Metformin
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Clinical data | |
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Other names | 1,1-dimethylbiguanide |
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Routes of administration | Oral |
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Pharmacokinetic data | |
Bioavailability | 50 to 60% under fasting conditions |
Metabolism | None |
Elimination half-life | 6.2 hours |
Excretion | Active renal tubular excretion by OCT2 |
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ECHA InfoCard | 100.010.472 |
Chemical and physical data | |
Formula | C4H11N5 |
Molar mass | 129.164 g/mol 165.63 g/mol (hydrochloride) g·mol−1 |
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Metformin (INN; trade names Glucophage, Glucophage XR, Riomet, Fortamet, Glumetza, Obimet, Dianben, Diabex, Diaformin, and others) (Template:Pron-en) is an oral anti-diabetic drug from the biguanide class. It is the first-line drug for the treatment of type 2 diabetes, particularly in overweight and obese people and those with normal kidney function,[2][3][4] and evidence suggests it may be the best choice for people with heart failure.[5] It is also used in the treatment of polycystic ovary syndrome.
Metformin is the most popular anti-diabetic drug in the United States and one of the most prescribed drugs in the country overall, with more than 40 million prescriptions filled in 2008 for generic metformin alone.[6] 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. It also helps reduce LDL cholesterol and triglyceride levels, and may aid weight loss. As of 2009[update], metformin is one of only two oral anti-diabetics in the World Health Organization Model List of Essential Medicines (the other being glibenclamide).[7]
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The biguanide class of anti-diabetic drugs, which also includes the withdrawn agents phenformin and buformin, originates from the French lilac (Galega officinalis), a plant known for several centuries to reduce the symptoms of diabetes mellitus.[8]
Metformin was first described in the scientific literature in 1957.[9] It was first marketed in France in 1979, but did not receive approval by the U.S. Food and Drug Administration (FDA) for Type 2 diabetes until 1994.[10] Bristol-Myers Squibb's Glucophage was the first branded formulation of metformin to be marketed in the United States, beginning on March 3, 1995.[11] Generic formulations are now available.
Mechanism of action
Metformin improves hyperglycemia primarily through its suppression of hepatic glucose production (hepatic gluconeogenesis).[12] The "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third.[13] 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;[14] activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells.[15] 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.[16] 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).[17]
In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake, increases fatty acid oxidation,[18] and decreases absorption of glucose from the gastrointestinal tract. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors.[19] AMPK probably also plays a role, as metformin administration increases AMPK activity in skeletal muscle.[20] 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."[21]
Clinical use
The main use for metformin is in the treatment of diabetes mellitus type 2, especially when this accompanies sexiness and insulin resistance. Metformin is the only anti-diabetic drug that has been proven to protect against the cardiovascular complications of diabetes.[22] This was first shown in the United Kingdom Prospective Diabetes Study, a large study of overweight patients with diabetes.[23]
Unlike the other most-commonly prescribed class of oral diabetes drugs, the sulfonylureas, metformin (taken alone) does not induce hypoglycemia.[24] Hypoglycemia during intense exercise has been documented, but is extremely rare.[25] It also does not cause weight gain, and may indeed produce minor weight loss.[26] Metformin also modestly reduces LDL and triglyceride levels.[27]
Off-label use
Metformin is being used increasingly in polycystic ovary syndrome (PCOS),[28] non-alcoholic fatty liver disease (NAFLD)[29] and premature puberty,[30] three other diseases that feature insulin resistance; these indications are still[update] considered experimental. Although metformin is not licensed for use in PCOS, the United Kingdom's National Institute for Health and Clinical Excellence recommends that women with PCOS and a body mass index above 25 be given metformin when other therapy has failed to produce results.[31] The benefit of metformin in NAFLD has not been extensively studied and may be only temporary;[32] although some randomized controlled trials have found significant improvement with its use, the evidence is still insufficient.[33][34]
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,[35][36][37] 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.[38] 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.[39]
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.[40] The study had several limitations, however, and the reason for this risk reduction is still unclear.[40] Observational studies conducted by the University of Dundee have shown a decrease of 25–37% in cancer cases in diabetics taking metformin.[41][42]
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).[43]
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,[44] 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.[5]
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.[45][46] It is recommended that metformin be resumed after two days, assuming kidney function is normal.[45][46]
Adverse effects
Lactic acidosis
The most serious potential side effect of metformin is lactic acidosis; this complication is very rare, and seems limited to those with impaired liver or kidney function. Phenformin, another biguanide, was withdrawn because of an increased risk of lactic acidosis (up to 60 cases per million patient-years). However, metformin is safer than phenformin, and the risk of developing lactic acidosis is not increased by the medication so long as it is not prescribed to known high-risk groups.[47]
The reason for the lactic acidosis is believed to be an increase in intestinal anaerobic respiration; normally, the liver would convert this lactate buildup into glucose via gluconeogenesis, but it is this very pathway that metformin inhibits.[12] Any condition which may precipitate lactic acidosis contraindicates the use of metformin.
Gastrointestinal
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.[27] 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.[48]
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[49] and malabsorption of vitamin B12.[50][51] Higher doses and prolonged use are associated with increased incidence of B12 deficiency, and some researchers recommend screening or prevention strategies.[52]
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.[53] Intentional overdoses with up to 63 g of metformin have been reported in the medical literature.[54] The major potentially life-threatening complication of metformin overdose is lactic acidosis. Treatment of metformin overdose is generally supportive, but may include sodium bicarbonate to address acidosis and standard hemodialysis or continuous veno-venous hemofiltration to rapidly remove metformin and correct acidosis.[55][56]
Pharmacokinetics
Metformin has an oral bioavailability of 50–60% under fasting conditions, and is absorbed slowly.[57][58] 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.[57][58] 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.[57]
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.[57][59] The average elimination half-life in plasma is 6.2 hours.[57] Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours[57] (reported as ranging from 18.5 to 31.5 hours in a single-dose study of non-diabetic people).[59]
Interactions
The H2-receptor antagonist cimetidine causes an increase in the plasma concentration of metformin, by reducing clearance of metformin by the kidneys;[60] 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.[61] A small double-blind, randomized study found the antibiotic cefalexin to also increase metformin concentrations by a similar mechanism;[62] theoretically, other cationic medications may produce the same effect.[61]
Formulations
![](http://upload.wikimedia.org/wikipedia/commons/thumb/d/db/Metformin_500mg_Tablets.jpg/200px-Metformin_500mg_Tablets.jpg)
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.
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.[63] 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.[64] 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.[65]
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External links
- Metformin at Curlie
- Metformin drug information from Lexi-Comp. Includes dosage information and a comprehensive list of international brand names