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Diabetes Drugs: Metformin

Mark Marino

August 14, 2009

Editor’s Note: This is the second post in our miniseries about diabetes drugs. Tune in on August 21 for the next installment.

metforminMetformin (brand names Glucophage, Glucophage XR, Riomet, Fortamet, Glumetza) is a member of a class of medicines known as biguanides. This type of medicine was first introduced into clinical practice in the 1950’s with a drug called phenformin. Unfortunately, phenformin was found to be associated with lactic acidosis, a serious and often fatal condition, and was removed from the U.S. market in 1977.

This situation most likely slowed the approval of metformin, which was not used in the U.S. until 1995. (By comparison, metformin has been used in Europe since the 1960’s.) The U.S. Food and Drug Administration (FDA) required large safety studies of metformin, the results of which demonstrated that the development of lactic acidosis as a result of metformin therapy is very rare. (A finding that has been confirmed in many other clinical trials to date.) Of note, the FDA officer involved in removing phenformin from the market recently wrote an article highlighting the safety of metformin.

Metformin works primarily by decreasing the amount of glucose made by the liver. It does this by activating a protein known as AMP-activated protein kinase, or AMPK. This protein acts much like an “energy sensor,” setting off cellular activities that result in glucose storage, enhanced entry of glucose into cells, and decreased creation of fatty acids and cholesterol.

A secondary effect of the enhanced entry of glucose into cells is improved glucose uptake and increased storage of glycogen (a form of glucose) by the muscles. Additionally, the decrease in fatty acid levels brought about by metformin may indirectly improve insulin resistance and beta cell function. As a result, both glucose and insulin levels in people with Type 2 diabetes decrease with metformin therapy.

The joint guidelines issued by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) for the treatment of people with Type 2 diabetes call for metformin to be used as the first-line drug therapy along with lifestyle interventions (a healthful diet and exercise). Large reviews of multiple studies have shown decreases in HbA1c (an indication of blood glucose control over the previous 2–3 months) from 1% to 2% in people using metformin. In the large United Kingdom Prospective Diabetes Study (UKPDS), metformin was associated with better health outcomes than various other therapies, including chlorpropamide (brand name Diabinese), glibenclamide, also known as glyburide, (DiaBeta and others), or insulin, and was additionally associated with less weight gain and fewer episodes of hypoglycemia (low blood glucose). In fact, the UKPDS is one of the major studies that lead the ADA and EASD to place metformin as the first-line therapy.

Metformin is available as a stand-alone pill and is also available in combination pills with several other types of oral medicines. Various studies have evaluated metformin in combination with glyburide, nateglinide (Starlix), pioglitazone (Actos), insulin, and acarbose (Precose). In all of these studies, there were better health outcomes associated with the combined therapies compared to each of the therapies used alone. Notably, the combination of metformin and insulin not only demonstrated a reduction in HbA1c in studies, but also a reduction in the insulin dose.

Moreover, in various trials using metformin, triglyceride (a type of blood fat) levels have been reduced by approximately 10% to 20%, with an additional reduction in LDL (“bad”) cholesterol.

Metformin has also been used for the treatment of polycystic ovary syndrome (PCOS), although this is not an FDA-approved use.

Metformin is eliminated from the body by the kidneys and has a half-life of 6 hours, meaning that roughly 94% of the drug is removed from the body in 24 hours. It is prescribed in doses from 500 milligrams to 2,000 milligrams and is given 1–3 times daily. It is usually started at a dose of 500 milligrams and slowly raised every one to two weeks to the maximum dose that can be tolerated without side effects. (Doses above 2,000 milligrams have not been shown to be any more effective than a 2,000-milligram dose.)

The major side effects of metformin are gastrointestinal and include an increase in the frequency of bowel movements, diarrhea, nausea, and abdominal pain. These effects may be reduced by taking metformin with meals, as well as by starting off at a low dose that is slowly increased. Some evidence suggests that using an extended-release form of metformin may also decrease gastrointestinal side effects.

Minor side effects of this medicine include a metallic taste and decreased absorption of vitamin B12. As mentioned above, the development of lactic acidosis with this medicine is rare and has been estimated at roughly 4–9 cases per 100,000 people. To prevent the occurrence of lactic acidosis, the use of metformin is not recommended for those older than 80 years old, and for people who have mild kidney dysfunction, congestive heart failure, or a previous history of acidosis, among several other conditions.

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