Metformin Glucophage

Structural Formula Ball-and-Stick Model Space-filling Model

Year of discovery; 1957; Year of introduction: 1979 (BMS; FDA approval only in 1994); Drug category: Antidiabetic biguanide; Main uses: To lower blood glucose and to reduce cardiovascular complications; Approximate number of people treated annually: Over 6 million; Other brand names: Diabex, Diaformin and Fortamet, Related drugs Troglitazone (Rezulin), Rosiglitazone (Avandia), Pioglitazone (Actos).

A key indicator of diabetes is persistent fasting blood glucose levels above a value of ca. 12.5 mg/mL, which arise from defective conversion of glucose into energy. The utilization of glucose by organs and tissues is controlled by the hormone insulin which is produced in the (3-islet cells of the pancreas. When this process becomes inefficient for any reason, blood glucose levels increase and cells are deprived of energy. Persistently high blood glucose levels (hyperglycemia) result in widespread damage in the body that can eventually lead to hypertension, heart disease, stroke, impaired circulation, nerve dysfunction, pain, infection, or organ failure.

There are two main categories of diabetes, type 1 and type 2. In type 1 diabetes, usually designated as insulin-dependent diabetes, the (3-cells of the pancreas no longer produce insulin (e.g., due to autoimmune destruction of these cells) and administered insulin is required to sustain life. In type 2 diabetes, noninsuiin-dependent or obesity related diabetes, insulin action is impaired (insulin resistance), blood glucose levels are elevated and both metabolism and energy production are compromised.

The onset of type 2 diabetes usually occurs in adults over the age of 40 and is often associated with excessive body weight (and especially abdominal fat).1 The type 2 condition is multifactorial with genetic, nutritional, body weight, physical activity, and other components. Type 2 diabetes accounts for 90% of all cases of diabetes and affects over 60 million people in the US and Europe. Type 2 diabetes is a progressive disease for which there is currently no cure, although it can be managed. If not treated, people eventually develop the more serious combined type 1 and type 2 condition.2

Several classes of blood glucose lowering medications have been developed over the past half century to help normalize blood glucose in type 2 diabetes. They each work by a different mechanism. The most commonly used oral drug for type 2 diabetes, metformin (a biguanide), works by reducing glucose release from the liver, increasing the transport of glucose into muscle, hence increasing insulin sensitivity, and also decreasing the absorption of glucose from the gastrointestinal tract. Metformin acts biochemically to increase the level of adenosine monophosphate-activated protein kinase (AMP-APK), an enzyme that plays a control role in energy production and fatty acid metabolism. In turn, AMP-APK raises the levels of ATP, the source of power in cells.3 Another beneficial effect of metformin is the downregulation of protein kinase C, a mediator of inflammation and, for example, a cause of macular degeneration.

Although metformin was discovered in 1957, it was not approved by the FDA until 1994 for the treatment of type 2 diabetes. Currently metformin is marketed both as a generic drug and under the brand name Glucophage. Metformin is also available in combination with the DPP-4 inhibitor sitagliptin (Janumetâ„¢, Merck; see page 63).

1. Annual Review of Pathology: Mechanisms of Disease 2007, 2, 31-56; 2. Int. J. Vitam. Nutr. Res. 2006, 76, 172177; 3, Diabetes, Obesity and Metabolism 2006, 8, 591-602; Refs. p. 82

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