Metformin

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

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The biguanide class of anti-diabetic drugs, which also includes the withdrawn agents phenformin and buformin, originates from the French lilac (Galega officinalis), a plant known for several centuries to reduce the symptoms of diabetes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

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

Indications

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

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

Mechanism of action

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

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

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

Adverse effects

Lactic acidosis

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

Phenformin, another biguanide, was withdrawn because of an increased risk of lactic acidosis (up to 60 cases per million patient-years). However, metformin is safer than phenformin, and the risk of developing lactic acidosis is not increased by the medication so long as it is not prescribed to known high-risk groups.^[24]

Gastrointestinal

The most common adverse effect of metformin is gastrointestinal upset, including diarrhea, cramps, nausea and vomiting; metformin is more commonly associated with gastrointestinal side effects than most other anti-diabetic drugs.^[14] In a clinical trial of 286 subjects, 53.2% of the 141 who were given immediate-release metformin (as opposed to placebo) reported diarrhea, versus 11.7% for placebo, and 25.5% reported nausea/vomiting, versus 8.3% for those on placebo.^[25]

Gastrointestinal upset can cause severe discomfort for patients; it is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1 to 1.7 grams per day) and increasing the dose gradually. Gastrointestinal upset after prolonged, steady use is less common.

Long-term use of metformin has been associated with increased homocysteine levels^[26] and malabsorption of vitamin B₁₂.^[27][28] Higher doses and prolonged use are associated with increased incidence of B₁₂ deficiency, and some researchers recommend screening or prevention strategies.^[29]

Hormonal

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

Interactions

The H₂-receptor antagonist cimetidine causes an increase in the plasma concentration of metformin, by reducing clearance of metformin by the kidneys;^[31] both metformin and cimetidine are cleared from the body by tubular secretion, and both, particularly the cationic (positively charged) form of cimetidine, may compete for the same transport mechanism.^[32] A small double-blind, randomized study found the antibiotic cefalexin to also increase metformin concentrations by a similar mechanism;^[33] theoretically, other cationic medications may produce the same effect.^[32]

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,^[34] although this is an arbitrary limit), lung disease and liver disease. Heart failure has long been considered a contraindication for metformin use, although a 2007 systematic review showed metformin to be the only anti-diabetic drug not associated with harm in people with heart failure.^[35]

It is recommended that metformin be temporarily discontinued before any radiographic study involving iodinated contrast (such as a contrast-enhanced CT scan or angiogram), as contrast dye may temporarily impair kidney function, indirectly leading to lactic acidosis by causing retention of metformin in the body.^[36][37] It is recommended that metformin be resumed after two days, assuming kidney function is normal.^[36][37]

Overdosage

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

Formulations

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

Metformin SR (slow release) or XR (extended release) was introduced in 2004, in 500 mg and 750 mg strengths, mainly to counteract the most common gastrointestinal side effects, as well as to increase patient compliance by reducing pill burden. No difference in effectiveness exists between the two preparations.

Combinations

Metformin is often prescribed to type 2 diabetes patients in combination with rosiglitazone. This drug actively reduces insulin resistance, complementing the action of the metformin. In 2002, the two drugs were combined into a single product, Avandamet, marketed by GlaxoSmithKline.^[42] In 2005, all current stock of Avandamet was seized by the FDA and removed from the market, after inspections showed the factory where it was produced was violating Good Manufacturing Practices.^[43] The drug pair continued to be prescribed separately in the absence of Avandamet, which was available again by the end of that year.

In the United States, metformin is also available in combination with pioglitazone (trade name Actoplus Met), the sulfonylureas glipizide (trade name Metaglip) and glibenclamide (trade name Glucovance), and the dipeptidyl peptidase-4 inhibitor sitagliptin (trade name Janumet).

References