View source for Metformin

{{drugbox | Watchedfields = changed
| verifiedrevid = 306518009
|
| IUPAC_name = ''N'',''N''-dimethylimidodicarbonimidic diamide
| image = Metformin.svg
| image2 = Metformin-from-xtal-3D-balls.png
| width2 = 200
| CASNo_Ref = {{cascite}}
| CAS_number = 657-24-9
| ATC_prefix = A10
| ATC_suffix = BA02
| ATC_supplemental = <br/>{{ATC|A10|BD02}}&nbsp;<small>(with&nbsp;[[sulfonylurea]]s)</small><br/>{{ATC|A10|BD03}}&nbsp;<small>(with&nbsp;[[rosiglitazone]])</small><br/>{{ATC|A10|BD05}}&nbsp;<small>(with&nbsp;[[pioglitazone]])</small><br/>{{ATC|A10|BD07}}&nbsp;<small>(with&nbsp;[[sitagliptin]])</small><br/>{{ATC|A10|BD08}}&nbsp;<small>(with&nbsp;[[vildagliptin]])</small>
| PubChem = 4091
| DrugBank = APRD01099
| C = 4 | H = 11 | N = 5
| molecular_weight = 129.164 g/mol ([[free base (chemistry)|free]])<br />165.63 g/mol ([[hydrochloride|HCl]])
| synonyms = 1,1-dimethylbiguanide
| bioavailability = 50 to 60% under fasting conditions
| metabolism = None
| elimination_half-life = 6.2 hours
| excretion = Active [[Kidney|renal]] tubular excretion by [[SLC22A2|OCT2]]
| licence_US = Metformin
| pregnancy_AU = C
| pregnancy_US = B
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = Oral
}}

'''Metformin''' ([[International Nonproprietary Name|INN]]) ({{pron-en|mɛtˈfɔrmɪn}}; originally sold as '''Glucophage''') is an oral [[anti-diabetic drug]] in the [[biguanide]] class. It is the [[first-line treatment|first-line]] drug of choice for the treatment of [[diabetes mellitus type 2|type 2 diabetes]], particularly in [[overweight]] and [[obesity|obese]] people and those with normal kidney function.<ref>Clinical Guidelines Task Force, [[International Diabetes Federation]] (2005). {{PDFlink|[http://www.idf.org/webdata/docs/GGT2D%2009%20Oral%20therapy.pdf "Glucose control: oral therapy"]|100&nbsp;KB}}. In: ''[http://www.idf.org/Global_guideline Global Guideline for Type 2 Diabetes]''. Brussels: International Diabetes Federation, 35–8. Retrieved on November 6, 2007.</ref><ref name=NICErecommendations>{{vcite book| author=National Collaborating Centre for Chronic Conditions | title=Type 2 diabetes: national clinical guideline for management in primary and secondary care (update) | location=London | publisher = Royal College of Physicians | year=2008 | isbn=9781860163333 | pages=86 | url=http://www.nice.org.uk/nicemedia/pdf/CG66FullGuideline0509.pdf | format=pdf }}</ref><ref name=ADAstandardsOfCare>{{vcite journal |author=[[American Diabetes Association]] |title=Standards of medical care in diabetes—2009 |journal=Diabetes Care |volume=32 Suppl 1 |pages=S13–61 |year=2009 |pmid=19118286 |doi=10.2337/dc09-S013 |url=http://care.diabetesjournals.org/content/32/Supplement_1/S13.full}}</ref> Evidence is also mounting for its efficacy in [[gestational diabetes]], although safety concerns still preclude its widespread use in this setting. It is also used in the treatment of [[polycystic ovary syndrome]] and has been investigated for other diseases where [[insulin resistance]] may be an important factor.

When prescribed appropriately, metformin causes few [[adverse drug reaction|adverse effects]]—the most common is gastrointestinal upset—and, unlike many other anti-diabetic drugs, does not cause [[hypoglycemia]] if used alone. [[Lactic acidosis]] (a buildup of [[lactic acid|lactate]] in the blood) can be a serious concern in [[overdose]] and when it is prescribed to people with [[contraindication]]s, but otherwise, there is no [[statistical significance|significant]] risk. Metformin helps reduce [[low-density lipoprotein|LDL cholesterol]] and [[triglyceride]] levels and is not associated with weight gain, and is the only anti-diabetic drug that has been conclusively shown to prevent the cardiovascular complications of diabetes. {{As of|2009}}, metformin is one of only two oral anti-diabetics in the [[World Health Organization Model List of Essential Medicines]] (the other being [[glibenclamide]]).<ref name=WHOessential>(March 2009) {{PDFlink|[http://www.who.int/selection_medicines/committees/expert/17/sixteenth_adult_list_en.pdf ''WHO Model List of Essential Medicines'']|612&nbsp;KB}}, 16<sup>th</sup> edition, [[World Health Organization]], p. 24. Retrieved on 19 December 2009.</ref>

First [[chemical synthesis|synthesized]] and found to reduce blood sugar in the 1920s, metformin was forgotten for the next two decades as research shifted to [[insulin]] and other anti-diabetic drugs. Interest in metformin was rekindled in the late 1940s after several reports that it could reduce blood sugar levels in people, and in 1957, French physician Jean Sterne published the first [[clinical trial]] of metformin as a treatment for diabetes. It was introduced to the United Kingdom in 1958, Canada in 1972, and the United States in 1995. Metformin is now believed to be the most widely prescribed anti-diabetic drug in the world; in the United States alone, more than 40 million prescriptions were filled in 2008 for its [[generic drug|generic formulations]].<ref name=Bailey/><ref>{{PDFlink|[http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/222009/599844/article.pdf 2008 Top 200 generic drugs by total prescriptions]|332.8&nbsp;KB}}. ''Drug Topics'' (May 26, 2009). Retrieved on July 24, 2009.</ref>

==History==
The [[biguanide]] class of anti-diabetic drugs, which also includes the withdrawn agents [[phenformin]] and [[buformin]], originates from the [[Galega officinalis|French lilac]] (''Galega officinalis''), a plant used in folk medicine for several centuries.<ref name = Witters>{{vcite journal |author=Witters L |title=The blooming of the French lilac |journal=J Clin Invest |volume=108 |issue=8 |pages=1105–7 |year=2001 |pmid=11602616 |doi=10.1172/JCI14178 |pmc=209536 |url=http://www.jci.org/articles/view/14178}}</ref>

Metformin was first described in the scientific literature in 1922, by Emil Werner and James Bell, as a side product in the synthesis of ''N'',''N''-dimethylguanidine.<ref name = werner>{{vcite journal |author=Werner E, Bell J |title=The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyanodiamide, and methylammonium and dimethylammonium chlorides respectively |journal=J Chem Soc, Transactions |volume=121|pages=1790–5 |year=1921 |doi=10.1039/CT9222101790}}</ref> In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, noting that it was the most potent of the biguanide analogs they studied.<ref name = slotta>See Chemical Abstracts, v.23, 42772 (1929) {{vcite journal |author=Werner E, Bell  J|title= Uber Biguanide. II. Die Blutzuckersenkende Wirkung der Biguanides|journal=Berichte der Deutschen Chemischen Gesellschaft B: Abhandlungen|volume=62|pages=1398–1405 |year=1929}}</ref> This result was completely forgotten as other [[guanidine]] analogs, such as the [[synthalin]]s, took over, and were themselves soon overshadowed by insulin.<ref name= fifty>{{vcite journal |editor=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|pages=247–252 |year=2007|doi=10.1177/14746514070070051001}}</ref>

Interest in metformin, however, picked up 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.<ref name="pmid15405470">{{vcite journal |author=Dawes GS, Mott JC |title=Circulatory and respiratory reflexes caused by aromatic guanidines |journal=Br J Pharmacol Chemother |volume=5 |issue=1 |pages=65–76 |year=1950 |month=March |pmid=15405470 |pmc=1509951 |doi= |url=}}</ref> That same year, a prominent Philippine physician, Eusebio Y. Garcia,<ref>About Eusebio Y. Garcia, see: {{vcite 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 |author=Carteciano J |date=2005 |publisher= Philippines Department of Science and Technology|accessdate=2009-12-05}}</ref> used metformin (he named it ''Fluamine'') to treat influenza; he noted that the drug "lowered the blood sugar to minimum physiological limit" in treated patients and was non-toxic. Garcia also believed metformin to have [[bacteriostatic]], [[antiviral]], [[antimalarial]], [[antipyretic]] and [[analgesic]] actions.<ref name=Garcia>Quoted from Chemical Abstracts, v.45, 24828 (1951) {{vcite journal |author=Garcia EY |title=Fluamine, a new synthetic analgesic and antiflu drug |journal=J Philippine Med Assoc |volume=26 |pages=287–93 |year=1950}}</ref> In a series of articles in 1954, Polish pharmacologist Janusz Supniewski<ref name="pmid16766803">About Janusz Supniewski, see: {{vcite journal |author=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=J Physiol Pharmacol |volume=57 Suppl 1 |issue= |pages=119–36 |year=2006 |month=April |pmid=16766803 |doi= |url=http://www.jpp.krakow.pl/journal/archive/0406_s1/pdf/119_0406_s1_article.pdf |format=pdf |issn= |accessdate=2009-12-05}}</ref> was unable to confirm most of these effects, including lowered blood sugar; he did, however, observe some antiviral effects in humans.<ref name="pmid13269290">See Chemical Abstracts, v.52, 22272 (1958) {{vcite journal |author=SUPNIEWSKI J, CHRUSCIEL T |title=[N-dimethyl-di-guanide and its biological properties.] |language=Polish |journal=Arch Immunol Ther Exp (Warsz) |volume=2 |issue= |pages=1–15 |year=1954 |pmid=13269290 |doi= |url=}}</ref><ref name=supniewski2> Quoted from Chemical Abstracts, v.49, 74699 (1955) {{vcite journal |author=Supniewski J, Krupinska, J |title=[Effect of biguanide derivatives on experimental cowpox in rabbits.] |language=French |journal=Bulletin de l'Academie Polonaise des Sciences, Classe 3: Mathematique, Astronomie, Physique, Chimie, Geologie et Geographie |volume=2(Classe II) |issue= |pages=161–5 |year=1954}}</ref>

While training at the [[Pitié-Salpêtrière Hospital|Hôpital de la Pitié]], French diabetologist Jean Sterne studied the antihyperglycemic properties of galegine, an [[alkaloid]] isolated from ''Galega officinalis'', which is structurally related to metformin and had seen brief use as an anti-diabetic before the synthalins were developed.<ref name=Bailey>{{vcite journal |author=Bailey CJ, Day C |title=Metformin: its botanical background |journal=Practical Diabetes International |volume=21 |issue=3 |pages=115–7 |year=2004 |doi=10.1002/pdi.606 |url=http://www3.interscience.wiley.com/cgi-bin/fulltext/108564133/HTMLSTART}}</ref> Later, working at Laboratoires Aron in Paris, he was prompted by Garcia's report to re-investigate 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 drug and published his results in 1957.<ref name=Bailey/><ref name= fifty/>

Metformin became available in the [[British National Formulary]] in 1958. It was sold in the UK by a small Aron subsidiary called Rona. <!--Being a generic drug, it was at a commercial disadvantage; phenformin and buformin were marketed as being more potent and were supported by large pharmaceutical companies with a large sales force. As a result, metformin was mostly used in Scotland and Northern Ireland, while phenformin and buformin achieved worldwide clinical acceptance.--><ref name="pmid16402501">{{vcite journal |author=Hadden DR |title=Goat's rue - French lilac - Italian fitch - Spanish sainfoin: gallega officinalis and metformin: the Edinburgh connection |journal=J R Coll Physicians Edinb |volume=35 |issue=3 |pages=258–60 |year=2005 |month=October |pmid=16402501 |doi= |url=http://www.rcpe.ac.uk/journal/issue/journal_35_3/hadden_goats%20rue.pdf}}</ref>

Broad interest in metformin was not rekindled until the withdrawal of the other biguanides in the 1970s. Metformin was approved in Canada in 1972,<ref>{{vcite journal |author=Lucis OJ |title=The status of metformin in Canada |journal=Can Med Assoc J |volume=128 |issue=1 |pages=24–6 |year=1983 |month=January |pmid=6847752 |pmc=1874707}}</ref> but did not receive approval by the U.S. [[Food and Drug Administration]] (FDA) for Type 2 diabetes until 1994.<ref name = FDAapproval>{{cite press release |author=Susan M. Cruzan |title=FDA Approves New Diabetes Drug |date=December 30, 1994 |publisher=U.S. [[Food and Drug Administration]] |accessdate=2007-01-06 |url=www.fda.gov/bbs/topics/ANSWERS/ANS00627.html |archiveurl=http://web.archive.org/web/20070929152824/http://www.fda.gov/bbs/topics/ANSWERS/ANS00627.html |archivedate=29 September 2007}}</ref> Produced under license by [[Bristol-Myers Squibb]], Glucophage was the first branded formulation of metformin to be marketed in the United States, beginning on March 3, 1995.<ref>GLUCOPHAGE Label and Approval History. U.S. [[Food and Drug Administration]]. Retrieved on 8 January 2007. Data available for download on [http://www.fda.gov/Drugs/InformationOnDrugs/ucm079750.htm FDA website].</ref> [[generic drug|Generic]] formulations are now available in several countries, and metformin is believed to have become the most widely prescribed anti-diabetic drug in the world.<ref name=Bailey/>

==Treatment of diabetes==
The main use for metformin is in the treatment of [[diabetes mellitus type 2]], especially in [[overweight]] people. In this group, over 10 years of treatment, metformin reduced diabetes complications and overall mortality by about 30% when compared with [[insulin]] and [[sulfonylurea]]s ([[glibenclamide]] and [[chlorpropamide]]) and by about 40% when compared with the group only given dietary advice.<ref name = UKPDS/> This difference held in the patients who were followed for 5–10 years after the study.<ref name="pmid18784090">{{vcite journal |author=Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA |title=10-year follow-up of intensive glucose control in type 2 diabetes |journal=N Engl J Med |volume=359 |issue=15 |pages=1577–89 |year=2008 |month=October |pmid=18784090 |doi=10.1056/NEJMoa0806470 |url=http://content.nejm.org/cgi/content/full/359/15/1577}}</ref> In addition, metformin had no effect on body weight: over the 10-year treatment period, the metformin group gained about 1&nbsp;kg, the same as the dietary advice group, while the sulfonylureas group gained 3&nbsp;kg, and the insulin group, 6&nbsp;kg.<ref name = UKPDS>{{vcite journal |title=Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group |journal=Lancet |volume=352 |issue=9131 |pages=854–65 |year=1998 |pmid=9742977|doi=10.1016/S0140-6736(98)07037-8}}</ref><ref>{{vcite journal |author=Selvin E, Bolen S, Yeh HC, ''et al.'' |author.= |title=Cardiovascular outcomes in trials of oral diabetes medications: a systematic review |journal=Arch Intern Med |volume=168 |issue=19 |pages=2070–80 |year=2008 |month=October |pmid=18955635 |doi=10.1001/archinte.168.19.2070 |url=http://archinte.ama-assn.org/cgi/content/full/168/19/2070}}</ref> As metformin affords a similar level of [[blood sugar]] control to insulin and sulfonylureas, it appears to decrease mortality primarily through decreasing heart attacks, strokes and other cardiovascular complications.

Unlike the other most-commonly prescribed class of oral diabetes drugs, the sulfonylureas, metformin does not induce [[hypoglycemia]] when taken alone and used at recommended dosages.<ref name=Umesh/><ref name=Bolen/> Hypoglycemia during intense exercise has been documented, but is extremely rare.<ref name="isbn0071416137 ">{{vcite book |author=DiPiro, Joseph T.; Talbert, Robert L.; Yee, Gary C.; Matzke, Gary R.; Wells, Barbara G.; Posey, L. Michael|title=Pharmacotherapy: a pathophysiologic approach |publisher=McGraw-Hill |location=New York |year=2005 |isbn=0071416137 }}</ref> It is also  not associated with weight gain, and modestly reduces [[low density lipoprotein|LDL]] and [[triglyceride]] levels.<ref name=Umesh/><ref name=Bolen/>

Several epidemiological and case-controlled studies found that diabetics using metformin may have lower cancer risk in comparison to those using other sugar-lowering medications. The causes of this phenomenon are unclear, and the results require confirmation in controlled studies.<ref name="pmid20007645">{{vcite journal |author=Chong CR, Chabner BA |title=Mysterious metformin |journal=Oncologist |volume=14 |issue=12 |pages=1178–81 |year=2009 |month=December |pmid=20007645 |doi=10.1634/theoncologist.2009-0286}}</ref>

==Off-label use==
Metformin is also being used increasingly in [[polycystic ovary syndrome]] (PCOS),<ref name=Lord>{{vcite journal |author=Lord JM, Flight IHK, Norman RJ |title=Metformin in polycystic ovary syndrome: systematic review and meta-analysis |journal=BMJ |year=2003 |volume=327 |issue=7421 |pages=951–3 |pmid=14576245 |url=http://www.bmj.com/cgi/content/full/327/7421/951 |doi=10.1136/bmj.327.7421.951 | pmc=259161}}</ref>
[[non-alcoholic fatty liver disease]] (NAFLD)<ref name=Marchesini>{{vcite journal |author=Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N |title=Metformin in non-alcoholic steatohepatitis |journal=[[The Lancet|Lancet]] |year=2001 |volume=358 |issue=9285 |pages=893–4 |pmid=11567710 |doi=10.1016/S0140-6736(01)06042-1}}</ref> and premature puberty,<ref>{{vcite journal |author=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=J Clin Endocrinol Metab |volume=91 |issue=8 |pages=2888–91 |year=2006 |pmid=16684823 |doi=10.1210/jc.2006-0336}}</ref> three other diseases that feature [[insulin resistance]]; these indications are {{As of|2009|alt=still}} considered experimental. The benefit of metformin in NAFLD has not been extensively studied and may be only temporary;<ref name=Nair>{{vcite journal |author=Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP |title=Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial |journal=Aliment Pharmacol Ther |year=2004 |volume=20 |issue=1 |pages=23–28 |pmid=15225167 |doi=10.1111/j.1365-2036.2004.02025.x}}</ref> although some [[randomized controlled trial]]s have found significant improvement with its use, the evidence is still insufficient.<ref>{{vcite journal |author=Angelico F, Burattin M, Alessandri C, Del Ben M, Lirussi F |title=Drugs improving insulin resistance for non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis |journal=Cochrane Database Syst Rev |volume=24 |issue=1 |pages=CD005166 |year=2007 |month=January |pmid=17253544|doi=10.1002/14651858.CD005166.pub2|url=http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD005166/frame.html}}</ref><ref>{{vcite journal |author=Socha P, Horvath A, Vajro P, Dziechciarz P, Dhawan A, Szajewska H |title=Pharmacological interventions for nonalcoholic fatty liver disease in adults and in children: a systematic review |journal=J Pediatr Gastroenterol Nutr |volume=48 |issue=5 |pages=587–96 |year=2009 |month=May |pmid=19412008}}</ref>

===Prediabetes===
Metformin treatment of people at risk for type 2 diabetes may decrease their chances of developing the disease, although intensive physical exercise and dieting work significantly better for this purpose. In a large U.S. study known as the Diabetes Prevention Program, participants were divided into groups and given either placebo, metformin, or lifestyle intervention, and followed for an average of three years. The intensive program of lifestyle modifications included a 16-lesson training on dieting and exercise followed by monthly individualized sessions with the goals to decrease the body weight by 7% and engage in a physical activity for at least 150 minutes per week.  The [[incidence (epidemiology)|incidence]] of diabetes was 58% lower in the lifestyle group and 31% lower in those given metformin. Among younger people with a higher body mass index, lifestyle modification was no more effective than metformin, and for older individuals with a lower body mass index, metformin was no better than placebo in preventing diabetes.<ref name=DPP>{{vcite journal |author=Knowler WC, Barrett-Connor E, Fowler SE, ''et al.'' |author.= |title=Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin |journal=N Engl J Med |volume=346 |issue=6 |pages=393–403 |year=2002 |month=February |pmid=11832527 |pmc=1370926 |doi=10.1056/NEJMoa012512}}</ref> After ten years, the incidence of diabetes was 34% lower in the group of participants given diet and exercise and 18% lower in those given metformin.<ref name=DPP10>{{vcite journal |author=Knowler WC, Fowler SE, Hamman RF, ''et al.'' |author.= |title=10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study |journal=Lancet |volume=374 |issue=9702 |pages=1677–86 |year=2009 |month=November |pmid=19878986 |doi=10.1016/S0140-6736(09)61457-4}}</ref> It is unclear whether metformin slowed down the progression of pre-diabetes to diabetes (true preventive effect), or the decrease of diabetes in the treated population was simply due to its glucose-lowering action (treatment effect).<ref>{{vcite journal |author=Lilly M, Godwin M |title=Treating prediabetes with metformin: systematic review and meta-analysis |journal=Can Fam Physician |volume=55 |issue=4 |pages=363–9 |year=2009 |month=April |pmid=19366942 |pmc=2669003}}</ref>

===Polycystic ovary syndrome===
Antidiabetic therapy has been proposed as a treatment for [[polycystic ovary syndrome]] (PCOS), a condition frequently associated with insulin resistance, since the late 1980s.<ref>{{vcite journal |author=Kidson W |title=Polycystic ovary syndrome: a new direction in treatment |journal=Med J Aust |volume=169 |issue=10 |pages=537–40 |year=1998 |month=November |pmid=9861912 |url=http://www.mja.com.au/public/issues/nov16/kidson/kidson.html}}</ref> The use of metformin in PCOS was first reported in 1994, in a small study conducted at the [[University of the Andes, Venezuela]].<ref>{{vcite journal |author=Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ |title=Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy |journal=Metab Clin Exp |volume=43 |issue=5 |pages=647–54 |year=1994 |month=May |pmid=8177055}}</ref><ref name=Teede>{{vcite book |author=Teede H |editor=Kovács GT, Norman RW |chapter=Insulin sensitizers in polycystic ovary syndrome |title=Polycystic ovary syndrome |publisher=Cambridge University Press |location=Cambridge, UK |year=2007 |pages=65–81 |isbn=0-521-84849-0}}</ref> 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 therapy has failed to produce results.<ref name=NICEfertility>{{vcite 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=1900364972 | pages=58–9 | url=http://www.nice.org.uk/nicemedia/pdf/cg011fullguideline.pdf | format=pdf }}</ref> However, two large clinical studies completed in 2006–2007 returned mostly negative results, with metformin being no better than placebo and metformin-[[clomifene]] combination no better than clomifene alone.<ref name="pmid17287476">{{vcite journal |author=Legro RS, Barnhart HX, Schlaff WD, ''et al.'' |author.= |title=Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome |journal=N Engl J Med |volume=356 |issue=6 |pages=551–66 |year=2007 |month=February |pmid=17287476 |doi=10.1056/NEJMoa063971 |url=}}</ref><ref name="pmid16769748">{{vcite journal |author=Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F |title=Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial |journal=BMJ |volume=332 |issue=7556 |pages=1485 |year=2006 |month=June |pmid=16769748 |pmc=1482338 |doi=10.1136/bmj.38867.631551.55 |url=}}</ref> Reflecting this, subsequent reviews noted that large [[randomized control trial]]s have in general not shown the promise suggested by the early small studies. U.K. and international [[clinical practice guideline]]s do not recommend metformin as a first-line treatment<ref>{{vcite web |author=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 |format=PDF |accessdate=2009-12-13}}</ref> or do not recommend it at all, except for women with [[glucose intolerance]].<ref name="pmid18308833">{{vcite journal |author=The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group |title=Consensus on infertility treatment related to polycystic ovary syndrome |journal=Hum Reprod |volume=23 |issue=3 |pages=462–77 |year=2008 |month=March |pmid=18308833 |doi=10.1093/humrep/dem426 |url=}}</ref> The guidelines suggest clomiphene as the first medication option and emphasize lifestyle modification independently from the drug treatment.

In a dissenting opinion, a systematic review of four head-to-head comparative trials of metformin and clomifene found them equally effective for infertility.<ref name="pmid18691273">{{vcite journal |author=Palomba S, Pasquali R, Orio F, Nestler JE |title=Clomiphene citrate, metformin or both as first-step approach in treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS): a systematic review of head-to-head randomized controlled studies and meta-analysis |journal=Clin. Endocrinol. (Oxf) |volume=70 |issue=2 |pages=311–21 |year=2009 |month=February |pmid=18691273 |doi=10.1111/j.1365-2265.2008.03369.x}}</ref> A BMJ editorial noted that four positive studies of metformin were in patients who did not respond to clomifene, while the population in the negative studies was drug-naive or uncontrolled for the previous treatment. The editorial suggested that metformin should be used as a second-line drug if clomifene treatment fails.<ref name="pmid16793784">{{vcite journal |author=Al-Inany H, Johnson N |title=Drugs for anovulatory infertility in polycystic ovary syndrome |journal=BMJ |volume=332 |issue=7556 |pages=1461–2 |year=2006 |month=June |pmid=16793784 |pmc=1482323 |doi=10.1136/bmj.332.7556.1461}}</ref> Another review recommended metformin unreservedly as a first-line treatment option because it has positive effects not only on anovulation but also on insulin resistance, hirsutism, and obesity often associated with PCOS.<ref name="pmid19405411">{{vcite journal |author=Radosh L |title=Drug treatments for polycystic ovary syndrome |journal=Am Fam Physician |volume=79 |issue=8 |pages=671–6 |year=2009 |month=April |pmid=19405411}}</ref> A large [[Cochrane Collaboration]] review of 27 randomized clinical trials found that metformin improves ovulation and pregnancy rates, particularly when combined with [[clomifene]], but is not associated with any increase in the number of live births.<ref>{{vcite journal |author=Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH |title=Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD003053 |year=2009 |pmid=19821299 |doi=10.1002/14651858.CD003053.pub3 |url=http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003053/frame.html}}</ref>

The design of the negative trials may be one of the explanations for the contradictory results. For example, using live birth rate instead of pregnancy as the end point may have biased some trials against metformin, which works slower than clomifene.<ref name="pmid17595241">{{vcite journal |author=Palomba S, Orio F, Falbo A, Russo T, Tolino A, Zullo F |title=Clomiphene citrate versus metformin as first-line approach for the treatment of anovulation in infertile patients with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=92 |issue=9 |pages=3498–503 |year=2007 |month=September |pmid=17595241 |doi=10.1210/jc.2007-1009}}</ref> Another explanation may be different efficacy of metformin in different populations of patients. The negative trials contained large percent of obese and previously untreated patients whose response to metformin may be weaker.<ref name="pmid17595241"/>

===Gestational diabetes===
Several [[observational study|observational studies]] and [[randomized controlled trial]]s have found that metformin is as effective and safe as insulin for the management of gestational diabetes,<ref>{{vcite journal |author=Tertti K, Ekblad U, Vahlberg T, Rönnemaa T |title=Comparison of metformin and insulin in the treatment of gestational diabetes: a retrospective, case-control study |journal=Rev Diabet Stud |volume=5 |issue=2 |pages=95–101 |year=2008 |pmid=18795211 |pmc=2556447 |url=http://www.soc-bdr.org/content/rds/archive/5/2_summer/original_data/treatment_of_gestational_diabetes/index_en.html?showfulltext=1 |doi=10.1900/RDS.2008.5.95}}</ref><ref name=MiG>{{vcite journal |author=Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators |title=Metformin versus insulin for the treatment of gestational diabetes |journal=N Engl J Med |volume=258 |issue=19 |pages=2003–15 |year=2008 |month=May |pmid=18463376 | url=http://content.nejm.org/cgi/content/full/358/19/2003}}</ref><ref name=Nicholson>{{vcite journal |author=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=Obstet Gynecol |volume=113 |issue=1 |pages=193–205 |year=2009 |month=January |pmid=19104375}}</ref> and a small [[case-control study]] has suggested that the children of women given metformin instead of insulin may be healthier in the [[infant|neonatal]] period.<ref>{{vcite journal |author=Balani J, Hyer SL, Rodin DA, Shehata H |title=Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case-control study |journal=Diabet Med |volume=26 |issue=8 |pages=798–802 |year=2009 |month=August |pmid=19709150}}</ref> Nonetheless, several concerns have been raised regarding studies published thus far, and evidence on the long-term safety of metformin for both mother and child is still lacking.<ref>{{vcite journal |author=Cheung NW |title=The management of gestational diabetes |journal=Vasc Health Risk Manag |volume=5 |issue=1 |pages=153–64 |year=2009 |pmid=19436673 |pmc=2672462 |url=http://www.dovepress.com/getfile.php?fileID=4160 |format=pdf}}</ref>

===Investigational findings===
A large [[case-control study]] conducted at [[M.D. Anderson Cancer Center]] has suggested that metformin may protect against [[pancreatic cancer]]. The risk of pancreatic cancer in study participants who took metformin was found to be 62% lower than in participants who had never taken it, whereas participants who had used insulin or [[secretagogue]]s (such as the sulfonylureas) were found to have a 5-fold and 2.5-fold higher risk of pancreatic cancer, respectively, compared to participants that had been treated with neither.<ref name=Li>{{vcite journal |author=Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL |title=Antidiabetic therapies affect risk of pancreatic cancer |journal=Gastroenterology |volume=137 |issue=2 |pages=482–8 |year=2009 |month=August |pmid=19375425 |doi=10.1053/j.gastro.2009.04.013 | url=http://www.gastrojournal.org/article/S0016-5085%2809%2900555-1/fulltext |laysummary=http://www.medscape.com/viewarticle/707523 |laysource=Medscape |laydate=August 18, 2009}}</ref> The study had several limitations, however, and the reason for this risk reduction is still unclear.<ref name=Li/> Observational studies conducted by the [[University of Dundee]] have shown a decrease of 25–37% in cancer cases in diabetics taking metformin.<ref>{{vcite journal |author=Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD |year=2005 |title=Metformin and reduced risk of cancer of 25–37% in diabetic patients |journal=BMJ |volume=330 |pages=1304–5 |url=http://www.bmj.com/cgi/content/full/330/7503/1304 |doi=10.1136/bmj.38415.708634.F7 |pmid=15849206 |pmc=558205 }}</ref><ref>{{vcite journal |author=Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM |year=2009 |title=New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes |journal=Diabetes Care |volume=32 |pages=1620–5 |url=http://care.diabetesjournals.org/content/32/9/1620.full |doi=10.2337/dc08-2175 |pmid=19564453 |pmc=2732153 }}</ref>

A single randomized controlled trial suggested that metformin may reduce weight gain in patients taking [[atypical antipsychotic]]s, particularly when combined with lifestyle interventions (education, dieting, and exercise).<ref name="pmid18182600">{{vcite journal |author=Wu RR, Zhao JP, Jin H, ''et al.'' |author.= |title=Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial |journal=JAMA |volume=299 |issue=2 |pages=185–93 |year=2008 |pmid=18182600 |doi=10.1001/jama.2007.56-b |url=http://jama.ama-assn.org/cgi/content/full/299/2/185}}</ref>

==Formulations==
[[Image:Metformin 500mg Tablets.jpg|200px|thumb|Metformin 500&nbsp;mg tablets]]

Metformin is sold under several [[trade name]]s, including ''Glucophage XR'', ''Riomet'', ''Fortamet'', ''Glumetza'', ''Obimet'', ''Dianben'', ''Diabex'', and ''Diaformin''. <!-- editors, please note that the trade names noted above redirect to this section i.e. Metformin#Formulations-->

Metformin IR (immediate release) is available in 500&nbsp;mg, 850&nbsp;mg, and 1000&nbsp;mg tablets, all now generic in the US.

Metformin SR (slow release) or XR (extended release) was introduced in 2004, in 500&nbsp;mg and 750&nbsp;mg strengths, mainly to counteract the most common gastrointestinal side effects, as well as to increase patient compliance by reducing [[pill burden]]. No difference in effectiveness exists between the two preparations.

===Combinations with other drugs===
Metformin is sometimes prescribed to [[Diabetes mellitus type 2|type 2]] diabetes patients in combination with [[rosiglitazone]].  This drug actively reduces insulin resistance, complementing the action of the metformin.  In 2002, the two drugs were combined into a single product, ''Avandamet'', marketed by [[GlaxoSmithKline]].<ref>{{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=October 12, 2002 |accessdate=2006-12-27 |url=http://www.docguide.com/news/content.nsf/news/8525697700573E1885256C4F0075B2B3}}</ref> In 2005, all current stock of Avandamet was seized by the FDA and removed from the market, after inspections showed the factory where it was produced was violating [[Good Manufacturing Practice]]s.<ref>{{cite press release |title=Questions and Answers about the Seizure of Paxil CR and Avandamet |publisher=U.S. [[Food and Drug Administration]] |date=March 4, 2005 |accessdate=2006-12-27 |url=http://www.fda.gov/oc/qanda/PaxilandAvandamet.html |archiveurl=http://web.archive.org/web/20071014014507/http://www.fda.gov/oc/qanda/PaxilandAvandamet.html |archivedate=14 October 2007}}</ref> The drug pair continued to be prescribed separately in the absence of Avandamet, which was available again by the end of that year.

In the United States, metformin is also available in combination with [[pioglitazone]] (trade name ''Actoplus Met''), the [[sulfonylurea]]s [[glipizide]] (trade name ''Metaglip'') and [[glibenclamide]] (known as ''glyburide'' in the United States, trade name ''Glucovance''), the [[dipeptidyl peptidase-4 inhibitors|dipeptidyl peptidase-4 inhibitor]] [[sitagliptin]] (trade name ''Janumet''), and the [[meglitinide]] [[repaglinide]] (''PrandiMet''). Generic formulations of metformin/glipizide and metformin/glibenclamide are available. A generic formulation of metformin/rosiglitazone from [[Teva Pharmaceutical Industries|Teva]] has received tentative approval from the FDA, and is expected to reach the market in early 2012.<ref>{{cite press release |url=http://www.reuters.com/article/inPlayBriefing/idUSIN20070927170530TEVA20070927 |title=Teva Pharm announces settlement of generic Avandia, Avandamet, and Avandaryl litigation with GlaxoSmithKline |publisher=Reuters |date=September 27, 2007 |accessdate=2009-02-17}}</ref>

==Contraindications==
Metformin is [[contraindication|contraindicated]] in people with any condition that could increase the risk of [[lactic acidosis]], including [[kidney]] disorders ([[creatinine]] levels over 150 μmol/l,<ref name="Jones2003">{{vcite journal |author=Jones G, Macklin J, Alexander W |title=Contraindications to the use of metformin |journal=BMJ |volume=326 |issue=7379 |pages=4–5 |year=2003 |pmid=12511434 |doi=10.1136/bmj.326.7379.4 |pmc=1124930 |url=http://www.bmj.com/cgi/content/full/326/7379/4}}</ref> although this is an arbitrary limit), [[lung disease]] and [[liver disease]]. According to the [[package insert|prescribing information]], [[heart failure]], in particular, unstable or acute congestive heart failure increases risk of lactic acidosis with metformin.<ref name="glucopi">{{vcite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020357s031,021202s016lbl.pdf|title=Glucophage Prescribing Information for the U.S.|format= PDF|publisher=US FDA|accessdate=2009-12-24}}</ref> A 2007 [[systematic review]] of controlled trials, however, suggested that metformin is the only anti-diabetic drug not associated with any measurable harm in people with heart failure, and that it may reduce mortality in comparison with other anti-diabetic agents.<ref name=Eurich>{{vcite journal |author=Eurich DT, McAlister FA, Blackburn DF, ''et al.'' |author.= |title=Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review |journal=BMJ |volume=335 |issue=7618 |page=497 |year=2007 |pmid=17761999 |doi=10.1136/bmj.39314.620174.80 |pmc=1971204 |url=http://www.bmj.com/cgi/content/full/335/7618/497}}</ref>

It is recommended that metformin be temporarily discontinued before any [[medical imaging|radiographic study]] involving [[iodine|iodinated]] [[radiocontrast|contrast]] (such as a contrast-enhanced [[computed tomography|CT scan]] or [[angiogram]]), as contrast dye may temporarily impair kidney function, indirectly leading to lactic acidosis by causing retention of metformin in the body.<!--really the main mechanism?--><ref name="RCR">Weir J (March 19, 1999). [http://web.archive.org/web/20040104141219/http://www.rcr.ac.uk/pubtop.asp?PublicationID=70 Guidelines with Regard to Metformin-Induced Lactic Acidosis and X-ray Contrast Medium Agents]. [[Royal College of Radiologists]]. Retrieved on 26 October 2007 through the [[Internet Archive]].</ref><ref name="ESUR">{{vcite journal |author=Thomsen HS, Morcos SK |title=Contrast media and the kidney: European Society of Urogenital Radiology (ESUR) guidelines |journal=Br J Radiol |volume=76 |issue=908 |pages=513–8 |year=2003 |pmid=12893691 |url=http://bjr.birjournals.org/cgi/content/full/76/908/513 |doi=10.1259/bjr/26964464}}</ref> It is recommended that metformin be resumed after two days, assuming kidney function is normal.<ref name="RCR"/><ref name="ESUR"/>

==Adverse effects==
The most common [[adverse drug reaction|adverse effect]] of metformin is gastrointestinal upset, including [[diarrhea]], cramps, nausea, vomiting and increased [[flatulence]]; metformin is more commonly associated with gastrointestinal side effects than most other anti-diabetic drugs.<ref name=Bolen>{{vcite journal |author=Bolen S, Feldman L, Vassy J, ''et al.'' |author.= |title=Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus |journal=Ann Intern Med |volume=147 |issue=6 |pages=386–99 |year=2007 |pmid=17638715 |url=http://www.annals.org/content/147/6/386.long }}</ref> The most serious potential side effect of metformin use is lactic acidosis; this complication is very rare, and the vast majority of these cases seem to be related to comorbid conditions such as impaired liver or kidney function, rather than to the metformin itself.<ref>{{vcite journal |author=Khurana R, Malik IS |title=Metformin: safety in cardiac patients |journal=Heart |volume=96 |issue=2 |pages=99–102 |year=2010 |pmid=19564648 |doi=10.1136/hrt.2009.173773 }}</ref>

Metformin has also been reported to decrease the blood levels of [[thyroid-stimulating hormone]] in patients with [[hypothyroidism]],<ref>{{vcite journal |author=Vigersky RA, Filmore-Nassar A, Glass AR |title=Thyrotropin suppression by metformin |journal=J Clin Endocrinol Metab |volume=91 |issue=1 |pages=225–7 |year=2006 |month=January |pmid=16219720 |doi=10.1210/jc.2005-1210 |url=http://jcem.endojournals.org/cgi/content/full/91/1/225}}</ref> and, in men, [[lutenizing hormone]] and [[testosterone]].<ref>{{vcite journal |author=Shegem NS, Nasir AM, Jbour AK, Batieha AM, El-Khateeb MS, Ajlouni KM |title=Effects of short term metformin administration on androgens in normal men |journal=Saudi Med J |volume=23 |issue=8 |pages=934–7 |year=2002 |month=August |pmid=12235466}}</ref><ref>{{vcite journal |author=Ozata M, Oktenli C, Bingol N, Ozdemir IC |title=The effects of metformin and diet on plasma testosterone and leptin levels in obese men |journal=Obes Res |volume=9 |issue=11 |pages=662–7 |year=2001 |month=November |pmid=11707532 |doi=10.1038/oby.2001.90 |url=http://www.nature.com/oby/journal/v9/n11/full/oby200190a.html}}</ref> The clinical significance of these changes is still unknown.

===Gastrointestinal===
In a clinical trial of 286 subjects, 53.2% of the 141 who were given immediate-release metformin (as opposed to [[placebo]]) reported diarrhea, versus 11.7% for placebo, and 25.5% reported nausea/vomiting, versus 8.3% for those on placebo.<ref name = DF&C>{{vcite book |title=Drug Facts and Comparisons 2005 |year=2004 |month=October |publisher=Facts and Comparisons |location=St. Louis, Mo |isbn=1574391933 }}</ref>

Gastrointestinal upset can cause severe discomfort for patients; it is most common when metformin is first administered, or when the dose is increased.  The discomfort can often be avoided by beginning at a low dose (1 to 1.7 grams per day) and increasing the dose gradually.  Gastrointestinal upset after prolonged, steady use is less common.

Long-term use of metformin has been associated with increased [[homocysteine]] levels<ref name=Wulffele>{{vcite journal |journal=J Intern Med |year=2003|month=November |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 |author=Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, Donker AJ, Stehouwer CD |volume=254 |issue=5 |pages=455–63|pmid=14535967 |doi=10.1046/j.1365-2796.2003.01213.x |url=http://www3.interscience.wiley.com/cgi-bin/fulltext/118889232/HTMLSTART}}</ref> and [[malabsorption]] of [[cyanocobalamin|vitamin B<sub>12</sub>]].<ref name = Andres>{{vcite journal |author=Andrès E, Noel E, Goichot B |title=Metformin-associated vitamin B12 deficiency |journal=Arch Intern Med |volume=162 |issue=19 |pages=2251–2 |year=2002 |pmid=12390080 |doi=10.1001/archinte.162.19.2251-a}}</ref><ref name = Gilligan>{{vcite journal |author=Gilligan M |title=Metformin and vitamin B12 deficiency |journal=Arch Intern Med |volume=162 |issue=4 |pages=484–5 |year=2002 |pmid=11863489 |doi=10.1001/archinte.162.4.484}}</ref> Higher doses and prolonged use are associated with increased incidence of B<sub>12</sub> deficiency,<ref>{{cite journal|author=de Jager J, Kooy A, Lehert P, ''et al.''|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|year=2010|volume=340|page=c2181}}</ref> and some researchers recommend screening or prevention strategies.<ref>{{vcite journal |author=Ting R, Szeto C, Chan M, Ma K, Chow K |title=Risk factors of vitamin B(12) deficiency in patients receiving metformin |journal=Arch Intern Med |volume=166 |issue=18 |pages=1975–9 |year=2006 |pmid=17030830 |doi=10.1001/archinte.166.18.1975 |url=http://archinte.ama-assn.org/cgi/content/full/166/18/1975}}</ref>

===Lactic acidosis===
The most serious potential adverse effect of biguanide use is [[lactic acidosis]]. [[Phenformin]], another biguanide, was withdrawn from the market because of an increased risk of lactic acidosis (up to 60 cases per [[million]] patient-years). However, metformin is safer than phenformin, and the risk of developing lactic acidosis is not increased by the medication so long as it is not prescribed to known high-risk groups.<ref name = Salpeter>{{vcite journal |author=Salpeter S, Greyber E, Pasternak G, Salpeter E |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|Arch Intern Med]] |volume=163 |issue=21 |pages=2594–602 |year=2003 |pmid=14638559 |doi=10.1001/archinte.163.21.2594 |url=http://archinte.ama-assn.org/cgi/content/full/163/21/2594}}</ref>

Lactate uptake by the liver is diminished with metformin administration because lactate is a substrate for hepatic [[gluconeogenesis]], a process which metformin inhibits. In healthy individuals, this slight excess is simply cleared by other mechanisms (including uptake by the kidneys, when their function is unimpaired), and no significant elevation in blood levels of lactate occurs.<ref name=Umesh>{{vcite book |author=Maharani U |editor=Papadakis MA, McPhee SJ |chapter=Chapter 27: Diabetes Mellitus & Hypoglycemia |title=CURRENT Medical Diagnosis and Treatment 2010 |edition=49th |publisher=McGraw-Hill Medical |location= |year=2009 |pages=1092–93 |isbn=0-07-162444-9}}</ref> When there is impaired renal function, however, clearance of metformin (and lactate) is reduced and the drug may accumulate, leading to lactic acidosis. Because metformin decreases liver uptake of lactate, any condition which may precipitate lactic acidosis is a contraindication to its use. Common causes of increased lactic acid production include [[alcoholism]] (due to depletion of [[nicotinamide adenine dinucleotide|NAD+]] stores), heart failure, and respiratory disease (due to inadequate oxygenation of tissues); the most common cause of impaired lactic acid excretion is kidney disease.<ref name=Golan>{{vcite book |author=Shu AD, Myers Jr MG, Shoelson SE |editor=Golan ED ''et al.'' (eds.) |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=0-7817-4678-7}}</ref>

It has also been suggested that metformin increases production of lactate in the small intestine; this could potentially contribute to lactic acidosis in patients with risk factors.<ref name=Kirpichnikov/> However, the clinical significance of this is unknown, and the risk of metformin-associated lactic acidosis is most commonly attributed to decreased hepatic uptake rather than increased intestinal production.<ref name=Umesh/><ref name=Golan/><ref>{{vcite book |author=Davis SN |editor=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=978-0071422802 |pages= |chapter=Chapter 60: Insulin, Oral Hypoglycemic Agents, and the Pharmacology of the Endocrine Pancreas}}</ref>

==Overdosage==
A review of intentional and accidental metformin overdoses reported to [[poison control center]]s over a five-year period found that serious adverse events were rare, though elderly patients appeared to be at greater risk.<ref>{{vcite journal |author=Spiller HA, Quadrani DA |title=Toxic effects from metformin exposure |journal=Ann Pharmacother |volume=38 |issue=5 |pages=776–80 |year=2004 |pmid=15031415 |doi=10.1345/aph.1D468}}</ref> A similar study where cases were reported to Texas poison control centers between the years 2000 and 2006 found that ingested doses of more than 5,000&nbsp;mg were more likely to involve serious medical outcomes in adults.<ref name="Forrester">{{vcite journal |author=Forrester MB |title=Adult metformin ingestions reported to Texas poison control centers, 2000-2006 |journal=Hum Exp Toxicol |volume=27 |issue=7 |pages=575–83 |year=2008 |month=July |pmid=18829734 |doi=10.1177/0960327108090589}}</ref> Survival following intentional overdoses with up to 63,000&nbsp;mg (63&nbsp;g) of metformin have been reported in the medical literature.<ref name="63g">{{vcite journal |author=Gjedde S, Christiansen A, Pedersen SB, Rungby J |title=Survival following a metformin overdose of 63 g: a case report |journal=Pharmacol Toxicol |volume=93 |issue=2 |pages=98–9 |year=2003 |pmid=12899672|doi=10.1034/j.1600-0773.2003.930207.x}}</ref> Fatalities following overdose are rare, but do occur.<ref>{{vcite journal |author=Nisse P, Mathieu-Nolf M, Deveaux M, Forceville X, Combes A |title=A fatal case of metformin poisoning |journal=J Toxicol Clin Toxicol |volume=41 |issue=7 |pages=1035–6 |year=2003 |pmid=14705855 |doi=10.1081/CLT-120026533}}</ref><ref name="Suchard">{{vcite journal |author=Suchard JR, Grotsky TA |title=Fatal metformin overdose presenting with progressive hyperglycemia |journal=West J Emerg Med |volume=9 |issue=3 |pages=160–4 |year=2008 |month=August |pmid=19561734 |pmc=2672258}}</ref><ref name="Teale"/> In healthy children, unintentional doses of less than 1,700&nbsp;mg are unlikely to cause any significant toxic effects.<ref>{{vcite journal |author=Spiller HA, Weber JA, Winter ML, Klein-Schwartz W, Hofman M, Gorman SE, Stork CM, Krenzelok EP |title=Multicenter case series of pediatric metformin ingestion |journal=Ann Pharmacother |volume=34 |issue=12 |pages=1385–8 |year=2000 |month=December |pmid=11144693|doi=10.1345/aph.10116}}</ref>

The most common symptoms following overdose appear to include [[vomiting]], [[diarrhea]], [[abdominal pain]], [[tachycardia]], drowsiness, and rarely, [[hypoglycemia]] or [[hyperglycemia]].<ref name="Forrester"/><ref name="Suchard"/> The major potentially life-threatening complication of metformin overdose is lactic acidosis, which is due to lactate accumulation.<ref>{{vcite journal |author=Dell'Aglio DM, Perino LJ, Kazzi Z, Abramson J, Schwartz MD, Morgan BW |title=Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature |journal=Ann Emerg Med |volume=54 |issue=6 |pages=818–23 |year=2009 |month=December |pmid=19556031 |doi=10.1016/j.annemergmed.2009.04.023}}</ref><ref>{{vcite journal |author=Lacher M, Hermanns-Clausen M, Haeffner K, Brandis M, Pohl M |title=Severe metformin intoxication with lactic acidosis in an adolescent |journal=Eur J Pediatr |volume=164 |issue=6 |pages=362–5 |year=2005 |month=June |pmid=15729560 |doi=10.1007/s00431-005-1634-y}}</ref> Treatment of metformin overdose is generally supportive as there is no specific antidote. Lactic acidosis is initially treated with [[sodium bicarbonate]], although high doses are not recommended as this may increase [[intracellular]] acidosis.<ref name="Teale">{{vcite journal |author=Teale KF, Devine A, Stewart H, Harper NJ |title=The management of metformin overdose |journal=Anaesthesia |volume=53 |issue=7 |pages=698–701 |year=1998 |month=July |pmid=9771180|doi=10.1046/j.1365-2044.1998.436-az0549.x}}</ref> Acidosis that does not respond to administration of sodium bicarbonate may require further management with [[hemodialysis|standard hemodialysis]] or [[hemofiltration|continuous veno-venous hemofiltration]]. Additionally, due to metformin’s low [[molecular weight]] and lack of [[plasma protein binding]], these techniques also have the benefit of efficiently removing metformin from [[blood plasma]], preventing further lactate over-production.<ref name="cvvh">{{vcite journal |author=Harvey B, Hickman C, Hinson G, Ralph T, Mayer A |title=Severe lactic acidosis complicating metformin overdose successfully treated with high-volume venovenous hemofiltration and aggressive alkalinization |journal=Pediatr Crit Care Med |volume=6 |issue=5 |pages=598–601 |year=2005 |pmid=16148825 |doi=10.1097/01.PCC.0000162451.47034.4F}}</ref><ref name="hd">{{vcite journal |author=Guo PY, Storsley LJ, Finkle SN |title=Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin |journal=Semin Dial |volume=19 |issue=1 |pages=80–3 |year=2006 |pmid=16423187 |doi=10.1111/j.1525-139X.2006.00123.x}}</ref><ref>{{vcite journal |author=Barrueto F, Meggs WJ, Barchman MJ |title=Clearance of metformin by hemofiltration in overdose |journal=J Toxicol Clin Toxicol |volume=40 |issue=2 |pages=177–80 |year=2002 |pmid=12126190 |doi= 10.1081/CLT-120004407}}</ref>

==Chemistry==
The usual [[chemical synthesis|synthesis]] of metformin, originally described in 1922 and reproduced in multiple later patents and publications, involves the reaction of [[dimethylamine]] [[hydrochloride]] and [[2-cyanoguanidine]] (dicyandiamide) with heating.<ref name = werner/><ref>{{vcite journal |author=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=2220–5 |doi=10.1021/ja01518a052}}</ref>

[[File:Metformin synthesis.svg|center|300px]]

According to the procedure described in 1975 Aron patent<ref>{{vcite journal |title=Procédé de préparation de chlorhydrate de diméthylbiguanide |journal=Patent FR 2322860|language=French|year=1975}}</ref> and the ''Pharmaceutical Manufacturing Encyclopedia'',<ref name="isbn0-8155-1526-X">{{vcite book |title=Pharmaceutical Manufacturing Encyclopedia (Sittig's Pharmaceutical Manufacturing Encyclopedia) |edition=3rd |volume=3 |publisher=William Andrew |location=Norwich, NY |year=2007 |pages=2208 |isbn=0-8155-1526-X}}</ref> [[equivalent weight|equimolar]] amounts of dimethylamine and 2-cyanoguanidine are dissolved in [[toluene]] with cooling to make a [[Concentration#Qualitative description|concentrated]] solution, and equimolar amount of [[hydrogen chloride]] is slowly added. The mixture begins to boil on its own, and after cooling, metformin hydrochloride [[precipitate]]s with 96% [[Yield (chemistry)|yield]].

==Pharmacokinetics==
Metformin  has an oral [[bioavailability]] of 50–60% under [[fasting]] conditions, and is absorbed slowly.<ref name=PI>{{vcite web |author=[[Bristol-Myers Squibb]] |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020357s031,021202s016lbl.pdf |title=Glucophage&reg; (metformin hydrochloride tablets) Label Information |year=August 27, 2008 |accessdate=2009-12-08 |publisher=U.S. Food and Drug Administration}}</ref><ref name = Heller>{{vcite journal |author=Heller JB |title=Metformin overdose in dogs and cats |journal=Veterinary Medicine |issue=April |year=2007 |pages=231–233 |url=http://www.aspca.org/site/DocServer/vetm0407_231-234.pdf?docID=11061 }}</ref> Peak plasma concentrations (C<sub>max</sub>) are reached within one to three hours of taking immediate-release metformin and four to eight hours with extended-release formulations.<ref name=PI/><ref name = Heller/> The [[plasma protein binding]] of metformin is negligible, as reflected by its very high [[volume of distribution|apparent volume of distribution]] (300–1000&nbsp;L after a single dose). [[Steady state]] is usually reached in one or two days.<ref name=PI/>

Metformin is not [[drug metabolism|metabolized]]. It is [[clearance (medicine)|cleared]] from the body by [[renal physiology#Secretion|tubular secretion]] and excreted unchanged in the urine; metformin is undetectable in [[blood plasma]] within 24 hours of a single oral dose.<ref name=PI/><ref name=Robert/> The average [[biological half-life|elimination half-life]] in plasma is 6.2 hours.<ref name=PI/> Metformin is distributed to (and appears to accumulate in) [[red blood cell]]s, with a much longer elimination half-life: 17.6 hours<ref name=PI/> (reported as ranging from 18.5 to 31.5 hours in a single-dose study of non-diabetic people).<ref name=Robert>{{vcite journal |author=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 Metab |volume=29 |issue=3 |pages=279–83 |year=2003 |month=June |pmid=12909816 |url=http://www.em-consulte.com/article/80210}}</ref>

==Mechanism of action==
Metformin improves hyperglycemia primarily through its suppression of hepatic glucose production (hepatic [[gluconeogenesis]]).<ref name=Kirpichnikov>{{vcite journal |author=Kirpichnikov D, McFarlane SI, Sowers JR |title=Metformin: an update |journal=Ann Intern Med |volume=137 |issue=1 |pages=25–33 |year=2002 |pmid=12093242 |url=http://www.annals.org/cgi/reprint/137/1/25.pdf|format=PDF}}</ref> The "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third.<ref name = Hundal>{{vcite journal |author=Hundal R, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi S, Schumann W, Petersen K, Landau B, Shulman G |title=Mechanism by which metformin reduces glucose production in type 2 diabetes |journal=Diabetes |volume=49 |issue=12 |pages=2063–9 |year=2000 |pmid=11118008 |doi=10.2337/diabetes.49.12.2063 |url=http://diabetes.diabetesjournals.org/cgi/reprint/49/12/2063 |format=PDF}}</ref> Metformin activates [[AMP-activated protein kinase]] (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and [[lipid|fat]]s;<ref>{{vcite journal |author=Towler MC, Hardie DG |title=AMP-activated protein kinase in metabolic control and insulin signaling |journal=Circ Res |volume=100 |issue=3 |pages=328–41 |year=2007 |pmid=17307971 |url=http://circres.ahajournals.org/cgi/content/full/100/3/328 |doi=10.1161/01.RES.0000256090.42690.05}}</ref> activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells.<ref name = Zhou>{{vcite journal |author=Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman M, Goodyear L, Moller D |title=Role of AMP-activated protein kinase in mechanism of metformin action |journal=J Clin Invest |volume=108 |issue=8 |pages=1167–74 |year=2001 |pmid=11602624 |url=http://www.jci.org/cgi/content/full/108/8/1167 |doi=10.1172/JCI13505}}</ref> Research published in 2008 further elucidated metformin's mechanism of action, showing that activation of AMPK is required for an increase in the expression of [[Small heterodimer partner|SHP]], which in turn inhibits the [[gene expression|expression]] of the hepatic gluconeogenic genes [[Phosphoenolpyruvate carboxykinase|PEPCK]] and [[Glucose 6-phosphatase|Glc-6-Pase]].<ref>{{vcite journal |author=Kim YD, Park KG, Lee YS, ''et al.'' |author.= |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 |year=2008 |pmid=17909097 |url=http://diabetes.diabetesjournals.org/cgi/content/full/57/2/306 |doi=10.2337/db07-0381}}</ref> Metformin is frequently used in research along with [[AICA ribonucleotide|AICAR]] as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain; however, research suggests that metformin increases the amount of [[cytosol]]ic [[Adenosine monophosphate|AMP]] (as opposed to a change in total AMP or total AMP/[[adenosine triphosphate|ATP]]).<ref>{{vcite journal |author=Zhang L, He H, Balschi JA |title=Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration |journal=Am J Physiol Heart Circ Physiol |volume=293 |issue=1 |pages=H457–66 |year=2007 |pmid=17369473 |url=http://ajpheart.physiology.org/cgi/content/full/293/1/H457 |doi=10.1152/ajpheart.00002.2007}}</ref>

In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral [[glucose uptake]], increases [[fatty acid metabolism|fatty acid oxidation]],<ref>{{vcite journal |author=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=Am J Physiol Endocrinol Metab |volume=291 |issue=1 |pages=E182–E189 |year=2006 |pmid=16478780 |doi=10.1152/ajpendo.00272.2005 |url=http://ajpendo.physiology.org/cgi/content/full/291/1/E182}}</ref> and decreases absorption of glucose from the [[gastrointestinal tract]]. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors.<ref>{{vcite journal |author=Bailey CJ, Turner RC |title=Metformin |journal=N Engl J Med |volume=334 |issue=9 |pages=574–9 |year=1996 |pmid=8569826 |doi=10.1056/NEJM199602293340906}}</ref> AMPK probably also plays a role, as metformin administration increases AMPK activity in skeletal muscle.<ref>{{vcite journal |author=Musi N, Hirshman MF, Nygren J, ''et al.'' |author.= |year=2002 |title=Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes |journal=Diabetes |volume=51 |issue=7 |pages=2074–81 |pmid=12086935 |url=http://diabetes.diabetesjournals.org/cgi/content/full/51/7/2074 |doi=10.2337/diabetes.51.7.2074}}</ref> AMPK is known to cause [[GLUT4]] deployment to the plasma membrane, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms; a 2008 study found that "the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by [[p38 mitogen-activated protein kinases|p38 MAPK]]- and [[Protein kinase C|PKC]]-dependent mechanisms."<ref>{{vcite journal |author=Saeedi R, Parsons HL, Wambolt RB, ''et al.'' |author.= |year=2008 |title=Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms |journal=Am J Physiol Heart Circ Physiol |volume=294 |issue=6 |pages=H2497–506 |pmid=18375721 |doi=10.1152/ajpheart.00873.2007 |url=http://ajpheart.physiology.org/cgi/content/full/294/6/H2497}}</ref>

==Interactions==
The [[H2 antagonist|H<sub>2</sub>-receptor antagonist]] [[cimetidine]] causes an increase in the plasma concentration of metformin, by reducing [[clearance (medicine)|clearance]] of metformin by the kidneys;<ref>{{vcite journal |author=Somogyi A, Stockley C, Keal J, Rolan P, Bochner F |title=Reduction of metformin renal tubular secretion by cimetidine in man |journal=Br J Clin Pharmacol |volume=23 |issue=5 |pages=545–51 |year=1987 |month=May |pmid=3593625 |pmc=1386190}}</ref> both metformin and cimetidine are cleared from the body by [[Renal physiology#Secretion|tubular secretion]], and both, particularly the [[cation]]ic (positively [[electric charge|charged]]) form of cimetidine, may compete for the same transport mechanism.<ref name=PI/> A small [[blind experiment|double-blind]], [[randomized controlled trial|randomized]] study found the [[antibiotic]] [[cefalexin]] to also increase metformin concentrations by a similar mechanism;<ref>{{vcite journal |author=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 Metabol Drug Interact |volume=19 |issue=1 |pages=41–8 |year=2002 |pmid=12222753 }}</ref> theoretically, other cationic medications may produce the same effect.<ref name=PI/>

==References==
{{Reflist|2}}

==External links==
{{Portal|Pharmacy and Pharmacology}}
*{{dmoz|Health/Pharmacy/Drugs_and_Medications/M/Metformin|Metformin}}
*[http://www.merck.com/mmpe/lexicomp/metformin.html Metformin drug information] from Lexi-Comp. Includes dosage information and a comprehensive list of international brand names
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Metformin U.S. National Library of Medicine: Drug Information Portal - Metformin]
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