-Nitrosodimethylamine (NDMA) | website=U.S. Food and Drug Administration (FDA) | date=2 June 2020 | url=https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/marksans-pharma-limited-issues-voluntary-nationwide-recall-metformin-hydrochloride-extended-release | access-date=5 June 2020 | archive-date=23 January 2021 | archive-url=https://web.archive.org/web/20210123205407/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/marksans-pharma-limited-issues-voluntary-nationwide-recall-metformin-hydrochloride-extended-release | url-status=live }} The five companies were not named, but they were revealed to be Amneal Pharmaceuticals, Actavis Pharma, Apotex Corp, Lupin Pharma, and Marksans Pharma Limited in a letter sent to Valisure, the pharmacy that had first alerted the FDA to this contaminant in metformin via a Citizen Petition.{{cite web |vauthors=Cavazzoni P |author-link1=Patrizia Cavazzoni |title=Re: Docket No. FDA-2020-P-0978 |url=https://downloads.regulations.gov/FDA-2020-P-0978-0007/attachment_1.pdf |publisher=U.S. Food and Drug Administration (FDA) |access-date=2 June 2020 |date=28 May 2020 |archive-date=8 February 2021 |archive-url=https://web.archive.org/web/20210208080851/https://downloads.regulations.gov/FDA-2020-P-0978-0007/attachment_1.pdf |url-status=live }}

In June 2020, the FDA posted its laboratory results showing NDMA amounts in metformin products it tested. It found NDMA in certain lots of ER metformin and is recommending companies recall lots with levels of NDMA above the acceptable intake limit of 96 nanograms per day. The FDA is also collaborating with international regulators to share testing results for metformin.{{cite web | title=Laboratory Tests - Metformin | website=U.S. Food and Drug Administration (FDA) | date=5 June 2020 | url=https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-tests-metformin | access-date=5 June 2020 | archive-date=22 April 2021 | archive-url=https://web.archive.org/web/20210422093108/https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-tests-metformin | url-status=live }} {{PD-notice}}

In July 2020, Lupin Pharmaceuticals pulled all lots (batches) of metformin after discovering unacceptably high levels of NDMA in tested samples.{{cite press release|publisher=Lupin Pharmaceuticals Inc|title=Lupin Pharmaceuticals, Inc. Issues Voluntarily Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets, 500mg and 1000mg Due to the Detection of N-Nitrosodimethylamine (NDMA) Impurity|url=https://www.prnewswire.com/news-releases/lupin-pharmaceuticals-inc-issues-voluntarily-nationwide-recall-of-metformin-hydrochloride-extended-release-tablets-500mg-and-1000mg-due-to-the-detection-of--n-nitrosodimethylamine-ndma-impurity-301089754.html|access-date=9 July 2020|via=PR Newswire|archive-date=9 June 2021|archive-url=https://web.archive.org/web/20210609205427/https://www.prnewswire.com/news-releases/lupin-pharmaceuticals-inc-issues-voluntarily-nationwide-recall-of-metformin-hydrochloride-extended-release-tablets-500mg-and-1000mg-due-to-the-detection-of--n-nitrosodimethylamine-ndma-impurity-301089754.html|url-status=live}}

In August 2020, Bayshore Pharmaceuticals recalled two lots of tablets.{{cite web | title=Bayshore Pharmaceuticals, LLC Issues Voluntary Nationwide Recall of Metformin Hydrochloride Extended-Release Tablets USP, 500 mg and 750 mg Due to the Detection of N-Nitrosodimethylamine (NDMA) Impurity | website=U.S. Food and Drug Administration (FDA) | date=19 August 2020 | url=https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/bayshore-pharmaceuticals-llc-issues-voluntary-nationwide-recall-metformin-hydrochloride-extended | access-date=25 August 2020 | archive-date=19 December 2020 | archive-url=https://web.archive.org/web/20201219234633/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/bayshore-pharmaceuticals-llc-issues-voluntary-nationwide-recall-metformin-hydrochloride-extended | url-status=live }}

The FDA issued revised guidelines about nitrosamine impurities in September 2024.{{cite web | title=Control of Nitrosamine Impurities in Human Drugs | website=U.S. Food and Drug Administration | date=24 February 2021 | url=https://www.fda.gov/regulatory-information/search-fda-guidance-documents/control-nitrosamine-impurities-human-drugs | access-date=6 September 2024 | archive-date=1 June 2022 | archive-url=https://web.archive.org/web/20220601224600/https://www.fda.gov/regulatory-information/search-fda-guidance-documents/control-nitrosamine-impurities-human-drugs | url-status=live }}

File:Galega officinalis1UME.jpg is a natural source of galegine.]]

The biguanide class of antidiabetic medications, which also includes the withdrawn agents phenformin and buformin, originates from the plant Goat's rue (Galega officinalis) also known as Galega, French lilac, Italian fitch, Spanish sainfoin, Pestilenzkraut, or Professor-weed. (The plant should not be confused with plants in the genus Tephrosia which are highly toxic and sometimes also called Goat's rue.) Galega officinalis has been used in folk medicine for several centuries.{{cite journal | vauthors = Witters LA | title = The blooming of the French lilac | journal = The Journal of Clinical Investigation | volume = 108 | issue = 8 | pages = 1105–7 | date = October 2001 | pmid = 11602616 | pmc = 209536 | doi = 10.1172/JCI14178 }} G. officinalis itself does not contain biguanide medications which are chemically synthesized compounds composed of two guanidine molecules and designed to be less toxic than the plant-derived parent compounds guanidine and galegine (isoamylene guanidine).

Metformin was first described in the scientific literature in 1922, by Emil Werner and James Bell, as a product in the synthesis of N,N-dimethylguanidine.{{cite journal |vauthors=Werner E, Bell J |title=The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyandiamide, and methylammonium and dimethylammonium chlorides respectively |journal=J. Chem. Soc., Trans. |volume=121 |pages=1790–95 |year=1922 |doi=10.1039/CT9222101790 |url=https://zenodo.org/record/1860743 |access-date=4 September 2020 |archive-date=8 June 2021 |archive-url=https://web.archive.org/web/20210608133134/https://zenodo.org/record/1860743 |url-status=live }} In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, finding it the most potent biguanide analog they studied.See Chemical Abstracts, v.23, 42772 (1929) {{cite journal | vauthors = Slotta KH, Tschesche R|title= Über Biguanide, II.: Die blutzucker-senkende Wirkung der Biguanide|journal= Berichte der Deutschen Chemischen Gesellschaft (A and B Series)|volume=62|issue= 6|pages=1398–1405 |year=1929 |doi=10.1002/cber.19290620605}} This result was ignored, as other guanidine analogs such as the synthalins, took over and were themselves soon overshadowed by insulin.{{cite journal | veditors = Campbell IW |title=Metformin – life begins at 50: A symposium held on the occasion of the 43rd Annual Meeting of the European Association for the Study of Diabetes, Amsterdam, the Netherlands, September 2007|journal=The British Journal of Diabetes & Vascular Disease|volume=7|issue=5|pages=247–52 |date=September 2007|doi=10.1177/14746514070070051001 }}

Interest in metformin resumed at the end of the 1940s. In 1950, metformin, unlike some other similar compounds, was found not to decrease blood pressure and heart rate in animals.{{cite journal | vauthors = Dawes GS, Mott JC | title = Circulatory and respiratory reflexes caused by aromatic guanidines | journal = British Journal of Pharmacology and Chemotherapy | volume = 5 | issue = 1 | pages = 65–76 | date = March 1950 | pmid = 15405470 | pmc = 1509951 | doi = 10.1111/j.1476-5381.1950.tb00578.x }} That year, Filipino physician Eusebio Y. GarciaAbout Eusebio Y. Garcia, see: {{cite web |url=http://sntpost.stii.dost.gov.ph/frames/aprtojun05/Search_for_DOST_NRCP_13to14.htm |title=Search for DOST-NRCP Dr. Eusebio Y. Garcia Award |vauthors=Carteciano J |date=2005 |publisher=Philippines Department of Science and Technology |access-date=5 December 2009 |url-status=dead |archive-url=https://web.archive.org/web/20091024075832/http://sntpost.stii.dost.gov.ph/frames/aprtojun05/Search_for_DOST_NRCP_13to14.htm |archive-date=24 October 2009 }} used metformin (he named it Fluamine) to treat influenza; he noted the medication "lowered the blood sugar to minimum physiological limit" and was not toxic. Garcia believed metformin to have bacteriostatic, antiviral, antimalarial, antipyretic, and analgesic actions.Quoted from Chemical Abstracts, v.45, 24828 (1951) {{cite journal | vauthors = Garcia EY | title = Flumamine, a new synthetic analgesic and anti-flu drug | journal = Journal of the Philippine Medical Association | volume = 26 | issue = 7 | pages = 287–93 | date = July 1950 | pmid = 14779282 }} In a series of articles in 1954, Polish pharmacologist Janusz SupniewskiAbout Janusz Supniewski, see: {{cite journal | vauthors = Wołkow PP, Korbut R | title = Pharmacology at the Jagiellonian University in Kracow, short review of contribution to global science and cardiovascular research through 400 years of history | journal = Journal of Physiology and Pharmacology | volume = 57 | issue = Suppl 1 | pages = 119–136 | date = April 2006 | pmid = 16766803 | url = http://www.jpp.krakow.pl/journal/archive/0406_s1/pdf/119_0406_s1_article.pdf | url-status = dead | access-date = 22 December 2009 | archive-url = https://web.archive.org/web/20091024211218/http://www.jpp.krakow.pl/journal/archive/0406_s1/pdf/119_0406_s1_article.pdf | archive-date = 24 October 2009 }} was unable to confirm most of these effects, including lowered blood sugar. Instead, he observed antiviral effects in humans.See Chemical Abstracts, v. 52, 22272 (1958) {{cite journal | vauthors = Supniewski J, Chrusciel T | title = [N-dimethyl-di-guanide and its biological properties] | language = pl | journal = Archivum Immunologiae et Therapiae Experimentalis | volume = 2 | pages = 1–15 | year = 1954 | pmid = 13269290 }}Quoted from Chemical Abstracts, v.49, 74699 (1955) {{cite journal | vauthors = Supniewski J, Krupinska J |title=[Effect of biguanide derivatives on experimental cowpox in rabbits] |language=fr |journal=Bulletin de l'Académie Polonaise des Sciences, Classe 3: Mathématique, Astronomie, Physique, Chimie, Géologie et Géographie |volume=2(Classe II) |pages=161–65 |year=1954}}

French diabetologist Jean Sterne studied the antihyperglycemic properties of galegine, an alkaloid isolated from G. officinalis, which is related in structure to metformin, and had seen brief use as an antidiabetic before the synthalins were developed.{{cite journal | vauthors = Bailey CJ, Day C |title=Metformin: its botanical background |journal=Practical Diabetes International |volume=21 |issue=3 |pages=115–17 |year=2004 |doi=10.1002/pdi.606 |s2cid=208203689 |doi-access=free }} Later, working at Laboratoires Aron in Paris, he was prompted by Garcia's report to reinvestigate the blood sugar-lowering activity of metformin and several biguanide analogs. Sterne was the first to try metformin on humans for the treatment of diabetes; he coined the name "Glucophage" (glucose eater) for the medication and published his results in 1957.

Metformin became available in the British National Formulary in 1958. It was sold in the UK by a small Aron subsidiary called Rona.{{cite journal | vauthors = Hadden DR | title = Goat's rue - French lilac - Italian fitch - Spanish sainfoin: gallega officinalis and metformin: the Edinburgh connection | journal = The Journal of the Royal College of Physicians of Edinburgh | volume = 35 | issue = 3 | pages = 258–60 | date = October 2005 | doi = 10.1177/1478271520053503010 | pmid = 16402501 | url = http://www.rcpe.ac.uk/journal/issue/journal_35_3/hadden_goats%20rue.pdf | access-date = 21 December 2009 | archive-date = 25 October 2020 | archive-url = https://web.archive.org/web/20201025214723/http://www.rcpe.ac.uk/journal/issue/journal_35_3/hadden_goats%20rue.pdf | url-status = live }}

Broad interest in metformin was not rekindled until the withdrawal of the other biguanides in the 1970s. Metformin was approved in Canada in 1972,{{cite journal | vauthors = Lucis OJ | title = The status of metformin in Canada | journal = Canadian Medical Association Journal | volume = 128 | issue = 1 | pages = 24–6 | date = January 1983 | pmid = 6847752 | pmc = 1874707 }} but did not receive approval by the U.S. Food and Drug Administration (FDA) for type{{nbsp}}2 diabetes until 1994.{{cite press release |title=FDA Approves New Diabetes Drug |date=30 December 1994 |publisher=U.S. Food and Drug Administration (FDA) |access-date=6 January 2007 |url=https://www.fda.gov/bbs/topics/ANSWERS/ANS00627.html |archive-url=https://web.archive.org/web/20070929152824/https://www.fda.gov/bbs/topics/ANSWERS/ANS00627.html |archive-date=29 September 2007 |url-status=dead }} Produced under license by Bristol-Myers Squibb, Glucophage was the first branded formulation of metformin to be marketed in the U.S., beginning on 3 March 1995.{{cite web | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/020357Orig1s000rev.pdf | title=Drug Approval Package: Glucophage (metformin) | website=U.S. Food and Drug Administration (FDA) | archive-url=https://web.archive.org/web/20200205051949/https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/020357Orig1s000rev.pdf | archive-date=5 February 2020 | url-status=live | access-date=8 January 2007}} Generic formulations are available in several countries.

The US FDA granted the application for metformin orphan drug designation.{{cite web | title=Metformin Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=432214 | access-date=15 September 2024 | archive-date=15 September 2024 | archive-url=https://web.archive.org/web/20240915044140/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=432214 | url-status=live }}{{cite web | title=Metformin Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=616117 | access-date=15 September 2024}} The European Medicines Agency granted orphan drug status to metformin.{{cite web | title=EU/3/16/1803 - orphan designation for treatment of progressive myoclonic epilepsy type 2 (Lafora disease) | website=European Medicines Agency (EMA) | date=12 December 2016 | url=https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-16-1803 | access-date=15 September 2024 | archive-date=15 September 2024 | archive-url=https://web.archive.org/web/20240915044135/https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-16-1803 | url-status=live }}

Metformin and its major transformation product {{ill|guanylurea|de|Guanylharnstoff}} are present in wastewater treatment plant effluents and regularly detected in surface waters. Guanylurea concentrations above 200 μg/L have been measured in the German river Erpe, which are amongst the highest reported for pharmaceutical transformation products in aquatic environments.{{cite journal | vauthors = Posselt M, Jaeger A, Schaper JL, Radke M, Benskin JP | title = Determination of polar organic micropollutants in surface and pore water by high-resolution sampling-direct injection-ultra high performance liquid chromatography-tandem mass spectrometry | journal = Environmental Science: Processes & Impacts | volume = 20 | issue = 12 | pages = 1716–1727 | date = December 2018 | pmid = 30350841 | doi = 10.1039/C8EM00390D | doi-access = free | title-link = doi }}

{{anchor|Formulations}}

File:Metformin 500mg Tablets.jpg

Metformin is the British Approved Name (BAN), the United States Adopted Name (USAN), and the International Nonproprietary Name (INN). It is sold under several brand names. Common brand names include Glucophage, Riomet, Fortamet, and Glumetza in the US.{{cite journal | vauthors = Christofides EA | title = Practical Insights Into Improving Adherence to Metformin Therapy in Patients With Type 2 Diabetes | journal = Clinical Diabetes | volume = 37 | issue = 3 | pages = 234–241 | date = July 2019 | pmid = 31371854 | pmc = 6640881 | doi = 10.2337/cd18-0063 }} In other areas of the world, there is also Obimet, Gluformin, Dianben, Diabex, Diaformin, Metsol, Siofor, Metfogamma and Glifor.{{cite journal | vauthors = Kaushik D, Karnes RJ, Eisenberg MS, Rangel LJ, Carlson RE, Bergstralh EJ | title = Effect of metformin on prostate cancer outcomes after radical prostatectomy | journal = Urologic Oncology | volume = 32 | issue = 1 | pages = 43.e1–7 | date = January 2014 | pmid = 23810664 | pmc = 4006350 | doi = 10.1016/j.urolonc.2013.05.005 }}{{cite web|title=Metformin|url=https://www.drugs.com/international/metformin.html|access-date=17 July 2020|website=Drugs.com|archive-date=28 November 2020|archive-url=https://web.archive.org/web/20201128083113/https://www.drugs.com/international/Metformin.html|url-status=live}} There are several formulations of metformin available on the market, and all but the liquid form have generic equivalents.

When used for type{{nbsp}}2 diabetes, metformin is often prescribed in combination with other medications. Several medications are available as fixed-dose combinations, with the potential to reduce pill burden, decrease cost, and simplify administration.{{cite journal | vauthors = Bailey CJ, Day C | title = Fixed-dose single tablet antidiabetic combinations | journal = Diabetes, Obesity & Metabolism | volume = 11 | issue = 6 | pages = 527–33 | date = June 2009 | pmid = 19175373 | doi = 10.1111/j.1463-1326.2008.00993.x | s2cid = 6569131 }}{{cite journal | vauthors = Sheehan MT | title = Current therapeutic options in type 2 diabetes mellitus: a practical approach | journal = Clinical Medicine & Research | volume = 1 | issue = 3 | pages = 189–200 | date = July 2003 | pmid = 15931309 | pmc = 1069045 | doi = 10.3121/cmr.1.3.189 }}

{{anchor|Rosiglitazone}}

A combination of metformin and rosiglitazone was released in 2002, and sold as Avandamet by GlaxoSmithKline,{{cite web | title=Drug Approval Package: Avandamet (rosiglitazone maleate/metformin HCL) NDA #021410 | website=U.S. Food and Drug Administration (FDA) | date=30 April 2003 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/021410_avandamet.cfm | access-date=10 June 2024 | archive-date=10 June 2024 | archive-url=https://web.archive.org/web/20240610053501/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/021410_avandamet.cfm | url-status=live }}{{cite press release|title=FDA Approves GlaxoSmithKline's Avandamet (rosiglitazone maleate and metformin HCl), The Latest Advancement in the Treatment of Type 2 Diabetes|publisher=GlaxoSmithKline|date=12 October 2002|access-date=27 December 2006|url=http://www.docguide.com/news/content.nsf/news/8525697700573E1885256C4F0075B2B3|url-status=live|archive-url=https://web.archive.org/web/20070121050431/http://www.docguide.com/news/content.nsf/news/8525697700573E1885256C4F0075B2B3|archive-date=21 January 2007}} or as a generic medication.{{cite web|title=Drugs@FDA: FDA-Approved Drugs|url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=077337|access-date=21 July 2020|website=U.S. Food and Drug Administration (FDA)|archive-date=21 March 2021|archive-url=https://web.archive.org/web/20210321033724/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=077337|url-status=live}} Formulations are 500/1, 500/2, 500/4, 1000/2, and 1000 mg/4 mg of metformin/rosiglitazone.

In 2009, it was the most popular metformin combination.{{cite web |url= http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/252010/674969/article.pdf |title= 2009 Top 200 branded drugs by total prescriptions |url-status=dead |archive-url= https://web.archive.org/web/20110714111215/http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/252010/674969/article.pdf |archive-date= 14 July 2011 }} {{small|(96.5 KB)}}. Drug Topics (17 June 2010). Retrieved 2 September 2010.

In 2005, the stock of Avandamet was removed from the market, after inspections showed the factory where it was produced was violating good manufacturing practices.{{cite press release |title=Questions and Answers about the Seizure of Paxil CR and Avandamet |publisher=U.S. Food and Drug Administration (FDA) |date=4 March 2005 |access-date=27 December 2006 |url=https://www.fda.gov/oc/qanda/PaxilandAvandamet.html |archive-url=https://web.archive.org/web/20071014014507/https://www.fda.gov/oc/qanda/PaxilandAvandamet.html |archive-date=14 October 2007 |url-status=dead }} The medication pair continued to be prescribed separately, and Avandamet was again available by the end of that year. A generic formulation of metformin/rosiglitazone from Teva received tentative approval from the FDA and reached the market in early 2012.{{cite web |url=https://www.reuters.com/article/inPlayBriefing/idUSIN20070927170530TEVA20070927 |title=Teva Pharm announces settlement of generic Avandia, Avandamet, and Avandaryl litigation with GlaxoSmithKline |publisher=Reuters |date=27 September 2007 |access-date=17 February 2009 |archive-date=3 May 2021 |archive-url=https://web.archive.org/web/20210503040949/https://www.reuters.com/article/inPlayBriefing/idUSIN20070927170530TEVA20070927 |url-status=live }}

However, following a meta-analysis in 2007, that linked the medication's use to an increased risk of heart attack,{{cite journal | vauthors = Nissen SE, Wolski K | title = Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes | journal = The New England Journal of Medicine | volume = 356 | issue = 24 | pages = 2457–71 | date = June 2007 | pmid = 17517853 | doi = 10.1056/NEJMoa072761 | doi-access = free | title-link = doi }} concerns were raised over the safety of medicines containing rosiglitazone. In September 2010, the European Medicines Agency recommended that the medication be suspended from the European market because the benefits of rosiglitazone no longer outweighed the risks.{{cite press release | url = https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-suspension-avandia-avandamet-avaglim | publisher = European Medicines Agency (EMA) | title = European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim | url-status=live | archive-url = https://web.archive.org/web/20150924052044/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fnews_and_events%2Fnews%2F2010%2F09%2Fnews_detail_001119.jsp&murl=menus%2Fnews_and_events%2Fnews_and_events.jsp&mid=WC0b01ac058004d5c1&jsenabled=false | archive-date = 24 September 2015 | date = 23 September 2010 }}{{cite news | url = https://www.bbc.co.uk/news/health-11397645 | work = BBC News Online | title = Call to 'suspend' diabetes drug | date = 23 September 2010 | url-status=live | archive-url = https://web.archive.org/web/20100924044603/http://www.bbc.co.uk/news/health-11397645 | archive-date = 24 September 2010 }}

It was withdrawn from the market in the UK and India in 2010,{{cite web|url=http://cdsco.nic.in/html/drugsbanned.html |title=Drugs banned in India |publisher=Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India |access-date=17 September 2013 |url-status=dead |archive-url=https://web.archive.org/web/20150221053621/http://cdsco.nic.in/html/drugsbanned.html |archive-date=21 February 2015 }} and in New Zealand and South Africa in 2011.{{cite news |url=http://www.stuff.co.nz/4669573 |title=Diabetes drug withdrawn |date=17 February 2011 |agency=NZPA |work=Stuff.co.nz |access-date=5 November 2011 |archive-date=13 October 2013 |archive-url=https://web.archive.org/web/20131013121141/http://www.stuff.co.nz/4669573 |url-status=dead }} From November 2011 until November 2013 the FDA{{cite news | url = https://www.nytimes.com/2010/02/20/health/policy/20avandia.html | title = Controversial Diabetes Drug Harms Heart, U.S. Concludes | vauthors = Harris G | work = The New York Times | date = 19 February 2010 | url-status=live | archive-url = https://web.archive.org/web/20170319173917/http://www.nytimes.com/2010/02/20/health/policy/20avandia.html | archive-date = 19 March 2017 }} did not allow rosiglitazone or metformin/rosiglitazone to be sold without a prescription; moreover, makers were required to notify patients of the risks associated with its use, and the drug had to be purchased by mail order through specified pharmacies.{{cite web | title=Updated Risk Evaluation and Mitigation Strategy (REMS) | website=U.S. Food and Drug Administration (FDA) | date=1 July 2021 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-updated-risk-evaluation-and-mitigation-strategy-rems-restrict-access | access-date=6 March 2023 | archive-date=6 March 2023 | archive-url=https://web.archive.org/web/20230306001836/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-updated-risk-evaluation-and-mitigation-strategy-rems-restrict-access | url-status=live }}{{cite web | title=FDA Drug Safety Communication: FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines | website=U.S. Food and Drug Administration (FDA) | date=21 June 2019 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-requires-removal-some-prescribing-and-dispensing-restrictions | access-date=6 March 2023 | archive-date=4 September 2022 | archive-url=https://web.archive.org/web/20220904175732/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-requires-removal-some-prescribing-and-dispensing-restrictions | url-status=live }}

In November 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of the 2009 RECORD clinical trial (a six-year, open-label randomized control trial), which failed to show elevated risk of heart attack or death associated with the medication.{{cite news | url = https://www.bloomberg.com/news/2013-11-25/glaxo-s-avandia-cleared-from-sales-restrictions-by-fda.html | title = Glaxo's Avandia Cleared From Sales Restrictions by FDA | publisher = Bloomberg | url-status=live | archive-url = https://web.archive.org/web/20141109083451/http://www.bloomberg.com/news/2013-11-25/glaxo-s-avandia-cleared-from-sales-restrictions-by-fda.html | archive-date = 9 November 2014 }}{{cite press release | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376516.htm | title = FDA requires removal of certain restrictions on the diabetes drug Avandia | date = 25 November 2013 | website = U.S. Food and Drug Administration (FDA) | url-status=dead | archive-url = https://web.archive.org/web/20150504051733/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376516.htm | archive-date = 4 May 2015 }}{{cite web|url=http://blogs.nature.com/news/2013/11/fda-reverses-stance-on-controversial-diabetes-drug.html|title=US agency reverses stance on controversial diabetes drug|url-status=live|archive-url=https://web.archive.org/web/20151211005224/http://blogs.nature.com/news/2013/11/fda-reverses-stance-on-controversial-diabetes-drug.html|archive-date=11 December 2015}}

{{anchor|Pioglitazone}}

The combination of metformin and pioglitazone (Actoplus Met, Piomet, Politor, Glubrava) is available in the US and the European Union.{{cite web | title=Glubrava EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/glubrava | access-date=31 March 2020 | archive-date=9 June 2021 | archive-url=https://web.archive.org/web/20210609205516/https://www.ema.europa.eu/en/medicines/human/EPAR/glubrava | url-status=live }}{{cite web | title=Competact EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/competact | access-date=31 March 2020 | archive-date=9 June 2021 | archive-url=https://web.archive.org/web/20210609205507/https://www.ema.europa.eu/en/medicines/human/EPAR/competact | url-status=live }}{{cite web | title=Pioglitazone (marketed as Actos, Actoplus Met, Duetact, and Oseni) Information | website=U.S. Food and Drug Administration (FDA) | date=11 January 2017 | url=http://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/pioglitazone-marketed-actos-actoplus-met-duetact-and-oseni-information | access-date=31 March 2020 | archive-date=17 January 2021 | archive-url=https://web.archive.org/web/20210117062857/https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/pioglitazone-marketed-actos-actoplus-met-duetact-and-oseni-information | url-status=live }}{{cite web | title=FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function | website=U.S. Food and Drug Administration (FDA) | date=3 April 2013 | url=http://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-warnings-regarding-use-diabetes-medicine-metformin-certain | access-date=31 March 2020 | archive-date=25 May 2021 | archive-url=https://web.archive.org/web/20210525210522/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-warnings-regarding-use-diabetes-medicine-metformin-certain | url-status=live }}{{cite web | title=FDA Drug Safety Communication: Updated FDA review concludes that use of type 2 diabetes medicine pioglitazone may be linked to an increased risk of bladder cancer | website=U.S. Food and Drug Administration (FDA) | date=4 August 2011 | url=http://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-updated-fda-review-concludes-use-type-2-diabetes-medicine-pioglitazone | access-date=31 March 2020 | archive-date=26 January 2021 | archive-url=https://web.archive.org/web/20210126071751/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-updated-fda-review-concludes-use-type-2-diabetes-medicine-pioglitazone | url-status=live }}

{{anchor|DPP-4 inhibitors}}

{{see also|GLP-1 receptor agonist}}

Dipeptidyl peptidase-4 inhibitors inhibit dipeptidyl peptidase-4 and thus reduce glucagon and blood glucose levels.

DPP-4 inhibitors combined with metformin include a sitagliptin/metformin combination (Janumet),{{cite web | title=Janumet- sitagliptin and metformin hydrochloride tablet, film coated | website=DailyMed | date=12 August 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d19c7ed0-ad5c-426e-b2df-722508f97d67 | access-date=15 May 2020 | archive-date=9 June 2021 | archive-url=https://web.archive.org/web/20210609205430/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d19c7ed0-ad5c-426e-b2df-722508f97d67 | url-status=live }}{{cite web | title=Janumet EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/janumet | access-date=15 May 2020 | archive-date=9 June 2021 | archive-url=https://web.archive.org/web/20210609205518/https://www.ema.europa.eu/en/medicines/human/EPAR/janumet | url-status=live }} a saxagliptin/metformin combination (Kombiglyze XR, Komboglyze),{{cite web | title=Kombiglyze XR- saxagliptin and metformin hydrochloride tablet, film coated, extended release | website=DailyMed | date=24 October 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fbd25da4-ebe6-45c9-beb8-93523d11a0b4 | access-date=15 May 2020 | archive-date=25 September 2020 | archive-url=https://web.archive.org/web/20200925063920/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fbd25da4-ebe6-45c9-beb8-93523d11a0b4 | url-status=live }}{{cite web | title=Komboglyze EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/komboglyze | access-date=15 May 2020 | archive-date=30 October 2020 | archive-url=https://web.archive.org/web/20201030073719/https://www.ema.europa.eu/en/medicines/human/EPAR/komboglyze | url-status=live }} and an alogliptin/metformin combination (Kazano, Vipdomet).{{cite web | title=Kazano- alogliptin and metformin hydrochloride tablet, film coated | website=DailyMed | date=14 June 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=83cb7914-a683-47bb-a713-f2bc6a596bd2 | access-date=15 May 2020 | archive-date=9 June 2021 | archive-url=https://web.archive.org/web/20210609205508/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=83cb7914-a683-47bb-a713-f2bc6a596bd2 | url-status=live }}{{cite web | title=Vipdomet EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/vipdomet | access-date=15 May 2020 | archive-date=9 June 2021 | archive-url=https://web.archive.org/web/20210609205455/https://www.ema.europa.eu/en/medicines/human/EPAR/vipdomet | url-status=live }}

Linagliptin combined with metformin hydrochloride is sold under the brand name Jentadueto.{{cite web | title=Jentadueto EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/jentadueto | access-date=31 March 2020 | archive-date=9 June 2021 | archive-url=https://web.archive.org/web/20210609205529/https://www.ema.europa.eu/en/medicines/human/EPAR/jentadueto | url-status=live }}{{cite web | title=Jentadueto- linagliptin and metformin hydrochloride tablet, film coated | website=DailyMed | date=18 July 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6dd9b86-0d18-95d4-2bc7-05591bfdd597 | access-date=31 March 2020 | archive-date=9 June 2021 | archive-url=https://web.archive.org/web/20210609205429/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6dd9b86-0d18-95d4-2bc7-05591bfdd597 | url-status=live }}{{cite web | title=Jentadueto XR- linagliptin and metformin hydrochloride tablet, film coated, extended release | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3d02a4d4-d312-80b4-05c4-691b8f0aa7aa | access-date=4 October 2021 | archive-date=5 October 2021 | archive-url=https://web.archive.org/web/20211005014130/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3d02a4d4-d312-80b4-05c4-691b8f0aa7aa | url-status=live }} As of August 2021, linagliptin/metformin is available as a generic medicine in the US.{{cite web | title=Linagliptin and Metformin Hydrochloride: FDA-Approved Drugs | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=208336 | access-date=24 September 2021 | archive-date=25 September 2021 | archive-url=https://web.archive.org/web/20210925023954/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=208336 | url-status=live }}

There are combinations of metformin with the SGLT2 inhibitors dapagliflozin, empagliflozin, and canagliflozin.

Sulfonylureas act by increasing insulin release from the beta cells in the pancreas.{{cite journal | vauthors = Grant JS, Graven LJ | title = Progressing From Metformin to Sulfonylureas or Meglitinides | language = en-US | journal = Workplace Health & Safety | volume = 64 | issue = 9 | pages = 433–9 | date = September 2016 | pmid = 27621259 | doi = 10.1177/2165079916644263 | doi-access = free | title-link = doi }}

A 2019 systematic review suggested that there is limited evidence if the combined use of metformin with sulfonylurea compared to the combination of metformin plus another glucose-lowering intervention, provides benefit or harm in mortality, severe adverse events, macrovascular and microvascular complications.{{cite journal | vauthors = Madsen KS, Kähler P, Kähler LK, Madsbad S, Gnesin F, Metzendorf MI, Richter B, Hemmingsen B | title = Metformin and second- or third-generation sulphonylurea combination therapy for adults with type 2 diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | volume = 4 | issue = 4 | pages = CD012368 | date = April 2019 | pmid = 30998259 | pmc = 6472662 | doi = 10.1002/14651858.CD012368.pub2 | collaboration = Cochrane Metabolic and Endocrine Disorders Group }} Combined metformin and sulfonylurea therapy did appear to lead to a higher risk of hypoglycemia.

Metformin is available combined with the sulfonylureas glipizide (Metaglip) and glibenclamide (US: glyburide) (Glucovance). Generic formulations of metformin/glipizide and metformin/glibenclamide are available (the latter is more popular).{{cite web |url= http://www.imshealth.com/deployedfiles/imshealth/Global/Content/IMS%20Institute/Static%20File/IHII_UseOfMed_report.pdf |title= The Use of Medicines in the United States: Review of 2010 |url-status=live |archive-url= https://web.archive.org/web/20110422165905/http://www.imshealth.com/deployedfiles/imshealth/Global/Content/IMS%20Institute/Static%20File/IHII_UseOfMed_report.pdf |archive-date= 22 April 2011 }} {{small|(1.79 MB)}}. IMS Institute for Healthcare Informatics (April 2011). Retrieved 28 April 2011.

Meglitinides are similar to sulfonylureas, as they bind to beta cells in the pancreas, but differ by the site of binding to the intended receptor and the drugs' affinities to the receptor. As a result, they have a shorter duration of action compared to sulfonylureas and require higher blood glucose levels to begin to secrete insulin. Both meglitinides, known as nateglinide and repanglinide, are sold in formulations combined with metformin. A repaglinide/metformin combination is sold as Prandimet, or as its generic equivalent.{{cite web|title=Drug Approval Package: PrandiMet (repaglinide/metformin HCI fixed-dose combination) NDA 22386|url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022386_prandimet_toc.cfm|access-date=21 July 2020|website=U.S. Food and Drug Administration (FDA)|archive-date=21 July 2020|archive-url=https://web.archive.org/web/20200721152208/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022386_prandimet_toc.cfm|url-status=live}}{{cite web|title=Drugs@FDA: FDA-Approved Drugs|url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=200624|access-date=21 July 2020|website=U.S. Food and Drug Administration (FDA) |archive-date=22 July 2020|archive-url=https://web.archive.org/web/20200722002042/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=200624|url-status=live}}

The combination of metformin with dapagliflozin and saxagliptin is available in the United States as Qternmet XR.{{cite web | title=Drug Approval Package: Qternmet XR | website=U.S. Food and Drug Administration (FDA) | date=27 January 2020 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/210874Orig1s000TOC.cfm | access-date=10 June 2024 | archive-date=17 February 2020 | archive-url=https://web.archive.org/web/20200217083231/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/210874Orig1s000TOC.cfm | url-status=live }}{{cite web | title=Qternmet XR (dapagliflozin, saxagliptin, and metformin hydrochloride) extended-release tablets, for oral use Initial U.S. Approval: 2019 | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=567183 | access-date=5 March 2023 | archive-date=6 March 2023 | archive-url=https://web.archive.org/web/20230306042913/https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=567183 | url-status=live }}

The combination of metformin with pioglitazone and glibenclamide{{cite journal | vauthors = Panikar V, Chandalia HB, Joshi SR, Fafadia A, Santvana C | title = Beneficial effects of triple drug combination of pioglitazone with glibenclamide and metformin in type 2 diabetes mellitus patients on insulin therapy | journal = The Journal of the Association of Physicians of India | volume = 51 | pages = 1061–4 | date = November 2003 | pmid = 15260389 | s2cid = 22085315 }} is available in India as Accuglim-MP, Adglim MP, and Alnamet-GP; and in the Philippines as Tri-Senza.

The combination of metformin with pioglitazone and lipoic acid is available in Turkey as Pional.

Metformin is a pleiotropic drug, with extensive off-target activity beyond its antidiabetic effect. Much of this has been attributed to its action on AMPK, although other mechanisms have been proposed.{{cite journal |vauthors=Dutta S, Shah RB, Singhal S, Dutta SB, Bansal S, Sinha S, Haque M |title=Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes |journal=Drug Des Devel Ther |volume=17 |issue= |pages=1907–1932 |date=2023 |pmid=37397787 |pmc=10312383 |doi=10.2147/DDDT.S409373 |doi-access=free }}{{cite journal |vauthors=Froldi G |title=View on Metformin: Antidiabetic and Pleiotropic Effects, Pharmacokinetics, Side Effects, and Sex-Related Differences |journal=Pharmaceuticals |volume=17 |issue=4 |date=April 2024 |page=478 |pmid=38675438 |pmc=11054066 |doi=10.3390/ph17040478|doi-access=free }} Metformin has been studied for its effects on multiple other conditions, including:

• Non-alcoholic fatty liver disease{{cite journal | vauthors = Jalali M, Rahimlou M, Mahmoodi M, Moosavian SP, Symonds ME, Jalali R, Zare M, Imanieh MH, Stasi C | title = The effects of metformin administration on liver enzymes and body composition in non-diabetic patients with non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis: An up-to date systematic review and meta-analysis of randomized controlled trials | journal = Pharmacological Research | volume = 159 | pages = 104799 | date = September 2020 | pmid = 32278041 | doi = 10.1016/j.phrs.2020.104799 | s2cid = 215741792 }}{{cite journal | vauthors = Blazina I, Selph S | title = Diabetes drugs for nonalcoholic fatty liver disease: a systematic review | journal = Systematic Reviews | volume = 8 | issue = 1 | pages = 295 | date = November 2019 | pmid = 31783920 | pmc = 6884753 | doi = 10.1186/s13643-019-1200-8 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L | title = Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis | journal = World Journal of Gastroenterology | volume = 24 | issue = 30 | pages = 3361–3373 | date = August 2018 | pmid = 30122876 | pmc = 6092580 | doi = 10.3748/wjg.v24.i30.3361 | doi-access = free | title-link = doi }}
• Premature puberty{{cite journal | vauthors = Ibáñez L, Ong K, Valls C, Marcos MV, Dunger DB, de Zegher F | title = Metformin treatment to prevent early puberty in girls with precocious pubarche | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 91 | issue = 8 | pages = 2888–91 | date = August 2006 | pmid = 16684823 | doi = 10.1210/jc.2006-0336 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Ibáñez L, López-Bermejo A, Díaz M, Marcos MV, de Zegher F | title = Early metformin therapy (age 8-12 years) in girls with precocious pubarche to reduce hirsutism, androgen excess, and oligomenorrhea in adolescence | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 96 | issue = 8 | pages = E1262-7 | date = August 2011 | pmid = 21632811 | doi = 10.1210/jc.2011-0555 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Ibáñez L, Díaz R, López-Bermejo A, Marcos MV | title = Clinical spectrum of premature pubarche: links to metabolic syndrome and ovarian hyperandrogenism | journal = Reviews in Endocrine & Metabolic Disorders | volume = 10 | issue = 1 | pages = 63–76 | date = March 2009 | pmid = 18726694 | doi = 10.1007/s11154-008-9096-y | s2cid = 9129907 }}
• Cancer{{cite journal | vauthors = Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F | title = Metformin in cancer therapy: a new perspective for an old antidiabetic drug? | journal = Molecular Cancer Therapeutics | volume = 9 | issue = 5 | pages = 1092–9 | date = May 2010 | pmid = 20442309 | doi = 10.1158/1535-7163.MCT-09-1186 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Malek M, Aghili R, Emami Z, Khamseh ME | title = Risk of cancer in diabetes: the effect of metformin | journal = ISRN Endocrinology | volume = 2013 | pages = 636927 | date = September 2013 | pmid = 24224094 | pmc = 3800579 | doi = 10.1155/2013/636927 | doi-access = free | title-link = doi }}
• Cardiovascular disease in people with diabetes{{cite journal | vauthors = Campbell JM, Bellman SM, Stephenson MD, Lisy K | title = Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis | journal = Ageing Research Reviews | volume = 40 | pages = 31–44 | date = November 2017 | pmid = 28802803 | doi = 10.1016/j.arr.2017.08.003 | s2cid = 20334490 }}
• Aging{{cite journal | vauthors = Soukas AA, Hao H, Wu L | title = Metformin as Anti-Aging Therapy: Is It for Everyone? | journal = Trends in Endocrinology and Metabolism | volume = 30 | issue = 10 | pages = 745–755 | date = October 2019 | pmid = 31405774 | pmc = 6779524 | doi = 10.1016/j.tem.2019.07.015 }}{{cite journal |vauthors=Novelle MG, Ali A, Diéguez C, Bernier M, de Cabo R |date=March 2016 |title=Metformin: A Hopeful Promise in Aging Research |journal=Cold Spring Harbor Perspectives in Medicine |volume=6 |issue=3 |pages=a025932 |doi=10.1101/cshperspect.a025932 |pmc=4772077 |pmid=26931809}}

No evidence shows that metformin extends the human lifespan.{{cn|date=January 2025}} Despite that, metformin has received substantial interest as an agent that delays aging; it has been shown to increase longevity in some animal models (e.g., C. elegans and crickets).{{cite journal | vauthors = Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA | title = Metformin as a Tool to Target Aging | journal = Cell Metabolism | volume = 23 | issue = 6 | pages = 1060–1065 | date = June 2016 | pmid = 27304507 | pmc = 5943638 | doi = 10.1016/j.cmet.2016.05.011 }} This effect may be mediated by insulin and carbohydrate regulation, similar to its effects on diabetes.{{cite journal |vauthors=Kulkarni AS, Gubbi S, Barzilai N |date=July 2020 |title=Benefits of Metformin in Attenuating the Hallmarks of Aging |journal=Cell Metabolism |volume=32 |issue=1 |pages=15–30 |doi=10.1016/j.cmet.2020.04.001 |pmc=7347426 |pmid=32333835}} Whether metformin may help extend life, even in otherwise healthy people, remains unknown; a 2021 review of the literature found it is likely to improve healthspan, i.e., the number of years spent in good health, rather than lifespan overall.{{cite journal |vauthors=Mohammed I, Hollenberg MD, Ding H, Triggle CR |date=2021 |title=A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan |journal=Frontiers in Endocrinology |volume=12 |issue= |pages=718942 |doi=10.3389/fendo.2021.718942 |pmc=8374068 |pmid=34421827 |doi-access=free |title-link=doi}}

A 2017 review found that people with diabetes who were taking metformin had lower all-cause mortality. They also had reduced cancer and cardiovascular disease compared with those on other therapies. In people without diabetes, metformin does not appear to reduce the risk of cancer and cardiovascular disease.{{cite journal | vauthors = Lee CG, Heckman-Stoddard B, Dabelea D, Gadde KM, Ehrmann D, Ford L, Prorok P, Boyko EJ, Pi-Sunyer X, Wallia A, Knowler WC, Crandall JP, Temprosa M | title = Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study | journal = Diabetes Care | volume = 44 | issue = 12 | pages = 2775–2782 | date = December 2021 | pmid = 34697033 | pmc = 8669534 | doi = 10.2337/dc21-1046 | doi-access = free | title-link = doi }}

The potential anticancer effects of metformin are believed to be mediated through multiple pathways, particularly involving AMPK activation and IGF-1R modulation.{{Citation needed|date=November 2024}} Research has focused particularly on stomach cancer, with evidence of protective impact (reducing the risk of cancer) and improving survival rates among patients in whom cancer has already developed.{{cite journal | vauthors = Zhang J, Wen L, Zhou Q, He K, Teng L | title = Preventative and Therapeutic Effects of Metformin in Gastric Cancer: A New Contribution of an Old Friend | language = English | journal = Cancer Management and Research | volume = 12 | pages = 8545–8554 | date = 16 September 2020 | pmid = 32982447 | pmc = 7505710 | doi = 10.2147/CMAR.S264032 | doi-access = free | title-link = doi }} Despite promising findings, evidence is still preliminary and there is no consensus on its preventive and therapeutic role.{{Cite web |vauthors=Sharma A |date=29 October 2023 |title=The Role of Metformin in Gastric Cancer Treatment |url=https://thewitfire.in/2023/10/29/the-role-of-metformin-in-gastric-cancer-treatment/ |access-date=3 November 2023 |website=Witfire |language=en-US |archive-date=3 November 2023 |archive-url=https://web.archive.org/web/20231103085807/https://thewitfire.in/2023/10/29/the-role-of-metformin-in-gastric-cancer-treatment/ |url-status=live }}

A study found a benefit using metformin to reduce the occurrence of long COVID.{{cite journal | vauthors = Bramante CT, Buse JB, Liebovitz DM, Nicklas JM, Puskarich MA, Cohen K, Belani HK, Anderson BJ, Huling JD, Tignanelli CJ, Thompson JL, Pullen M, Wirtz EL, Siegel LK, Proper JL, Odde DJ, Klatt NR, Sherwood NE, Lindberg SM, Karger AB, Beckman KB, Erickson SM, Fenno SL, Hartman KM, Rose MR, Mehta T, Patel B, Griffiths G, Bhat NS, Murray TA, Boulware DR | title = Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial | journal = The Lancet. Infectious Diseases | volume = 23 | issue = 10 | pages = 1119–1129 | date = October 2023 | pmid = 37302406 | doi = 10.1016/S1473-3099(23)00299-2 | doi-access = free | title-link = doi | pmc = 11259948 }}{{cite journal | vauthors = Wise J | title = Covid-19: Metformin reduces the risk of developing long term symptoms by 40%, study finds | journal = BMJ (Clinical Research Ed.) | volume = 381 | issue = | pages = 1306 | date = June 2023 | pmid = 37290779 | doi = 10.1136/bmj.p1306 }}{{cite journal | vauthors = Bramante CT, Huling JD, Tignanelli CJ, Buse JB, Liebovitz DM, Nicklas JM, Cohen K, Puskarich MA, Belani HK, Proper JL, Siegel LK, Klatt NR, Odde DJ, Luke DG, Anderson B, Karger AB, Ingraham NE, Hartman KM, Rao V, Hagen AA, Patel B, Fenno SL, Avula N, Reddy NV, Erickson SM, Lindberg S, Fricton R, Lee S, Zaman A, Saveraid HG, Tordsen WJ, Pullen MF, Biros M, Sherwood NE, Thompson JL, Boulware DR, Murray TA | title = Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19 | journal = The New England Journal of Medicine | volume = 387 | issue = 7 | pages = 599–610 | date = August 2022 | pmid = 36070710 | pmc = 9945922 | doi = 10.1056/NEJMoa2201662 }}{{cite journal | title=COVID-OUT: Early Outpatient Treatment for SARS-CoV-2 Infection (COVID-19) | website=ClinicalTrials.gov | date=13 May 2024 | url=https://classic.clinicaltrials.gov/ct2/show/NCT04510194 | access-date=9 June 2024 | archive-date=9 June 2024 | archive-url=https://web.archive.org/web/20240609054010/https://classic.clinicaltrials.gov/ct2/show/NCT04510194 | url-status=live }}

It is unclear if there is a reduced risk of death using metformin to treat people with COVID-19.{{cite journal | vauthors = Li Y, Yang X, Yan P, Sun T, Zeng Z, Li S | title = Metformin in Patients With COVID-19: A Systematic Review and Meta-Analysis | journal = Frontiers in Medicine | volume = 8 | issue = | pages = 704666 | date = 2021 | pmid = 34490296 | pmc = 8416892 | doi = 10.3389/fmed.2021.704666 | doi-access = free }}{{cite journal | vauthors = Ibrahim S, Lowe JR, Bramante CT, Shah S, Klatt NR, Sherwood N, Aronne L, Puskarich M, Tamariz L, Palacio A, Bomberg E, Usher M, King S, Benson B, Vojta D, Tignanelli C, Ingraham N | title = Metformin and Covid-19: Focused Review of Mechanisms and Current Literature Suggesting Benefit | journal = Frontiers in Endocrinology | volume = 12 | issue = | pages = 587801 | date = 2021 | pmid = 34367059 | pmc = 8342037 | doi = 10.3389/fendo.2021.587801 | doi-access = free }}{{cite journal | vauthors = Bramante CT, Ingraham NE, Murray TA, Marmor S, Hovertsen S, Gronski J, McNeil C, Feng R, Guzman G, Abdelwahab N, King S, Tamariz L, Meehan T, Pendleton KM, Benson B, Vojta D, Tignanelli CJ | title = Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis | journal = The Lancet. Healthy Longevity | volume = 2 | issue = 1 | pages = e34–e41 | date = January 2021 | pmid = 33521772 | pmc = 7832552 | doi = 10.1016/S2666-7568(20)30033-7 }}

There has been extensive research into the potential neuroprotective effects of metformin in developmental and neurodegenerative diseases, including Alzheimer's disease and other dementias, Parkinson's disease, Huntington's disease, certain types of epilepsy, and fragile X syndrome, with mixed results.{{cite journal | vauthors = Gantois I, Popic J, Khoutorsky A, Sonenberg N | title = Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders | journal = Annual Review of Medicine | volume = 70 | pages = 167–181 | date = January 2019 | pmid = 30365357 | doi = 10.1146/annurev-med-081117-041238 | s2cid = 53093694 | url = https://escholarship.mcgill.ca/concern/articles/2j62s977h | access-date = 9 October 2022 | archive-date = 6 March 2023 | archive-url = https://web.archive.org/web/20230306042913/https://escholarship.mcgill.ca/concern/articles/2j62s977h | url-status = live | doi-access = free | title-link = doi }}

Preliminary studies have examined whether metformin can reduce the risk of Alzheimer's disease and whether there is a correlation between type{{nbsp}}2 diabetes and the risk of Alzheimer's disease.{{cite journal | vauthors = Campbell JM, Stephenson MD, de Courten B, Chapman I, Bellman SM, Aromataris E | title = Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis | journal = Journal of Alzheimer's Disease | volume = 65 | issue = 4 | pages = 1225–1236 | year = 2018 | pmid = 30149446 | doi = 10.3233/jad-180263 | pmc = 6218120 }}{{cite journal | vauthors = Campbell JM, Stephenson MD, de Courten B, Chapman I, Bellman SM, Aromataris E | title = Metformin and Alzheimer's disease, dementia and cognitive impairment: a systematic review protocol | journal = JBI Database of Systematic Reviews and Implementation Reports | volume = 15 | issue = 8 | pages = 2055–2059 | date = August 2017 | pmid = 28800055 | doi = 10.11124/JBISRIR-2017-003380 }}

While metformin may reduce body weight in persons with fragile X syndrome, whether it improves neurological or psychiatric symptoms is uncertain.

A derivative HL156A, also known as IM156, is a potential new drug for medical use.{{cite journal | vauthors = Lam TG, Jeong YS, Kim SA, Ahn SG | title = New metformin derivative HL156A prevents oral cancer progression by inhibiting the insulin-like growth factor/AKT/mammalian target of rapamycin pathways | journal = Cancer Science | volume = 109 | issue = 3 | pages = 699–709 | date = March 2018 | pmid = 29285837 | pmc = 5834796 | doi = 10.1111/cas.13482 }}{{cite journal | vauthors = Tsogbadrakh B, Ju KD, Lee J, Han M, Koh J, Yu Y, Lee H, Yu KS, Oh YK, Kim HJ, Ahn C, Oh KH | title = HL156A, a novel pharmacological agent with potent adenosine-monophosphate-activated protein kinase (AMPK) activator activity ameliorates renal fibrosis in a rat unilateral ureteral obstruction model | journal = PLOS ONE | volume = 13 | issue = 8 | pages = e0201692 | date = 2018 | pmid = 30161162 | pmc = 6116936 | doi = 10.1371/journal.pone.0201692 | bibcode = 2018PLoSO..1301692T | doi-access = free | title-link = doi }}{{cite journal | vauthors = Jeong YS, Lam TG, Jeong S, Ahn SG | title = Metformin Derivative HL156A Reverses Multidrug Resistance by Inhibiting HOXC6/ERK1/2 Signaling in Multidrug-Resistant Human Cancer Cells | journal = Pharmaceuticals | volume = 13 | issue = 9 | pages = 218 | date = August 2020 | pmid = 32872293 | doi = 10.3390/ph13090218 | pmc = 7560051 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Kim SA, Lam TG, Yook JI, Ahn SG | title = Antioxidant modifications induced by the new metformin derivative HL156A regulate metabolic reprogramming in SAMP1/kl (-/-) mice | journal = Aging | volume = 10 | issue = 9 | pages = 2338–2355 | date = September 2018 | pmid = 30222592 | pmc = 6188477 | doi = 10.18632/aging.101549 }}{{cite journal | vauthors = Choi J, Lee JH, Koh I, Shim JK, Park J, Jeon JY, Yun M, Kim SH, Yook JI, Kim EH, Chang JH, Kim SH, Huh YM, Lee SJ, Pollak M, Kim P, Kang SG, Cheong JH | title = Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A) | journal = Oncotarget | volume = 7 | issue = 40 | pages = 65643–65659 | date = October 2016 | pmid = 27582539 | pmc = 5323181 | doi = 10.18632/oncotarget.11595 }}{{cite journal | vauthors = Ju KD, Kim HJ, Tsogbadrakh B, Lee J, Ryu H, Cho EJ, Hwang YH, Kim K, Yang J, Ahn C, Oh KH | title = HL156A, a novel AMP-activated protein kinase activator, is protective against peritoneal fibrosis in an in vivo and in vitro model of peritoneal fibrosis | journal = American Journal of Physiology. Renal Physiology | volume = 310 | issue = 5 | pages = F342-50 | date = March 2016 | pmid = 26661649 | doi = 10.1152/ajprenal.00204.2015 | doi-access = free | title-link = doi }}

{{Reflist}}

{{refbegin}}

• {{cite journal | vauthors = Markowicz-Piasecka M, Huttunen KM, Mateusiak L, Mikiciuk-Olasik E, Sikora J | title = Is Metformin a Perfect Drug? Updates in Pharmacokinetics and Pharmacodynamics | journal = Current Pharmaceutical Design | volume = 23 | issue = 17 | pages = 2532–2550 | date = 2017 | pmid = 27908266 | doi = 10.2174/1381612822666161201152941 }}
• {{cite journal | vauthors = McCreight LJ, Bailey CJ, Pearson ER | title = Metformin and the gastrointestinal tract | journal = Diabetologia | volume = 59 | issue = 3 | pages = 426–35 | date = March 2016 | pmid = 26780750 | pmc = 4742508 | doi = 10.1007/s00125-015-3844-9 }}
• {{cite journal | vauthors = Moin T, Schmittdiel JA, Flory JH, Yeh J, Karter AJ, Kruge LE, Schillinger D, Mangione CM, Herman WH, Walker EA | title = Review of Metformin Use for Type 2 Diabetes Prevention | journal = American Journal of Preventive Medicine | volume = 55 | issue = 4 | pages = 565–574 | date = October 2018 | pmid = 30126667 | pmc = 6613947 | doi = 10.1016/j.amepre.2018.04.038 }}
• {{cite journal | vauthors = Rena G, Hardie DG, Pearson ER | title = The mechanisms of action of metformin | journal = Diabetologia | volume = 60 | issue = 9 | pages = 1577–1585 | date = September 2017 | pmid = 28776086 | pmc = 5552828 | doi = 10.1007/s00125-017-4342-z }}
• {{cite journal | vauthors = Sanchez-Rangel E, Inzucchi SE | title = Metformin: clinical use in type 2 diabetes | journal = Diabetologia | volume = 60 | issue = 9 | pages = 1586–1593 | date = September 2017 | pmid = 28770321 | doi = 10.1007/s00125-017-4336-x | doi-access = free | title-link = doi }}
• {{cite journal | vauthors = Zhou J, Massey S, Story D, Li L | title = Metformin: An Old Drug with New Applications | journal = International Journal of Molecular Sciences | volume = 19 | issue = 10 | pages = 2863 | date = September 2018 | pmid = 30241400 | pmc = 6213209 | doi = 10.3390/ijms19102863 | doi-access = free | title-link = doi }}
• {{cite journal | vauthors = Zhou T, Xu X, Du M, Zhao T, Wang J | title = A preclinical overview of metformin for the treatment of type 2 diabetes | journal = Biomedicine & Pharmacotherapy | volume = 106 | pages = 1227–1235 | date = October 2018 | pmid = 30119191 | doi = 10.1016/j.biopha.2018.07.085 | s2cid = 52031602 }}

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{{Commons category|Metformin}}

• {{cite web | title=Nitrosamine impurities in medications: Guidance | website=Health Canada | date=4 April 2022 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/information-health-product/drugs/nitrosamine-impurities/medications-guidance.html }}

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