Metformin
Systematic (IUPAC) name
1-(diaminomethylidene)-3,3-dimethyl-guanidine
Identifiers
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)
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	US Metformin HCl, biguanide antidiabetic drug I composed this image myself in OpenOffice Draw, based on web resources. ... Image File history File links Size of this preview: 800 × 520 pixel Image in higher resolution (1000 × 650 pixel, file size: 107 KB, MIME type: image/png) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): Metformin ... IUPAC nomenclature is a system of naming chemical compounds and of describing the science of chemistry in general. ... CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences, mixtures and alloys. ... The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. ... A division of the Anatomical Therapeutic Chemical Classification System A Alimentary tract and metabolism A10A Insulins and analogues A10AB Insulins and analogues, fast-acting A10AB01 Insulin (human) A10AB02 Insulin (beef) A10AB03 Insulin (pork) A10AB04 Insulin lispro A10AB05 Insulin aspart A10AB30 Combinations A10AC Insulins and analogues, intermediate-acting A10AC01 Insulin (human... PubChem is a database of chemical molecules. ... The DrugBank database available at the University of Alberta is a unique bioinformatics and cheminformatics resource that combines detailed drug (i. ... A chemical formula (also called molecular formula) is a concise way of expressing information about the atoms that constitute a particular chemical compound. ... General Name, Symbol, Number carbon, C, 6 Chemical series nonmetals Group, Period, Block 14, 2, p Appearance black (graphite) colorless (diamond) Atomic mass 12. ... This article is about the chemistry of hydrogen. ... General Name, Symbol, Number nitrogen, N, 7 Chemical series nonmetals Group, Period, Block 15, 2, p Appearance colorless gas Atomic mass 14. ... The molecular mass (abbreviated MM) of a substance, formerly also called molecular weight and abbreviated as MW, is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... In chemistry, hydrochlorides are salts resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (mostly amines). ... In pharmacology, bioavailability is used to describe the fraction of an administered dose of medication that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. ... It has been suggested that Effective half-life be merged into this article or section. ... Excretion is the process of eliminating waste products of metabolism and other materials that are of no use. ... It has been suggested that Renal anomalies and Renal plasma threshold be merged into this article or section. ... The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ...
Pregnancy cat.	C(AU) B(US) The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. ... Anthem: Advance Australia Fair Royal anthem: God Save the Queen Capital Canberra Largest city Sydney Official languages English (de facto 1) Government Constitutional monarchy (federal)  - Queen Elizabeth II  - Governor-General Michael Jeffery  - Prime Minister John Howard Independence from the UK   - Constitution 1 January 1901   - Statute of Westminster 11 December 1931... Motto: (Out Of Many, One) (traditional) In God We Trust (1956 to date) Anthem: The Star-Spangled Banner Capital Washington D.C. Largest city New York City None at federal level (English de facto) Government Federal constitutional republic  - President George Walker Bush (R)  - Vice President Dick Cheney (R) Independence from...
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Routes	Oral

Metformin (INN; trade names Glucophage, Diabex, Diaformin, Fortamet, Riomet, Glumetza and others) is an anti-diabetic drug from the biguanide class of oral hypoglycemic agents. Other biguanides include the withdrawn agents phenformin and buformin. Metformin is the most popular anti-diabetic drug in the United States and one of the most prescribed drugs overall, with nearly 30 million prescriptions filled in 2005.^[1] In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body 1. ... An International Nonproprietary Name (INN) is the official non-proprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization. ... An anti-diabetic drug or oral hypoglycemic agent is used to treat diabetes mellitus. ... Biguanides (ATC A10 BA) form a class of oral hypoglycemic drugs used for diabetes mellitus treatment. ... Phenformin is an anti-diabetic drug from the biguanide class. ... Buformin is an anti-diabetic drug of the biguanide class, chemically related to metformin and phenformin. ...

History

The biguanide class of anti-diabetic drugs originates from the French lilac (Galega officinalis), a plant known for several centuries to reduce the symptoms of diabetes mellitus.^[2] Binomial name Galega officinalis L. Galega officinalis (also known as Goats Rue, French Lilac, Italian Fitch or Professor-weed) is a plant from the Galega genus of the Faboideae. ... For the disease characterized by excretion of large amounts of severely diluted urine, see diabetes insipidus. ...

Metformin was first described in the scientific literature in 1957.^[3] 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.^[4] Bristol-Myers Squibb's Glucophage was the first presentation of metformin to be marketed in the United States, on March 3, 1996.^[5] Generic formulations are now available. The Food and Drug Administration (FDA) is an agency of the United States Department of Health and Human Services and is responsible for regulating food (humans and animal), dietary supplements, drugs (human and animal), cosmetics, medical devices (human and animal) and radiation emitting devices (including non-medical devices), biologics, and... Bristol-Myers Squibb (NYSE: BMY), colloquially referred to as BMS, is a pharmaceutical corporation, formed by a 1989 merger between pharmaceutical companies Bristol-Myers Company, founded in 1887 by William McLaren Bristol and John Ripley Myers in Clinton, NY (both were graduates of Hamilton College), and Squibb Corporation. ... A generic drug (pl. ...

Indications

The main use for metformin is in the treatment of diabetes mellitus type 2, especially when this accompanies obesity and insulin resistance. See diabetes mellitus for further general information on diabetes. ... Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. ...

It is also being used increasingly in polycystic ovarian syndrome (PCOS),^[6] non-alcoholic fatty liver disease (NAFLD)^[7] and premature puberty,^[8] 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.^[9] The benefit of metformin in NAFLD has not been extensively studied and may be only temporary.^[10] Polycystic ovary syndrome (PCOS, also known clinically as Stein-Leventhal syndrome), is an endocrine disorder that affects 5–10% of women. ... Non-alcoholic fatty liver disease (NAFLD) is fatty inflammation of the liver when this is not due to excessive alcohol use. ... Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. ... 2007 is a common year starting on Monday of the Gregorian calendar. ... Off-label use is the practice of prescribing drugs for a purpose outside the scope of the drugs approved label, most often concerning the drugs indication. ... The National Institute for Health and Clinical Excellence or NICE is an agency of the National Health Service in the United Kingdom. ... A graph of body mass index is shown above. ...

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.^[11] Unlike the other most-commonly prescribed oral diabetes drugs, the sulfonylureas, metformin monotherapy will not induce hypoglycemia.^[12] Sulfonylurea derivatives are a class of antidiabetic drugs that are used in the management of diabetes mellitus type 2 (adult-onset). They act by increasing insulin release from the beta cells in the pancreas. ... Hypoglycemia (hypoglycæmia in the UK) is a medical term referring to a pathologic state produced by a lower than normal amount of sugar (glucose) in the blood. ...

Mechanism of action

The exact mechanism of action of metformin is uncertain despite its known therapeutic benefits. Its mode of action appears to be reduction of hepatic gluconeogenesis, decreased absorption of glucose from the gastrointestinal tract, and increased insulin sensitivity. The 'average' person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third.^[13] It has also been shown to decrease intestinal absorption of glucose, and may also improve insulin sensitivity by increasing peripheral glucose uptake and utilization, although such an effect will occur nonspecifically following the lowering of glucose levels, regardless of how this lowering was achieved. 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.^[14] Wikipedia does not yet have an article with this exact name. ... Pyruvic acid Oxaloacetic acid Phosphoenolpyruvate Fructose 1,6-bisphosphate Fructose 6-phosphate Glucose-6-phosphate Glucose Gluconeogenesis is the generation of glucose from non-sugar carbon substrates like pyruvate, lactate, glycerol, and amino acids (primarily alanine and glutamine). ... The gastrointestinal tract (GI tract), also called the digestive tract, alimentary canal, or gut, is the system of organs within multicellular animals that takes in food, digests it to extract energy and nutrients, and expels the remaining waste. ... 5AMP-activated protein kinase or AMPK consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans, that plays a role in cellular energy homeostasis. ... A polyunsaturated triglyceride. ...

Adverse effects

Lactic acidosis

The most serious side effect of metformin is lactic acidosis; this complication is rare if the contra-indications are followed, as it seems limited to those with impaired liver or kidney function. An adverse drug reaction (abbreviated ADR) is a term to describe the unwanted, negative consequences sometimes associated with the use of medications. ... Lactic acidosis is a condition caused by the buildup of lactic acid in the body. ...

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 and the risk of developing lactic acidosis is not changed by the medication, so long as it is not prescribed to the known high-risk groups.^[15] Phenformin is an anti-diabetic drug from the biguanide class. ... Lactic acidosis is a condition caused by the buildup of lactic acid in the body. ... Look up million in Wiktionary, the free dictionary. ...

Gastrointestinal

The most common side effect of metformin is gastrointestinal upset, including diarrhea, cramps, nausea and vomiting. In a clinical trial of 286 subjects, 53.2% of the 141 who were given Metformin IR (as opposed to placebo) reported diarrhea, versus 11.7% for placebo, and 25.5% reported nausea/vomiting, versus 8.3% for those on placebo.^[16] Types 5-7 on the Bristol Stool Chart are often associated with diarrhea Diarrhea (in American English) or diarrhoea (in British English) is a generally unpleasant condition in which the sufferer has frequent watery, loose bowel movements (from the ancient Greek word διαρροή = leakage; literally meaning to run through). Acute infectious... A placebo is a medicine or preparation which has no inheren pertinent pharmacologic activity but which is effective only by virtue of the factor of suggestion attendant upon its administration. ...

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^[17] and malabsorption of vitamin B₁₂.^[18][19] Higher doses and prolonged use are associated with increased incidence of B₁₂ deficiency, and some researchers recommend screening or prevention strategies.^[20] Homocysteine is a variant of the amino acid cysteine, differing in that its side-chain contains an additional methylene (-CH2-) group before the thiol (-SH) group. ... Malabsorption is the state of impaired absorption of nutrients in the small intestine. ... Cyanocobalamin is a vitamin commonly known as vitamin B12 (or B12 for short). ...

Contraindications

Metformin is contraindicated in any condition that may increase the risk of lactic acidosis, including heart failure, kidney disorders (creatinine levels over 150 μmol/l,^[21] although this is an arbitrary limit), lung disease and liver disease. It is recommended that metformin be temporarily discontinued before any radiographic procedure involving iodinated contrast (such as a CT scan or angiogram) as contrast may temporarily impair kidney function and indirectly lead to lactic acidosis. Lactic acidosis is a condition caused by the buildup of lactic acid in the body. ... It has been suggested that Renal anomalies and Renal plasma threshold be merged into this article or section. ... Chemical structure of creatinine. ... In medicine, pulmonology is the specialty that deals with diseases of the lungs and the respiratory tract. ... The liver is an organ in vertebrates including humans. ... General Name, Symbol, Number iodine, I, 53 Chemical series halogens Group, Period, Block 17, 5, p Appearance violet-dark gray, lustrous Atomic mass 126. ... Radiocontrast agents (or simply contrast agents) are compounds used to improve the visibility of internal bodily structures in an X-ray image. ... This article does not adequately cite its references or sources. ... Patient about to undergo an angiogram, image courtesy of WHO. Angiography or arteriography is a medical imaging technique in which an X-ray picture is taken to visualize the inner opening of blood filled structures, including arteries, veins and the heart chambers. ...

Formulations

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 side effects, as well as increase patient compliance (e.g. taking one tablet once a day instead of one tablet multiple times per day). No difference in glycemic control exists between the two preparations.

Combinations

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.^[22] 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.^[23] The drug pair continued to be prescribed separately in the absence of Avandamet, which was available again by the end of that year. See diabetes mellitus for further general information on diabetes. ... Rosiglitazone is an anti-diabetic drug from the thiazolidinedione class. ... GlaxoSmithKline plc (LSE: GSK NYSE: GSK) is a British based pharmaceutical, biologicals, and healthcare company. ... Good Manufacturing Practice is a set of regulations, codes, and guidelines for the manufacture of drug substances (also known as active pharmaceutical ingredients (APIs)) and drug products (known as medicinal products in Europe), medical devices, in vivo and in vitro diagnostic products, and foods. ...

In the United States, metformin is also available in combination with pioglitazone (trade name Actoplus Met) and the sulfonylureas glipizide (trade name Metaglip) and glibenclamide (trade name Glucovance). In medicine and pharmacology, pioglitazone is a member of the drug class of the thiazolidinediones. ... Sulfonylurea derivatives are a class of antidiabetic drugs that are used in the management of diabetes mellitus type 2 (adult-onset). They act by increasing insulin release from the beta cells in the pancreas. ... Glipizide is an oral medium-to-long acting anti-diabetic drug from the sulfonylurea class. ... Glibenclamide is a class of drug known as sulphonylureas. ...

References