Metformin

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Metformin

Metformin (Glucophage®, Fortamet®, Riomet®) is an anti-diabetic drug from the biguanide class (its other members are the withdrawn agents phenformin and buformin).

Uses

The main use for metformin is for the treatment of diabetes mellitus, especially when it is concomitant with obesity and insulin resistance.

It is also being used increasingly in polycystic ovarian syndrome (PCOS) and non-alcoholic steatohepatitis, two other diseases that feature insulin resistance; these indications are still considered experimental.

Metformin is the only anti-diabetic drug that has been proven to reduce the complications of diabetes, as evidenced in a large study of overweight patients with diabetes (UKPDS 1998).

Metformin is often prescribed to type 2 diabetes patients in combination with rosiglitazone maleate. 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. This was due to problems at the manufacturing plants, not to any medical issues resulting from the drugs use. [http://www.fda.gov/oc/qanda/PaxilandAvandamet.html The drug pair continued to be prescribed separately in the absence of Avandamet itself, which was readily available by the end of that year.

Mechanism of action

Despite its therapeutic benefits, the mechanism of action of metformin is uncertain. Its mode of action appears to be reduction of hepatic gluconeogenesis; the "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis. Metformin treatment reduces this by one third to two thirds. It has been shown that metformin also decreases intestinal absorption of glucose. A third mechanism is that metformin improves insulin sensitivity by increasing peripheral glucose uptake and utilization (although such an effect will occur nonspecifically following the lowering of glucose however achieved). Zhou et al (2001) showed that metformin stimulates the hepatic enzyme AMP-activated protein kinase.

Side effects

The most serious side effect of metformin is lactic acidosis. However, this complication is rare if the contra-indications are followed, as it seems limited to those with impaired liver and/or kidney function.

Phenformin was withdrawn because of an increased risk of lactic acidosis (up to 60 cases per million patient-years). In recent studies it was revealed that, as long as it is not prescribed to patients who are at risk, metformin is much safer, and the risk of lactic acidosis approximates that of people who are not on the medication (Salpeter SR et al 2003).

The most common side effect of metformin is gastrointestinal upset. This includes diarrhea, cramps, nausea and vomiting. In a clinical trial of 286 subjects, 53.2% of the 141 who were given Metformin IR (as opposed to placebo) reported diarrhea, and 25.5% reported nausea/vomiting (source: Drug Facts & Comparisons 2005).

The side effect of gastrointestinal upset can be source of severe discomfort for patients. It is very common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning and increasing the dose gradually. Gastrointestinal upset after prolonged, steady use is less common. For the relief of diarrhea and intestinal cramping, a small, non-prescription dose (~10mg) of codeine should be effective.

Contraindications

Metformin should not be used in any condition that may increase the risk of lactic acidosis. This includes heart failure, kidney disorders (creatinine over 150 μmol/l), lung disease and liver disease. Metformin should be temporarily discontinued before any radiographic procedure involving iodinated contrast (such as a CT scan or angiogram) as contrast may indirectly cause lactic acidosis due to temporary impairment of kidney fuction. Patients should always inform their physician if they are taking metformin before consenting to any radiographic procedure.

History

The class of biguanide originates from the French lilac (Galega officinalis), a plant known for several centuries to improve the symptoms of diabetes mellitus (Witters 2001).

Metformin was first described in the scientific literature in 1957 (Unger et al). It was first marketed in France in 1979 but did not receive FDA approval for Type 2 diabetes until 1994. In recent studies, metformin has been used in treating PCOS. A group of women with PCOS have been put on metformin 500mg three times a day for 8 weeks. Ten out of them got pregnant and 6 started to have regular periods.

Sources

Unger G, Fredman L, Shapiro SL. Pharmacologic studies of a new oral hypoglycemic drug. Proc Soc Exp Biol Med. 1957; 95:190-92.
Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Arch Intern Med 2003;163:2594-602. PMID 14638559.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65. PMID 9742977.
Witters LA. The blooming of the French lilac. J Clin Invest 2001;108:1105-1107. DOI 10.1172/JCI200114178.
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167-1174. DOI 10.1172/JCI200113505.

References

Anti-diabetic drugs | Diabetes