Metformin

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Metformin
Systematic (IUPAC) name
N,N-dimethylimidodicarbonimidic diamide
Identifiers
CAS number 657-24-9
ATC code A10BA02
A10BD02 (with sulfonylureas)
A10BD03 (with rosiglitazone)
A10BD05 (with pioglitazone)
A10BD07 (with sitagliptin)
A10BD08 (with vildagliptin)
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

US FDA:link
Pregnancy cat.

C(AU) B(US)
Legal status

POM(UK) ℞-only(US)
Routes Oral
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Metformin (INN) (pronounced /mɛtˈfɔrmɪn/; originally sold as Glucophage) is an oral anti-diabetic drug. 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] and studies suggest it may be the best choice for people with heart failure.[4] Evidence is also mounting for its efficacy in gestational diabetes, although safety concerns still preclude its widespread use in this setting. It is also used in the treatment of polycystic ovary syndrome and has been investigated for other diseases where insulin resistance may be an important factor.

When prescribed appropriately, metformin causes few adverse effects—the most common is gastrointestinal upset—and, unlike many other anti-diabetic drugs, does not cause hypoglycemia if used alone. Lactic acidosis (a buildup of lactate in the blood) can be a serious concern in overdose and when it is prescribed to people with contraindications, but otherwise, there is no significant risk. Metformin helps reduce LDL cholesterol and triglyceride levels and may aid weight loss, and is the only anti-diabetic drug that has been conclusively shown to prevent the cardiovascular complications of diabetes. As of 2009, metformin is one of only two oral anti-diabetics in the World Health Organization Model List of Essential Medicines (the other being glibenclamide).[5]

First synthesised and found to reduce blood sugar in the 1920s, metformin was forgotten for the next two decades as research shifted to insulin and other anti-diabetic drugs. Interest in metformin was rekindled in the late 1940s after several reports that it could reduce blood sugar levels in people, and in 1957, French physician Jean Sterne published the first clinical trial of metformin as a treatment for diabetes. It was introduced to the UK in 1958, Canada in 1972, and was approved by the U.S. FDA in 1995. Metformin is now believed to be the most widely prescribed anti-diabetic drug in the world; in the United States alone, more than 40 million prescriptions were filled in 2008 for its generic formulations.[6][7]

Contents

[edit] History

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 used in folk medicine for several centuries.[8]

Metformin was first described in the scientific literature in 1922, by Emil Werner and James Bell, as a side product in the synthesis of N,N-dimethylguanidine.[9] In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, noting that it was the most potent of the biguanide analogs they studied.[10] This result was completely forgotten as other guanidine analogs, such as the synthalins, took over, and were themselves soon overshadowed by insulin.[11]

Interest in metformin, however, picked up at the end of the 1940s. In 1948, Boots Pure Drug Company (now Boots Pharmacy) took a patent on an improved method of preparing metformin and its analogs.[12] In 1950, metformin, unlike some other similar compounds, was found not to decrease blood pressure and heart rate in animals.[13] That same year, a prominent Philippine physician, Eusebio Y. Garcia,[14] used metformin (he named it Fluamine) to treat influenza; he noted that the drug "lowered the blood sugar to minimum physiological limit" in treated patients and was non-toxic. Garcia also believed metformin to have bacteriostatic, antiviral, antimalarial, antipyretic and analgesic actions.[15] In a series of articles in 1954, Polish pharmacologist Janusz Supniewski[16] was unable to confirm most of these effects, including lowered blood sugar; he did, however, observe some antiviral effects in humans.[17][18]

While training at the Hôpital de la Pitié, French diabetologist Jean Sterne studied the antihyperglycemic properties of galegine, an alkaloid isolated from Galega officinalis, which is structurally related to metformin and had seen brief use as an anti-diabetic before the synthalins were developed.[6] Later, working at Laboratoires Aron in Paris, he was prompted by Garcia's report to re-investigate the blood sugar lowering activity of metformin and several biguanide analogs. Sterne was the first to try metformin on humans for the treatment of diabetes; he coined the name "Glucophage" (glucose eater) for the drug and published his results in 1957.[6][11]

Metformin became available in the British National Formulary in 1958. It was sold in the UK by a small Aron subsidiary called Rona. Being a generic drug, it was at a commercial disadvantage; phenformin and buformin were marketed as being more potent and were supported by large pharmaceutical companies with a large sales force. As a result, metformin was mostly used in Scotland and Northern Ireland, while phenformin and buformin achieved worldwide clinical acceptance.[19]

Broad interest in metformin was not rekindled until the withdrawal of the other biguanides in the 1970s. Metformin was approved in Canada in 1972,[20] but did not receive approval by the U.S. Food and Drug Administration (FDA) for Type 2 diabetes until 1994.[21] Produced under license by Bristol-Myers Squibb, Glucophage was the first branded formulation of metformin to be marketed in the United States, beginning on March 3, 1995.[22] Generic formulations are now available in several countries, and metformin is believed to have become the most widely prescribed anti-diabetic drug in the world.[6]

[edit] Therapeutic uses

The main use for metformin is in the treatment of diabetes mellitus type 2, especially in overweight people. In this group, over 10 years of treatment, metformin reduced diabetes complications and overall mortality by about by about 30% when compared with insulin and sulfonylureas (glibenclamide and chlorpropamide) and by about 40% when compared with the group only given dietary advice.[23] This difference held in the patients who were followed for 5–10 years after the study.[24] As metformin affords a similar level of blood sugar control to insulin and sulfonylureas, it appears to decrease mortality primarily through decreasing heart attacks, strokes and other cardiovascular complications. In addition, metformin has no effect on the 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 insulin group - 6 kg.[23][25]

Unlike the other most-commonly prescribed class of oral diabetes drugs, the sulfonylureas, metformin (taken alone) does not induce hypoglycemia.[26] Hypoglycemia during intense exercise has been documented, but is extremely rare.[27] It also does not cause weight gain, and may indeed produce minor weight loss.[28] Metformin also modestly reduces LDL and triglyceride levels.[29]

[edit] Off-label use

Metformin is also being used increasingly in polycystic ovary syndrome (PCOS),[30] non-alcoholic fatty liver disease (NAFLD)[31] and premature puberty,[32] three other diseases that feature insulin resistance; these indications are still considered experimental. The benefit of metformin in NAFLD has not been extensively studied and may be only temporary;[33] although some randomized controlled trials have found significant improvement with its use, the evidence is still insufficient.[34][35]

[edit] Polycystic ovary syndrome

Although metformin is not licensed for use in PCOS, the United Kingdom's National Institute for Health and Clinical Excellence recommended in 2004 that women with PCOS and a body mass index above 25 be given metformin when other therapy has failed to produce results,[36] but subsequent reviews in 2008 and 2009 noted that randomized control trials have in general not shown the promise suggested by the early observational studies, and U.S. and European clinical practice guidelines do not recommend it as a first-line treatment.[37][38] A large Cochrane Collaboration review of 27 randomized clinical trials found that metformin improves ovulation and pregnancy rates, particularly when combined with clomifene, but is not associated with any increase in the number of live births.[39]

[edit] Gestational diabetes

Several observational studies and randomized controlled trials have found that metformin is as effective and safe as insulin for the management of gestational diabetes,[40][41][42] and a small case-control study has suggested that the children of women given metformin instead of insulin may be healthier in the neonatal period.[43] 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.[44]

[edit] Investigational findings

A large case-control study conducted at M.D. Anderson Cancer Center has suggested that metformin may protect against pancreatic cancer. The risk of pancreatic cancer in study participants who took metformin was found to be 62% lower than in participants who had never taken it, whereas participants who had used insulin or secretagogues (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.[45] The study had several limitations, however, and the reason for this risk reduction is still unclear.[45] Observational studies conducted by the University of Dundee have shown a decrease of 25–37% in cancer cases in diabetics taking metformin.[46][47]

A single randomized controlled trial suggested that metformin may reduce weight gain in patients taking atypical antipsychotics, particularly when combined with lifestyle interventions (education, dieting, and exercise).[48]

[edit] Contraindications

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,[49] 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.[4]

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.[50][51] It is recommended that metformin be resumed after two days, assuming kidney function is normal.[50][51]

[edit] Adverse effects

The most common adverse effect of metformin is gastrointestinal upset, including diarrhea, cramps, nausea, vomiting and increased flatulence; metformin is more commonly associated with gastrointestinal side effects than most other anti-diabetic drugs.[29] The most serious potential side effect of metformin use is lactic acidosis; this complication is very rare, and seems limited to people with impaired liver or kidney function.

Metformin has also been reported to reduce the blood levels of thyroid-stimulating hormone in patients with hypothyroidism,[52] and, in men, lutenizing hormone and testosterone.[53][54] The clinical significance of these changes is still unknown.

[edit] Gastrointestinal

In a clinical trial of 286 subjects, 53.2% of the 141 who were given immediate-release metformin (as opposed to placebo) reported diarrhea, versus 11.7% for placebo, and 25.5% reported nausea/vomiting, versus 8.3% for those on placebo.[55]

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[56] and malabsorption of vitamin B12.[57][58] Higher doses and prolonged use are associated with increased incidence of B12 deficiency, and some researchers recommend screening or prevention strategies.[59]

[edit] Lactic acidosis

The most serious potential adverse effect of biguanide use is lactic acidosis. Phenformin, another biguanide, was withdrawn from the market because of an increased risk of lactic acidosis (up to 60 cases per million patient-years). However, metformin is safer than phenformin, and the risk of developing lactic acidosis is not increased by the medication so long as it is not prescribed to known high-risk groups.[60]

[edit] Mechanism

Lactate uptake by the liver is diminished with metformin administration because lactate is a substrate for hepatic gluconeogenesis, a process which metformin inhibits. In healthy individuals, this slight excess is simply cleared by other mechanisms (including uptake by the kidneys, when their function is unimpaired), and no significant elevation in blood levels of lactate occurs.[61] When there is impaired renal function, however, clearance of metformin (and lactate) is reduced and the drug may accumulate, leading to lactic acidosis. Because metformin decreases liver uptake of lactate, any condition which may precipitate lactic acidosis is a contraindication to its use. Common causes of increased lactic acid production include alcoholism (due to depletion of NAD+ stores), heart failure, and respiratory disease (due to inadequate oxygenation of tissues); the most common cause of impaired lactic acid excretion is kidney disease.[62]

It has also been suggested that metformin increases production of lactate in the small intestine; this could potentially contribute to lactic acidosis in patients with risk factors.[63] 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.[61][62][64]

[edit] Overdosage

A review of intentional and accidental metformin overdoses reported to poison control centers over a five-year period found that serious adverse events were rare, though elderly patients appeared to be at greater risk.[65] A similar study where cases were reported to Texas poison control centers between the years 2000 and 2006 found that ingested doses of more than 5,000 mg were more likely to involve serious medical outcomes in adults.[66] Survival following intentional overdoses with up to 63,000 mg (63 g) of metformin have been reported in the medical literature.[67] Fatalities following overdose are rare, but do occur.[68][69][70] In healthy children, unintentional doses of less than 1,700 mg are unlikely to cause any significant toxic effects.[71]

The most common symptoms following overdose appear to include vomiting, diarrhea, abdominal pain, tachycardia, drowsiness, and hyperglycemia.[66][69] The major potentially life-threatening complication of metformin overdose is lactic acidosis, which is due to lactate accumulation.[72][73] Treatment of metformin overdose is generally supportive as there is no specific antidote. Lactic acidosis is initially treated with sodium bicarbonate, although high doses are not recommended as this may increase intracellular acidosis.[70] Acidosis that does not respond to administration of sodium bicarbonate may require further management with standard hemodialysis or continuous veno-venous hemofiltration. Additionally, due to metformin’s low molecular weight and lack of plasma protein binding, these techniques also have the benefit of efficiently removing metformin from blood plasma, preventing further lactate over-production.[74][75][76]

[edit] Chemistry

The usual synthesis of metformin involves reaction of dimethylamine and 2-cyanoguanidine (dicyandiamide) at 120–150°C, and has a yield of 69%:[77][78]

Metformin synthesis.svg

In 2008, an Iranian researcher reported a green synthesis of metformin. A solution of the same reactants used in the Shapiro synthesis was applied to a thin layer chromatography plate and microwaved intermittently for five minutes, obtaining a 92% yield.[78]

[edit] Pharmacokinetics

Metformin has an oral bioavailability of 50–60% under fasting conditions, and is absorbed slowly.[79][80] 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.[79][80] The plasma protein binding of metformin is negligible, as reflected by its very high apparent volume of distribution (300–1000 L after a single dose). Steady state is usually reached in one or two days.[79]

Metformin is not metabolized. It is cleared from the body by tubular secretion and excreted unchanged in the urine; metformin is undetectable in blood plasma within 24 hours of a single oral dose.[79][81] The average elimination half-life in plasma is 6.2 hours.[79] Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours[79] (reported as ranging from 18.5 to 31.5 hours in a single-dose study of non-diabetic people).[81]

[edit] Mechanism of action

Metformin improves hyperglycemia primarily through its suppression of hepatic glucose production (hepatic gluconeogenesis).[63] The "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third.[82] Metformin activates AMP-activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats;[83] activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells.[84] Research published in 2008 further elucidated metformin's mechanism of action, showing that activation of AMPK is required for an increase in the expression of SHP, which in turn inhibits the expression of the hepatic gluconeogenic genes PEPCK and Glc-6-Pase.[85] Metformin is frequently used in research along with AICAR as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain; however, research suggests that metformin increases the amount of cytosolic AMP (as opposed to a change in total AMP or total AMP/ATP).[86]

In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake, increases fatty acid oxidation,[87] and decreases absorption of glucose from the gastrointestinal tract. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors.[88] AMPK probably also plays a role, as metformin administration increases AMPK activity in skeletal muscle.[89] AMPK is known to cause GLUT4 translocation, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms; a 2008 study found that "the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms."[90]

[edit] Interactions

The H2-receptor antagonist cimetidine causes an increase in the plasma concentration of metformin, by reducing clearance of metformin by the kidneys;[91] 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.[79] A small double-blind, randomized study found the antibiotic cefalexin to also increase metformin concentrations by a similar mechanism;[92] theoretically, other cationic medications may produce the same effect.[79]

[edit] Formulations

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Metformin 500 mg tablets

Metformin is sold under several trade names, including Glucophage XR, Riomet, Fortamet, Glumetza, Obimet, Dianben, Diabex, and Diaformin.

Metformin IR (immediate release) is available in 500 mg, 850 mg, and 1000 mg tablets, all 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 patient compliance by reducing pill burden. No difference in effectiveness exists between the two preparations.

[edit] Combinations with other drugs

Metformin is sometimes 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.[93] 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.[94] 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 (known as glyburide in the United States, trade name Glucovance), the dipeptidyl peptidase-4 inhibitor sitagliptin (trade name Janumet), and the meglitinide repaglinide (PrandiMet). Generic formulations of metformin/glipizide and metformin/glibenclamide are available. A generic formulation of metformin/rosiglitazone from Teva has received tentative approval from the FDA, and is expected to reach the market in early 2012.[95]

[edit] References

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