My watch list  


Systematic (IUPAC) name
N,N-dimethylimidodicarbonimidic diamide
CAS number 657-24-9
ATC code A10BA02
PubChem 4091
DrugBank APRD01099
Chemical data
Formula C4H11N5 
Mol. mass 129.164 g/mol
165.63 g/mol (hydrochloride)
Synonyms 1,1-dimethylbiguanide
Pharmacokinetic data
Bioavailability 50 to 60% under fasting conditions
Metabolism None
Half life 6.2 hours
Excretion Active renal tubular excretion by OCT2
Therapeutic considerations
Licence data


Pregnancy cat.


Legal status

POM(UK) -only(US)

Routes Oral

Metformin (INN; trade names Glucophage, Riomet, Fortamet, Glumetza, Diabex, Diaformin, and others) (IPA: /mɛtˈfɔrmɪn/) is an oral anti-diabetic drug from the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, particularly in overweight and obese people and those with normal kidney function.[1][2][3] Metformin is the most popular anti-diabetic drug in the United States and one of the most prescribed drugs in the country overall, with nearly 35 million prescriptions filled in 2006 for generic metformin alone.[4] As of 2007, it is one of only two oral anti-diabetics in the World Health Organization Model List of Essential Medicines (the other being glibenclamide).[5]



The biguanide class of anti-diabetic drugs, which also includes the withdrawn agents phenformin and buformin, originates from the French lilac (Galega officinalis), a plant known for several centuries to reduce the symptoms of diabetes mellitus.[6]

Metformin was first described in the scientific literature in 1957.[7] It was first marketed in France in 1979, but did not receive approval by the U.S. Food and Drug Administration (FDA) for Type 2 diabetes until 1994.[8] Bristol-Myers Squibb's Glucophage was the first branded formulation of metformin to be marketed in the United States, beginning on March 3 1995.[9] Generic formulations are now available.


The main use for metformin is in the treatment of diabetes mellitus type 2, especially when this accompanies obesity and insulin resistance. Metformin is the only anti-diabetic drug that has been proven to reduce the cardiovascular complications of diabetes, as shown in a large study of overweight patients with diabetes.[10] Unlike the other most-commonly prescribed class of oral diabetes drugs, the sulfonylureas, metformin (taken alone) does not induce hypoglycemia.[11] Hypoglycemia during intense exercise has been documented, but is extremely rare.[12] It also does not cause weight gain, and may indeed produce minor weight loss.[13] Metformin also modestly reduces LDL and triglyceride levels.[14]

It is also being used increasingly in polycystic ovarian syndrome (PCOS),[15] non-alcoholic fatty liver disease (NAFLD)[16] and premature puberty,[17] three other diseases that feature insulin resistance; these indications are still considered experimental. Although metformin is not licenced for use in PCOS, the United Kingdom's National Institute for Health and Clinical Excellence recommends that women with PCOS and a body mass index above 25 be given metformin when other therapy has failed to produce results.[18] The benefit of metformin in NAFLD has not been extensively studied and may be only temporary.[19]

Mechanism of action

The exact mechanism of action of metformin is uncertain, despite its known therapeutic benefits. It appears to act mainly by reducing hepatic gluconeogenesis, but it also decreases absorption of glucose from the gastrointestinal tract and increases insulin sensitivity by increasing peripheral utilization of glucose.[20] The 'average' person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third.[21]

A 2001 study showed that metformin stimulates the hepatic enzyme AMP-activated protein kinase (AMPK), which plays an important role in the metabolism of fats and glucose.[22] The molecular targets with which metformin directly interacts remain elusive.

Metformin is not metabolized, rather it is primarily excreted in the urine with an elimination half-life of 6.2 hours. [23]

Adverse effects

Lactic acidosis

The most serious potential side effect of metformin is lactic acidosis; this complication is very rare, and seems limited to those with impaired liver or kidney function.

Phenformin, another biguanide, was withdrawn 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.[24]


The most common adverse effect of metformin is gastrointestinal upset, including diarrhea, cramps, nausea and vomiting; metformin is more commonly associated with gastrointestinal side effects than most other anti-diabetic drugs.[14] 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.[25]

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[26] and malabsorption of vitamin B12.[27][28] Higher doses and prolonged use are associated with increased incidence of B12 deficiency, and some researchers recommend screening or prevention strategies.[29]


There is an initial report, involving four patients with impaired thyroid function, that metformin can suppress the TSH level with no accompanying symptoms of hyperthyroidism or changes in measured thyroid hormone levels. The mechanism is currently unknown.[30]


The H2-receptor antagonist cimetidine causes an increase in the plasma concentration of metformin, by reducing clearance of metformin by the kidneys;[31] 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.[32] A small double-blind, randomized study found the antibiotic cefalexin to also increase metformin concentrations by a similar mechanism;[33] theoretically, other cationic medications may produce the same effect.[32]


Metformin is contraindicated in people with any condition that could increase the risk of lactic acidosis, including kidney disorders (creatinine levels over 150 μmol/l,[34] although this is an arbitrary limit), lung disease and liver disease. Heart failure has long been considered a contraindication for metformin use, although a 2007 systematic review showed metformin to be the only anti-diabetic drug not associated with harm in people with heart failure.[35]

It is recommended that metformin be temporarily discontinued before any radiographic study involving iodinated contrast (such as a contrast-enhanced 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.[36][37] It is recommended that metformin be resumed after two days, assuming kidney function is normal.[36][37]


A review of intentional and accidental metformin overdoses reported to Poison control centers over a 5-year period found that serious adverse events were rare, though elderly patients appeared to be at greater risk.[38] Intentional overdoses with up to 63 g of metformin have been reported in the medical literature.[39] The major potentially life-threatening complication of metformin overdose is lactic acidosis. Treatment of metformin overdose is generally supportive, but may include sodium bicarbonate to address acidosis and standard hemodialysis or continuous veno-venous hemofiltration to rapidly remove metformin and correct acidosis.[40][41]


  Metformin IR (immediate release) is available in 500 mg, 850 mg, and 1000 mg tablets.

Metformin SR (slow release) or XR (extended release) was introduced in 2004, in 500 mg and 750 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.


Metformin is often prescribed to 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.[42] 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 Practices.[43] 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 sulfonylureas glipizide (trade name Metaglip) and glibenclamide (trade name Glucovance), and the dipeptidyl peptidase-4 inhibitor sitagliptin (trade name Janumet).


  1. ^ Clinical Guidelines Task Force, International Diabetes Federation (2005). "Glucose control: oral therapy"PDF (100 KiB). In: Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation, 35–8. Retrieved on November 6 2007.
  2. ^ McIntosh A, Hutchinson A, Home PD, et al. (2001). Clinical guidelines and evidence review for Type 2 diabetes: management of blood glucose.PDF (894 KiB) Sheffield: University of Sheffield, 62–5. Retrieved on November 6 2007.
  3. ^ American Diabetes Association (2007). "Standards of medical care in diabetes—2007". Diabetes Care 30 Suppl 1: S4–S41. doi:10.2337/dc07-S004. PMID 17192377. Free full text
  4. ^ Top 200 Generic Drugs by Units in 2006PDF (19.4 KiB). Drug Topics (March 5, 2007). Retrieved on April 8, 2007.
  5. ^ (March 2007) WHO Model List of Essential MedicinesPDF (612 KiB), 15th edition, World Health Organization, p. 21. Retrieved on 2007-11-19.
  6. ^ Witters L (2001). "The blooming of the French lilac". J Clin Invest 108 (8): 1105–7. PMID 11602616. Full text at PMC: 209536
  7. ^ Ungar G, Freedman L, Shapiro S (1957). "Pharmacological studies of a new oral hypoglycemic drug". Proc Soc Exp Biol Med 95 (1): 190–2. PMID 13432032.
  8. ^ U.S. Food and Drug Administration (December 30, 1994). "FDA Approves New Diabetes Drug". Press release. Retrieved on 2007-01-06.
  9. ^ GLUCOPHAGE Label and Approval History. U.S. Food and Drug Administration. Retrieved on 2007-01-08. Data available for download on FDA website.
  10. ^ (1998) "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". Lancet 352 (9131): 854–65. PMID 9742977.
  11. ^ Kilo C, Mezitis N, Jain R, Mersey J, McGill J, Raskin P. "Starting patients with type 2 diabetes on insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin". J Diabetes Complications 17 (6): 307-13. PMID 14583174.
  12. ^ DiPiro, Joseph T.; Talbert, Robert L.; Yee, Gary C.; Matzke, Gary R.; Wells, Barbara G.; Posey, L. Michael (2005). Pharmacotherapy: a pathophysiologic approach. New York: McGraw-Hill. ISBN 0071416137. 
  13. ^ Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE (1995). "Metabolic effects of metformin in non-insulin-dependent diabetes mellitus". N Engl J Med 333 (9): 550–4. PMID 7623903. Free full text with registration.
  14. ^ a b Bolen S, Feldman L, Vassy J, et al (2007). "Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus". Ann Intern Med 147 (6): 386–99. PMID 17638715.
  15. ^ Lord JM, Flight IHK, Norman RJ (2003). "Metformin in polycystic ovary syndrome: systematic review and meta-analysis". BMJ 327 (7421): 951–3. PMID 14576245.
  16. ^ Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N (2001). "Metformin in non-alcoholic steatohepatitis". Lancet 358 (9285): 893–4. PMID 11567710.
  17. ^ Ibáñez L, Ong K, Valls C, Marcos MV, Dunger DB, de Zegher F (2006). "Metformin treatment to prevent early puberty in girls with precocious pubarche". J. Clin. Endocrinol. Metab. 91 (8): 2888–91. doi:10.1210/jc.2006-0336. PMID 16684823.
  18. ^ UK National Collaborating Centre for Women's and Children’s Health (February 2004). Fertility: assessment and treatment for people with fertility problems. Clinical Guideline 11. UK National Institute for Clinical Excellence. ISBN 1-84257-546-5.  Free full textPDF (161 KiB)
  19. ^ Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP (2004). "Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial". Aliment Pharmacol Ther 20 (1): 23–28. PMID 15225167.
  20. ^ Royal Pharmaceutical Society of Great Britain and the British Medical Association. "Chapter 6:Endocrine system -- Biguanides", British National Formulary, 54. 
  21. ^ Hundal R, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi S, Schumann W, Petersen K, Landau B, Shulman G (2000). "Mechanism by which metformin reduces glucose production in type 2 diabetes". Diabetes 49 (12): 2063–9. PMID 11118008. Free full textPDF (82 KiB)
  22. ^ 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 (2001). "Role of AMP-activated protein kinase in mechanism of metformin action". J Clin Invest 108 (8): 1167–74. PMID 11602624.
  23. ^ Heller, Jacqueline B. (2007). "Metformin overdose in dogs and cats". Veterinary Medicine (April): 231-233.
  24. ^ Salpeter S, Greyber E, Pasternak G, Salpeter E (2003). "Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis". Arch Intern Med 163 (21): 2594–602. PMID 14638559.
  25. ^ (October 2004) Drug Facts and Comparisons 2005, 59th edition, Lippincott Williams & Wilkins. ISBN 1-57439-193-3. 
  26. ^ Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, Donker AJ, Stehouwer CD. (Nov 2003). "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.". J Intern Med 254 (5): 455–63. PMID 14535967.
  27. ^ Andrès E, Noel E, Goichot B (2002). "Metformin-associated vitamin B12 deficiency". Arch Intern Med 162 (19): 2251–2. PMID 12390080.
  28. ^ Gilligan M (2002). "Metformin and vitamin B12 deficiency". Arch Intern Med 162 (4): 484–5. PMID 11863489.
  29. ^ Ting R, Szeto C, Chan M, Ma K, Chow K (2006). "Risk factors of vitamin B(12) deficiency in patients receiving metformin". Arch Intern Med 166 (18): 1975–9. PMID 17030830.
  30. ^ Vigersky RA, Filmore-Nassar A, Glass AR (2006). "Thyrotropin suppression by metformin". J Clin Endocrinol Metab 91 (1): 225–7. doi:10.1210/jc.2005-1210. PMID 16219720.
  31. ^ Somogyi A, Stockley C, Keal J, Rolan P, Bochner F (1987). "Reduction of metformin renal tubular secretion by cimetidine in man". Br J Clin Pharmacol 23 (5): 545–51. PMID 3593625.
  32. ^ a b Glucophage Side Effects & Drug Interactions. (2007). Retrieved on 2007-11-19.
  33. ^ Jayasagar G, Krishna Kumar M, Chandrasekhar K, Madhusudan Rao C, Madhusudan Rao Y (2002). "Effect of cephalexin on the pharmacokinetics of metformin in healthy human volunteers". Drug Metabol Drug Interact 19 (1): 41–8. PMID 12222753.
  34. ^ Jones G, Macklin J, Alexander W (2003). "Contraindications to the use of metformin". BMJ 326 (7379): 4–5. PMID 12511434. Free full text
  35. ^ Eurich DT, McAlister FA, Blackburn DF, et al. (2007). "Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review". BMJ 335 (7618): 497. doi:10.1136/bmj.39314.620174.80. PMID 17761999. Free full text
  36. ^ a b Weir J (March 19 1999). Guidelines with Regard to Metformin-Induced Lactic Acidosis and X-ray Contrast Medium Agents. Royal College of Radiologists. Retrieved on 2007-10-26 through the Internet Archive.
  37. ^ a b Thomsen HS, Morcos SK (2003). "Contrast media and the kidney: European Society of Urogenital Radiology (ESUR) guidelines". Br J Radiol 76 (908): 513–8. PMID 12893691. Free full text
  38. ^ Spiller HA, Quadrani DA (2004). "Toxic effects from metformin exposure". The Annals of pharmacotherapy 38 (5): 776–80. doi:10.1345/aph.1D468. PMID 15031415.
  39. ^ Gjedde S, Christiansen A, Pedersen SB, Rungby J (2003). "Survival following a metformin overdose of 63 g: a case report". Pharmacol. Toxicol. 93 (2): 98–9. PMID 12899672.
  40. ^ Harvey B, Hickman C, Hinson G, Ralph T, Mayer A (2005). "Severe lactic acidosis complicating metformin overdose successfully treated with high-volume venovenous hemofiltration and aggressive alkalinization". Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 6 (5): 598–601. PMID 16148825.
  41. ^ Guo PY, Storsley LJ, Finkle SN (2006). "Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin". Seminars in dialysis 19 (1): 80–3. doi:10.1111/j.1525-139X.2006.00123.x. PMID 16423187.
  42. ^ GlaxoSmithKline (October 12, 2002). "FDA Approves GlaxoSmithKline's Avandamet™ (rosiglitazone maleate and metformin HCl), The Latest Advancement in the Treatment of Type 2 Diabetes". Press release. Retrieved on 2006-12-27.
  43. ^ U.S. Food and Drug Administration (March 4, 2005). "Questions and Answers about the Seizure of Paxil CR and Avandamet". Press release. Retrieved on 2006-12-27.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Metformin". A list of authors is available in Wikipedia.
Your browser is not current. Microsoft Internet Explorer 6.0 does not support some functions on Chemie.DE