METFORMIN

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.Combinations with other drugsMetformin 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. 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.

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.ContraindicationsMetformin is contraindicated in people with any condition that could increase the risk of lactic acidosis, including kidney disorders (creatinine levels over 150 μmol/l, although this is an arbitrary limit), lung disease and liver disease.

According to the prescribing information, heart failure, in particular, unstable or acute congestive heart failure increases risk of lactic acidosis with metformin. A 2007 systematic review of controlled trials, however, suggested that metformin is the only anti-diabetic drug not associated with any measurable harm in people with heart failure, and that it may reduce mortality in comparison with other anti-diabetic agents.

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

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.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 reduce the blood levels of thyroid-stimulating hormone in patients with hypothyroidism and, in men, lutenizing hormone and testosterone. The clinical significance of these changes is still unknown.

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.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 and malabsorption of vitamin B12.

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

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.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.

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.

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. 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.

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. 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.

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, diarrhea, abdominal pain, tachycardia, drowsiness, and hyperglycemia. 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, although high doses are not recommended as this may increase intracellular acidosis. 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