Metformin
Overview
 
Metformin is an oral antidiabetic drug in the biguanide
Biguanide
Biguanide can refer to a molecule, or to a class of drugs based upon this molecule. Biguanides can function as oral antihyperglycemic drugs used for diabetes mellitus or prediabetes treatment...

 class. It is the first-line drug of choice for the treatment of type 2 diabetes
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...

, in particular, in overweight
Overweight
Overweight is generally defined as having more body fat than is optimally healthy. Being overweight is a common condition, especially where food supplies are plentiful and lifestyles are sedentary...

 and obese
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...

 people and those with normal kidney function. Its use in gestational diabetes
Gestational diabetes
Gestational diabetes is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy . It is widely accepted as a disease only in the United States, there is some question whether the condition is natural during pregnancy...

 has been limited by safety concerns. It is also used in the treatment of polycystic ovary syndrome
Polycystic ovary syndrome
Polycystic ovary syndrome is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain aetiology, but there is strong evidence that it can to a large degree be classified as a genetic disease....

, and has been investigated for other diseases where insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

 may be an important factor. Metformin works by suppressing glucose production by the liver.

Metformin is the only antidiabetic drug that has been conclusively shown to prevent the cardiovascular complications of diabetes.
Encyclopedia
Metformin is an oral antidiabetic drug in the biguanide
Biguanide
Biguanide can refer to a molecule, or to a class of drugs based upon this molecule. Biguanides can function as oral antihyperglycemic drugs used for diabetes mellitus or prediabetes treatment...

 class. It is the first-line drug of choice for the treatment of type 2 diabetes
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...

, in particular, in overweight
Overweight
Overweight is generally defined as having more body fat than is optimally healthy. Being overweight is a common condition, especially where food supplies are plentiful and lifestyles are sedentary...

 and obese
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...

 people and those with normal kidney function. Its use in gestational diabetes
Gestational diabetes
Gestational diabetes is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy . It is widely accepted as a disease only in the United States, there is some question whether the condition is natural during pregnancy...

 has been limited by safety concerns. It is also used in the treatment of polycystic ovary syndrome
Polycystic ovary syndrome
Polycystic ovary syndrome is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain aetiology, but there is strong evidence that it can to a large degree be classified as a genetic disease....

, and has been investigated for other diseases where insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

 may be an important factor. Metformin works by suppressing glucose production by the liver.

Metformin is the only antidiabetic drug that has been conclusively shown to prevent the cardiovascular complications of diabetes. It helps reduce LDL cholesterol and triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....

 levels, and is not associated with weight gain. , metformin is one of only two oral antidiabetics in the World Health Organization Model List of Essential Medicines (the other being glibenclamide
Glibenclamide
Glibenclamide , also known as glyburide , is an antidiabetic drug in a class of medications known as sulfonylureas, closely related to sulfa drugs...

).

When prescribed appropriately, metformin causes few adverse effects
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

—the most common is gastrointestinal upset—and is associated with a low risk of hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...

. Lactic acidosis
Lactic acidosis
Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood accompanied by the buildup of lactate especially D-lactate, and is considered a distinct form of metabolic acidosis. The condition typically occurs when cells receive too little oxygen , for example...

 (a buildup of lactate
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...

 in the blood) can be a serious concern in overdose and when it is prescribed to people with contraindication
Contraindication
In medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...

s, but otherwise, there is no significant
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....

 risk.

First synthesized
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...

 and found to reduce blood sugar in the 1920s, metformin was forgotten for the next two decades as research shifted to insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

 and other antidiabetic 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
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

 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 antidiabetic drug in the world; in the United States alone, more than 48 million prescriptions were filled in 2010 for its generic formulations
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...

.

Medical uses

Metformin is primarily used for type 2 diabetes however is increasingly being used in polycystic ovary syndrome
Polycystic ovary syndrome
Polycystic ovary syndrome is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain aetiology, but there is strong evidence that it can to a large degree be classified as a genetic disease....

 (PCOS),
non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease is one cause of a fatty liver, occurring when fat is deposited in the liver not due to excessive alcohol use. It is related to insulin resistance and the metabolic syndrome and may respond to treatments originally developed for other insulin-resistant states...

 (NAFLD) and premature puberty, three other diseases that feature insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

; these indications are considered experimental. The benefit of metformin in NAFLD has not been extensively studied and may be only temporary; although some randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...

s have found significant improvement with its use, the evidence is still insufficient.

Type 2 diabetes

The main use for metformin is in the treatment of diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...

 type 2, especially in overweight
Overweight
Overweight is generally defined as having more body fat than is optimally healthy. Being overweight is a common condition, especially where food supplies are plentiful and lifestyles are sedentary...

 people. In this group, over 10 years of treatment, metformin reduced diabetes complications and overall mortality by about 30% when compared with insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

 and sulfonylurea
Sulfonylurea
Sulfonylurea derivatives are a class of antidiabetic drugs that are used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta cells in the pancreas.-First generation:* Carbutamide...

s (glibenclamide
Glibenclamide
Glibenclamide , also known as glyburide , is an antidiabetic drug in a class of medications known as sulfonylureas, closely related to sulfa drugs...

 and chlorpropamide
Chlorpropamide
Chlorpropamide is a drug in the sulphonylurea class used to treat type 2 diabetes mellitus. It is a long-acting sulphonylurea. It has more side effects than other sulphonylureas and its use is no longer recommended.-Mechanism of action:...

) and by about 40% when compared with the group only given dietary advice. This difference held in people who were followed up for five to 10 years after the study. Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight people with diabetes, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in this group. In addition, metformin had no effect on body weight: Over the 10-year treatment period, the metformin group gained about 1 kg, the same as the dietary advice group, while the sulfonylureas group gained 3 kg, and the insulin group, 6 kg. As metformin affords a similar level of blood sugar
Blood sugar
The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally in mammals, the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM , or 64.8 and 104.4 mg/dL...

 control to insulin and sulfonylureas, it appears to decrease mortality primarily through decreasing heart attacks, strokes and other cardiovascular complications.

Metformin has a lower risk of hypoglycemia than the sulfonylureas, although it has uncommonly occurred during intense exercise, calorie deficit, or when used with other agents to lower blood glucose. Metformin is also not associated with weight gain, and modestly reduces LDL
Low density lipoprotein
Low-density lipoprotein is one of the five major groups of lipoproteins, which in order of size, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, that enable transport of cholesterol within the water-based bloodstream...

 and triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....

 levels.

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
Incidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...

 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. 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. It is unclear whether metformin slowed down the progression of prediabetes to diabetes (true preventive effect), or the decrease of diabetes in the treated population was simply due to its glucose-lowering action (treatment effect).

Polycystic ovary syndrome

Antidiabetic therapy has been proposed as a treatment for polycystic ovary syndrome
Polycystic ovary syndrome
Polycystic ovary syndrome is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain aetiology, but there is strong evidence that it can to a large degree be classified as a genetic disease....

 (PCOS), a condition frequently associated with insulin resistance, since the late 1980s. The use of metformin in PCOS was first reported in 1994, in a small study conducted at the University of the Andes, Venezuela. The United Kingdom's National Institute for Health and Clinical Excellence
National Institute for Health and Clinical Excellence
The National Institute for Health and Clinical Excellence is a special health authority of the English National Health Service , serving both English NHS and the Welsh NHS...

 recommended in 2004 that women with PCOS and a body mass index
Body mass index
The body mass index , or Quetelet index, is a heuristic proxy for human body fat based on an individual's weight and height. BMI does not actually measure the percentage of body fat. It was invented between 1830 and 1850 by the Belgian polymath Adolphe Quetelet during the course of developing...

 above 25 be given metformin for anovulation
Anovulation
An anovulatory cycle is a menstrual cycle during which the ovaries do not release an oocyte. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause...

 and infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...

 when other therapy has failed to produce results. However, two large clinical studies completed in 2006–2007 returned mostly negative results, with metformin being no better than placebo, and a metformin-clomifene
Clomifene
Clomifene or clomiphene or Clomid or Clomifert is a selective estrogen receptor modulator that increases production of gonadotropins by inhibiting negative feedback on the hypothalamus...

 combination no better than clomifene alone. Reflecting this, subsequent reviews noted large randomized control trials have in general not shown the promise suggested by the early small studies. U.K. and international clinical practice guidelines do not recommend metformin as a first-line treatment or do not recommend it at all, except for women with glucose intolerance. 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. A BMJ editorial noted four positive studies of metformin were in people not responding to clomifene, while the population in the negative studies was drug-naive or uncontrolled for the previous treatment. The editorial suggested metformin should be used as a second-line drug if clomifene treatment fails. 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. A large Cochrane Collaboration
Cochrane Collaboration
The Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...

 review of 27 randomized clinical trials found metformin improves ovulation and pregnancy rates, particularly when combined with clomifene
Clomifene
Clomifene or clomiphene or Clomid or Clomifert is a selective estrogen receptor modulator that increases production of gonadotropins by inhibiting negative feedback on the hypothalamus...

, but is not associated with any increase in the number of live births.

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 endpoint may have biased some trials against metformin, which works slower than clomifene. Another explanation may be different efficacy of metformin in different populations. The negative trials contained a large percent of obese and previously untreated people whose response to metformin may be weaker.

Gestational diabetes

Several observational studies
Observational study
In epidemiology and statistics, an observational study draws inferences about the possible effect of a treatment on subjects, where the assignment of subjects into a treated group versus a control group is outside the control of the investigator...

 and randomized controlled trials have found metformin is as effective and safe as insulin for the management of gestational diabetes, and a small case-control study has suggested the children of women given metformin instead of insulin may be healthier in the neonatal
Infant
A newborn or baby is the very young offspring of a human or other mammal. A newborn is an infant who is within hours, days, or up to a few weeks from birth. In medical contexts, newborn or neonate refers to an infant in the first 28 days after birth...

 period. 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.

Investigational findings

A large case-control study conducted at M.D. Anderson Cancer Center has suggested metformin may protect against pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...

. The risk of pancreatic cancer in study participants having taken metformin was found to be 62% lower than in participants never having taken it, whereas participants that had used insulin or secretagogue
Secretagogue
A secretagogue is a substance that causes another substance to be secreted. One example is gastrin,, which stimulates the H/K ATPase in the parietal cells...

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. The study had several limitations, however, and the reason for this risk reduction is still unclear. Observational studies conducted by the University of Dundee
University of Dundee
The University of Dundee is a university based in the city and Royal burgh of Dundee on eastern coast of the central Lowlands of Scotland and with a small number of institutions elsewhere....

 have shown a decrease of 25–37% in cancer cases in diabetics taking metformin. Several epidemiological and case-controlled studies found diabetics using metformin may have lower cancer risk in comparison to those using other antidiabetic medications. The causes of this phenomenon are unclear, and the results require confirmation in controlled studies. A direct action of metformin on cancer cells is suspected. Indeed, metformin exhibits a strong and consistent anti-proliferative action on several cancer cell lines including breast, colon, ovarian, pancreatic, lung and prostate cancer cells. These cellular studies were generally completed by preclinical studies showing a reliable anti-tumoral effect in various mouse models. In addition, the first clinical trials demonstrate a beneficial effect in breast and colon cancer.

A single randomized controlled trial suggested metformin may reduce weight gain in people taking atypical antipsychotic
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...

s, in particular, when combined with lifestyle interventions (education, dieting, and exercise).

Contraindications

Metformin is contraindicated
Contraindication
In medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...

 in people with any condition that could increase the risk of lactic acidosis
Lactic acidosis
Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood accompanied by the buildup of lactate especially D-lactate, and is considered a distinct form of metabolic acidosis. The condition typically occurs when cells receive too little oxygen , for example...

, including kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

 disorders (creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...

 levels over 150 μmol/l (1.7 mg/dL), although this is an arbitrary limit), lung disease and liver disease
Liver disease
Liver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...

. According to the prescribing information
Package insert
A package insert or prescribing information is a document provided along with a prescription medication to provide additional information about that drug.-Responsible agencies:In the United States, the Food and Drug Administration determines the requirements...

, heart failure, in particular, unstable or acute congestive heart failure, increases risk of lactic acidosis with metformin. A 2007 systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...

 of controlled trials, however, suggested metformin is the only antidiabetic drug not associated with any measurable harm in people with heart failure, and that it may reduce mortality in comparison with other antidiabetic agents.

Metformin is recommended to be temporarily discontinued before any radiographic study
Medical imaging
Medical imaging is the technique and process used to create images of the human body for clinical purposes or medical science...

 involving iodinated
Iodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....

 contrast
Radiocontrast
Radiocontrast agents are a type of medical contrast medium used to improve the visibility of internal bodily structures in an X-ray based imaging techniques such as computed tomography or radiography...

 agents, (such as a contrast-enhanced CT scan
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...

 or angiogram
Angiogram
Angiography or arteriography is a medical imaging technique used to visualize the inside, or lumen, of blood vessels and organs of the body, with particular interest in the arteries, veins and the heart chambers...

), as the contrast dye may temporarily impair kidney function, indirectly leading to lactic acidosis by causing retention of metformin in the body. Metformin can be resumed after two days, assuming kidney function is normal.

Adverse effects

The most common adverse effect
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

 of metformin is gastrointestinal upset, including diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

, cramps, nausea, vomiting and increased flatulence
Flatulence
Flatulence is the expulsion through the rectum of a mixture of gases that are byproducts of the digestion process of mammals and other animals. The medical term for the mixture of gases is flatus, informally known as a fart, or simply gas...

; metformin is more commonly associated with gastrointestinal side effects than most other antidiabetic drugs. 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.

Metformin has also been reported to decrease the blood levels of thyroid-stimulating hormone
Thyroid-stimulating hormone
Thyrotrophin-stimulating hormone is a peptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid gland.- Physiology :...

 in people with hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...

, and, in men, testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...

. The clinical significance of these changes is still unknown.

Gastrointestinal

In a clinical trial of 286 subjects, 53.2% of the 141 given immediate-release metformin (as opposed to placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...

) reported diarrhea, versus 11.7% for placebo, and 25.5% reported nausea/vomiting, versus 8.3% for those on placebo.

Gastrointestinal upset can cause severe discomfort; 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
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...

 levels and malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...

 of vitamin B12
Cyanocobalamin
Cyanocobalamin is an especially common vitamer of the vitamin B12 family. It is the most famous vitamer of the family, because it is, in chemical terms, the most air-stable...

. Higher doses and prolonged use are associated with increased incidence of vitamin B12 deficiency, and some researchers recommend screening or prevention strategies.

Lactic acidosis

The most serious potential adverse effect of biguanide use is lactic acidosis
Lactic acidosis
Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood accompanied by the buildup of lactate especially D-lactate, and is considered a distinct form of metabolic acidosis. The condition typically occurs when cells receive too little oxygen , for example...

, the incidence for which is 9 per 100,000 person-years. Phenformin
Phenformin
Phenformin is an anti-diabetic drug from the biguanide class. It was marketed as DBI by Ciba-Geigy but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases....

, another biguanide, was withdrawn from the market because of an increased risk of lactic acidosis (rate of 40-64 per 100,000 patient-years). However, metformin is safer than phenformin, and the risk of developing lactic acidosis is not increased by the medication as long as it is not prescribed to known high-risk groups.

Lactate uptake by the liver is diminished with metformin administration because lactate is a substrate for hepatic gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....

, a process that 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. When there is impaired renal function, however, clearance of metformin and lactate is reduced, leading to increased levels of both, and possibly causing lactic acidosis due to a buildup of lactic acid. Because metformin decreases liver uptake of lactate, any condition that may precipitate lactic acidosis is a contraindication to its use. Common causes of increased lactic acid production include alcoholism
Alcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...

 (due to depletion of NAD+
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...

 stores), heart failure, and respiratory disease (due to inadequate oxygenation of tissues); the most common cause of impaired lactic acid excretion is kidney disease.

Metformin has also been suggested to increase production of lactate in the small intestine; this could potentially contribute to lactic acidosis in those with risk factors. 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.

Overdose

A review of intentional and accidental metformin overdoses reported to poison control center
Poison control center
A poison control center is a medical facility that is able to provide immediate, free, and expert treatment advice and assistance over the telephone in case of exposure to poisonous or hazardous substances...

s over a five-year period found serious adverse events were rare, though the elderly appeared to be at greater risk. A similar study where cases were reported to Texas poison control centers between the years 2000 and 2006 found ingested doses of more than 5,000 mg were more likely to involve serious medical outcomes in adults. Survival following intentional overdoses with up to 63,000 mg (63 g) of metformin have been reported in the medical literature. Fatalities following overdose are rare, but do occur. In healthy children, unintentional doses of less than 1,700 mg are unlikely to cause any significant toxic effects.

The most common symptoms following overdose appear to include vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

, abdominal pain
Abdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...

, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...

, drowsiness, and, rarely, hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...

 or hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...

. The major potentially life-threatening complication of metformin overdose is lactic acidosis, which is due to lactate accumulation. Treatment of metformin overdose is generally supportive, as there is no specific antidote. Lactic acidosis is initially treated with sodium bicarbonate
Sodium bicarbonate
Sodium bicarbonate or sodium hydrogen carbonate is the chemical compound with the formula Na HCO3. Sodium bicarbonate is a white solid that is crystalline but often appears as a fine powder. It has a slightly salty, alkaline taste resembling that of washing soda . The natural mineral form is...

, although high doses are not recommended, as this may increase intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...

 acidosis. Acidosis that does not respond to administration of sodium bicarbonate may require further management with standard hemodialysis
Hemodialysis
In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...

 or continuous veno-venous hemofiltration
Hemofiltration
In medicine, hemofiltration, also haemofiltration, is a renal replacement therapy similar to hemodialysis which is used almost exclusively in the intensive care setting...

. In addition, due to metformin’s low molecular weight and lack of plasma protein binding
Plasma protein binding
A drug's efficiency may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, α, β‚ and γ...

, these techniques also have the benefit of efficiently removing metformin from blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

, preventing further lactate overproduction.

Metformin may be quantitated in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Blood or plasma metformin concentrations are usually in a range of 1–4 mg/L in persons receiving the drug therapeutically, 40–120 mg/L in victims of acute overdosage, and 80–200 mg/L in fatalities. Chromatographic techniques are commonly employed.

Interactions

The H2-receptor antagonist cimetidine
Cimetidine
Cimetidine INN is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet...

 causes an increase in the plasma concentration of metformin, by reducing clearance
Clearance (medicine)
In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics...

 of metformin by the kidneys; both metformin and cimetidine are cleared from the body by tubular secretion, and both, particularly the cationic (positively charged
Electric charge
Electric charge is a physical property of matter that causes it to experience a force when near other electrically charged matter. Electric charge comes in two types, called positive and negative. Two positively charged substances, or objects, experience a mutual repulsive force, as do two...

) form of cimetidine, may compete for the same transport mechanism. A small double-blind, randomized study found the antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...

 cefalexin
Cefalexin
Cefalexin or more commonly cephalexin is a first-generation cephalosporin antibiotic introduced in 1967 by Eli Lilly and Company. It is an orally administered agent with a similar antimicrobial spectrum to the intravenous agents cefalotin and cefazolin...

 to also increase metformin concentrations by a similar mechanism; theoretically, other cationic medications may produce the same effect.

Mechanism of action

Metformin improves hyperglycemia primarily by suppressing glucose production by the liver (hepatic gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....

). The "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third. Metformin activates AMP-activated protein kinase
AMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. It consists of three proteins that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of...

 (AMPK), an enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fat
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...

s; activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells. Research published in 2008 further elucidated metformin's mechanism of action, showing activation of AMPK is required for an increase in the expression of SHP
Small heterodimer partner
The small heterodimer partner also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain...

, which in turn inhibits the expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...

 of the hepatic gluconeogenic genes PEPCK
Phosphoenolpyruvate carboxykinase
Phosphoenolpyruvate carboxykinase is an enzyme in the lyase family used in the metabolic pathway of gluconeogenesis. It converts oxaloacetate into phosphoenolpyruvate and carbon dioxide.It is found in two forms, cytosolic and mitochondrial....

 and Glc-6-Pase
Glucose 6-phosphatase
Glucose 6-phosphatase is an enzyme that hydrolyzes glucose-6-phosphate resulting in the creation of a phosphate group and free glucose. Glucose is then exported from the cell via glucose transporter membrane proteins...

. Metformin is frequently used in research along with AICAR
AICA ribonucleotide
5-Aminoimidazole-4-carboxamide ribotide is an intermediate in the generation of inosine monophosphate....

 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
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....

ic AMP
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...

 (as opposed to a change in total AMP or total AMP/ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

).

In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake
Glucose uptake
Method of glucose uptake differs throughout tissues depending on two factors; the metabolic needs of the tissue and availability of glucose. The two ways in which glucose uptake can take place are facilitated diffusion and secondary active transport .- Facilitated diffusion :There are over 10...

 (by phosphorylating GLUT-4 enhancer factor), increases fatty acid oxidation
Fatty acid metabolism
Fatty acids are an important source of energy and adenosine triphosphate for many cellular organisms. Excess fatty acids, glucose, and other nutrients can be stored efficiently as fat. Triglycerides yield more than twice as much energy for the same mass as do carbohydrates or proteins. All cell...

, and decreases absorption of glucose from the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....

. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors. AMPK probably also plays a role, as metformin administration increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4
GLUT4
Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle that is responsible for insulin-regulated glucose translocation into the cell...

 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 "the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK
P38 mitogen-activated protein kinases
P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis....

- and PKC
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...

-dependent mechanisms."

Chemistry

The usual synthesis
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...

 of metformin, originally described in 1922 and reproduced in multiple later patents and publications, involves the reaction of dimethylamine
Dimethylamine
Dimethylamine is an organic compound with the formula 2NH. This secondary amine is a colorless, flammable liquified gas with an ammonia-like odor. Dimethylamine is generally encountered as a solution in water at concentrations up to around 40%...

 hydrochloride
Hydrochloride
In chemistry, hydrochlorides are salts resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base . This is also known as muriate, derived from hydrochloric acid's other name: muriatic acid....

 and 2-cyanoguanidine
2-Cyanoguanidine
2-Cyanoguanidine or commonly dicyandiamide is an nitrile derived from guanidine. It is a dimer of cyanamide, from which it can be prepared. 2-Cyanoguanidine is a colourless solid that is soluble in water, acetone, and alcohol, but not in diethyl ether or chloroform.-Production and...

 (dicyandiamide) with heating.
According to the procedure described in the 1975 Aron patent, and the Pharmaceutical Manufacturing Encyclopedia, equimolar
Equivalent weight
Equivalent weight is a term which has been used in several contexts in chemistry. In its most general usage, it is the mass of one equivalent, that is the mass of a given substance which will:...

 amounts of dimethylamine and 2-cyanoguanidine are dissolved in toluene
Toluene
Toluene, formerly known as toluol, is a clear, water-insoluble liquid with the typical smell of paint thinners. It is a mono-substituted benzene derivative, i.e., one in which a single hydrogen atom from the benzene molecule has been replaced by a univalent group, in this case CH3.It is an aromatic...

 with cooling to make a concentrated solution, and an equimolar amount of hydrogen chloride
Hydrogen chloride
The compound hydrogen chloride has the formula HCl. At room temperature, it is a colorless gas, which forms white fumes of hydrochloric acid upon contact with atmospheric humidity. Hydrogen chloride gas and hydrochloric acid are important in technology and industry...

 is slowly added. The mixture begins to boil on its own, and after cooling, metformin hydrochloride precipitates with a 96% yield
Yield (chemistry)
In chemistry, yield, also referred to as chemical yield and reaction yield, is the amount of product obtained in a chemical reaction. The absolute yield can be given as the weight in grams or in moles...

.

Structure

The structure of metformin was generally represented in a wrong tautomeric form for a number of years. This was corrected in 2005. The energy difference between the correct tautomer and the generally represented tautomer is about 9 kcal/mol. The drug is administered as metformin hydrochloride. The structure of the metformin hydrochloride was also corrected recently. According to these studies, the metformin has different electronic structure compared to its protonated form. The neutral species is a simple conjugated system. Upon protonation, (i) the conjugation breaks down, (ii) the intramolecular hydrogen bond breaks down, (iii) the molecule becomes non-planar (iv) two lone pairs get accumulated at the central nitrogen (v) dynamism increases in the system via C=N rotational process and via N-inversion process. Thus, electronically, metformin hydrochloride should be treated as a simple extension of metformin. The nucleophilicity of metformin hydrochloride is moderate and that is a desired property. Metformin is shown to belong to a new class of compounds called nitreones.

Pharmacokinetics

Metformin has an oral bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...

 of 50–60% under fasting
Fasting
Fasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. An absolute fast is normally defined as abstinence from all food and liquid for a defined period, usually a single day , or several days. Other fasts may be only partially restrictive,...

 conditions, and is absorbed slowly. Peak plasma concentrations (Cmax) are reached within one to three hours of taking immediate-release metformin and four to eight hours with extended-release formulations. The plasma protein binding
Plasma protein binding
A drug's efficiency may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, α, β‚ and γ...

 of metformin is negligible, as reflected by its very high apparent volume of distribution
Volume of distribution
The volume of distribution , also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing...

 (300–1000 L after a single dose). Steady state
Steady state
A system in a steady state has numerous properties that are unchanging in time. This implies that for any property p of the system, the partial derivative with respect to time is zero:...

 is usually reached in one or two days.

Metformin has acid dissociation constant values (pKa) of 2.8 and 11.5 and, therefore, exists very largely as the hydrophilic cationic species at physiological pH values. The metformin acid dissociation constant values (pKa) make metformin a stronger base than most other basic drugs with less than 0.01% unionized in blood. Furthermore, the lipid solubility of the unionized species is slight as shown by its low logP value [log(10) of the distribution coefficient of the unionized form between octanol and water] of -1.43. These chemical parameters indicate low lipophilicity and, consequently, rapid passive diffusion of metformin through cell membranes is unlikely. The logP of metformin is less than that of phenformin
Phenformin
Phenformin is an anti-diabetic drug from the biguanide class. It was marketed as DBI by Ciba-Geigy but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases....

 (-0.84) because two methyl substituents on metformin impart lesser lipophilicity than the larger phenylethyl side chain in phenformin. More lipophilic derivatives of metformin are presently being investigated with the aim of producing prodrugs with better oral absorption than metformin itself.

Metformin is not metabolized
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...

. It is cleared
Clearance (medicine)
In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics...

 from the body by tubular secretion and excreted unchanged in the urine; metformin is undetectable in blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 within 24 hours of a single oral dose. The average elimination half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...

 in plasma is 6.2 hours. Metformin is distributed to (and appears to accumulate in) red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...

s, with a much longer elimination half-life: 17.6 hours (reported as ranging from 18.5 to 31.5 hours in a single-dose study of non-diabetic people).

History

The biguanide
Biguanide
Biguanide can refer to a molecule, or to a class of drugs based upon this molecule. Biguanides can function as oral antihyperglycemic drugs used for diabetes mellitus or prediabetes treatment...

 class of antidiabetic drugs, which also includes the withdrawn agents phenformin
Phenformin
Phenformin is an anti-diabetic drug from the biguanide class. It was marketed as DBI by Ciba-Geigy but was withdrawn from most markets in the late 1970s due to a high risk of lactic acidosis, which was fatal in 50% of cases....

 and buformin
Buformin
Buformin is an oral anti-diabetic drug of the biguanide class, chemically related to metformin and phenformin. Buformin was marketed by German pharmaceutical company Grünenthal as Silubin.-Chemistry and Animal Toxicology:...

, originates from the French lilac
Galega officinalis
Galega officinalis, commonly known as goat's rue, French lilac, Italian fitch or professor-weed, is an herbaceous plant in the Faboideae subfamily. It is native to the Middle East, but it has been naturalised in Europe, western Asia, and western Pakistan...

 or goat's rue (Galega officinalis), a plant used in folk medicine for several centuries.
Metformin was first described in the scientific literature in 1922, by Emil Werner and James Bell, as a product in the synthesis of N,N-dimethylguanidine. In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, noting it was the most potent of the biguanide analogs they studied. This result was completely forgotten, as other guanidine
Guanidine
Guanidine is a crystalline compound of strong alkalinity formed by the oxidation of guanine. It is used in the manufacture of plastics and explosives. It is found in urine as a normal product of protein metabolism. The molecule was first synthesized in 1861 by the oxidative degradation of an...

 analogs, such as the synthalin
Synthalin
Synthalin was an oral anti-diabetic drug. Discovered in 1926 it was marketed in Europe by Schering AG of Berlin as a synthetic drug with insulin-like properties that could be taken orally...

s, took over, and were themselves soon overshadowed by insulin.

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. That same year, a prominent Philippine physician, Eusebio Y. Garcia, used metformin (he named it Fluamine) to treat influenza; he noted the drug "lowered the blood sugar to minimum physiological limit" and was nontoxic. Garcia also believed metformin to have bacteriostatic, antiviral
Antiviral
Antiviral may refer to:*Antiviral drug*Antiviral protein*Antivirus software*Antiviral Therapy, an academic journal...

, antimalarial, antipyretic
Antipyretic
Antipyretics ; an-tee-pahy-ret-iks; from the Greek anti, against, and pyreticus, are drugs or herbs that reduce fever. Normally, they will not lower body temperature if one does not have a fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature...

 and analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 actions. In a series of articles in 1954, Polish pharmacologist Janusz Supniewski was unable to confirm most of these effects, including lowered blood sugar; he did, however, observe some antiviral effects in humans.

While training at the Hôpital de la Pitié
Pitié-Salpêtrière Hospital
The Pitié-Salpêtrière Hospital is a teaching hospital located in Paris, France. Part of the Assistance publique - Hôpitaux de Paris, it is one of Europe's largest hospitals...

, French diabetologist Jean Sterne studied the antihyperglycemic properties of galegine, an alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

 isolated from Galega officinalis, which is related in structure to metformin and had seen brief use as an antidiabetic before the synthalins were developed. Later, working at Laboratoires Aron in Paris, he was prompted by Garcia's report to reinvestigate the blood sugar lowering activity of metformin and several biguanide analogs. Sterne was the first to try metformin on humans for the treatment of diabetes; he coined the name "Glucophage" (glucose eater) for the drug and published his results in 1957.

Metformin became available in the British National Formulary
British National Formulary
The British National Formulary is a medical and pharmaceutical reference book that contains a wide spectrum of information and advice on prescribing and pharmacology, along with specific facts and details about all medicines available on the National Health Service , including indication,...

 in 1958. It was sold in the UK by a small Aron subsidiary called Rona.

Broad interest in metformin was not rekindled until the withdrawal of the other biguanides in the 1970s. Metformin was approved in Canada in 1972, but did not receive approval by the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 (FDA) for type 2 diabetes until 1994. Produced under license by Bristol-Myers Squibb
Bristol-Myers Squibb
Bristol-Myers Squibb , often referred to as BMS, is a pharmaceutical company, headquartered in New York City. The company was formed in 1989, following the merger of its predecessors Bristol-Myers and the Squibb Corporation...

, Glucophage was the first branded formulation of metformin to be marketed in the United States, beginning on March 3, 1995. Generic
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...

 formulations are now available in several countries, and metformin is believed to have become the most widely prescribed antidiabetic drug in the world.

Formulations

Metformin is sold under several trade name
Trade name
A trade name, also known as a trading name or a business name, is the name which a business trades under for commercial purposes, although its registered, legal name, used for contracts and other formal situations, may be another....

s, including Glucophage XR, Riomet, Fortamet, Glumetza, Obimet, Gluformin, Dianben, Diabex, and Diaformin.

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

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 compliance by reducing pill burden. No difference in effectiveness exists between the two preparations.

Combinations with other drugs

When used for type 2 diabetes, metformin is often prescribed in combination with other drugs. Several are available as fixed-dose combinations, also with the purpose of reducing pill burden and making administration simpler and more convenient.

As of 2009, the most popular brand-name combination was metformin with rosiglitazone
Rosiglitazone
Rosiglitazone is an antidiabetic drug in the thiazolidinedione class of drugs. It works as an insulin sensitizer, by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin...

, sold as Avandamet by GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...

 since 2002. Rosiglitazone actively makes cells more sensitive to insulin, complementing the action of the metformin. 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
Good Manufacturing Practice
"Good manufacturing practice" or "GMP" are practices and the systems required to be adapted in pharmaceutical manufacturing, quality control, quality system covering the manufacture and testing of pharmaceuticals or drugs including active pharmaceutical ingredients, diagnostics, foods,...

s. 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
Pioglitazone
Pioglitazone is a prescription drug of the class thiazolidinedione with hypoglycemic action.Pioglitazone is marketed as trademarks Actos in the USA, Canada, the UK and Germany, Glustin in Europe,"Glizone" and "Pioz" in India by Zydus CND and USV respectively and Zactos in Mexico by Takeda...

 (trade name Actoplus Met), the sulfonylureas glipizide
Glipizide
Glipizide is an oral medium-to-long acting anti-diabetic drug from the sulfonylurea class. It is classified as a second generation sulfonylurea, which means that it undergoes enterohepatic circulation. The structure on the R2 group is a much larger cyclo or aromatic group compared to the 1st...

 (trade name Metaglip) and glibenclamide
Glibenclamide
Glibenclamide , also known as glyburide , is an antidiabetic drug in a class of medications known as sulfonylureas, closely related to sulfa drugs...

 (known as glyburide in the United States, trade name Glucovance), the dipeptidyl peptidase-4 inhibitor
Dipeptidyl peptidase-4 inhibitors
Inhibitors of dipeptidyl peptidase 4, also DPP-4 inhibitors or gliptins, are a class of oral hypoglycemics that block DPP-4. They can be used to treat diabetes mellitus type 2....

 sitagliptin
Sitagliptin
Sitagliptin is an oral antihyperglycemic of the dipeptidyl peptidase-4 inhibitor class. It was developed, and is marketed, by Merck & Co...

 (with the combination sold under the trade name Janumet), the dipeptidyl peptidase-4 inhibitor
Dipeptidyl peptidase-4 inhibitors
Inhibitors of dipeptidyl peptidase 4, also DPP-4 inhibitors or gliptins, are a class of oral hypoglycemics that block DPP-4. They can be used to treat diabetes mellitus type 2....

 saxagliptin
Saxagliptin
Saxagliptin , previously identified as BMS-477118, is a new oral hypoglycemic of the new dipeptidyl peptidase-4 inhibitor class of drugs. Early development was solely by Bristol-Myers Squibb; in 2007 AstraZeneca joined with Bristol-Myers Squibb to co-develop the final compound and collaborate on...

 (with the combination sold under the trade name Kombiglyze XR), and the meglitinide
Meglitinide
Meglitinides, aka "Glinides", are a class of drugs used treat diabetes type 2.They bind to an ATP-dependent K+ channel on the cell membrane of pancreatic beta cells in a similar manner to sulfonylureas but at a separate binding site. This inhibits a tonic, hyperpolarizing outflux of potassium,...

 repaglinide
Repaglinide
Repaglinide is for the treatment of type II diabetes. It is supplied by Novo Nordisk...

 (PrandiMet). Generic formulations of metformin/glipizide and metformin/glibenclamide are available (the latter being more popular). A generic formulation of metformin/rosiglitazone from Teva
Teva Pharmaceutical Industries
Teva Pharmaceutical Industries Ltd. , is an international pharmaceutical company headquartered in Petah Tikva, Israel. It specializes in generic and proprietary pharmaceuticals and active pharmaceutical ingredients...

has received tentative approval from the FDA, and is expected to reach the market in early 2012.

External links

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