Questions and Anwers About Metformin and Type 2 Diabetes

DIABETES HEALTH: What is metformin?

Dr. Einhorn: Metformin hydrochloride is a new oral anti-hyperglycemic for the treatment of type 2 diabetes. It has been available for decades in other countries but has only been available in the United States since May 1995.

Metformin increases insulin sensitivity and inhibits liver glucose output. It may decrease the absorption of glucose from the intestine. This is different from sulfonylureas like Glucotrol, Micronase, Glynase, and DiaBeta, which act mainly by increasing insulin production. Because of these different effects, metformin works well in combination with sulfonylureas.

DI: Who should take metformin?

DE: The drug is ideal for people with type 2 diabetes who also suffer from obesity and abnormal cholesterol and triglycerides. In combination with sulfonylureas like glyburide and glipizide, metformin works well and may take the place of insulin.

Metformin is a good first or second line agent for the treatment of obese type 2 diabetics, especially those with resistance to insulin. Typically these are individuals with upper body obesity, hypertension, and lipid imbalances in the blood. Since metformin promotes weight loss, decreases hyperglycemia, and improves lipid levels, the drug offers clear advantages.

DI: What are the advantages of Metformin?

DE: As a single agent, metformin is as effective as sulfonylureas for lowering blood glucose. It lowers fasting glucoses by approximately 60 mg/dl, lowers after meal glucoses by approximately 80 mg/dl, and lowers glycohemoglobin by approximately 1.8%.

However, unlike sulfonylureas, metformin actually assists in weight loss, produces no hypoglycemia (when used alone), and lowers triglycerides, total cholesterol and LDL cholesterol. If a patient has good glucose control with sulfonylureas but has side-effects like weight gain or hypoglycemia, the doctor can replace the sulfonylureas with metformin.

Some physicians have used metformin in combination with insulin so as to minimize the insulin dose. This is not an officially recommended use for metformin in the United States but ongoing studies are in progress.

It is believed that millions of patients with type 2 diabetes find that their sulfonylureas are failing them and are afraid to take insulin. The development of metformin may be a very important advance for this group.

DI: How is Metformin given?

DE: Metformin is available in two strengths, 500 mg and 850 mg. It is currently recommended that patients start with 500 mg twice daily with food and increase by 500 mg weekly up to a maximum dose of 2500 mg. An alternative regimen, especially if maximum dose is anticipated, is to begin at 500 mg twice daily for the first week, and then increase to 850 mg twice daily in the second week. This is in preparation for a maximum dose of 850 mg three times a day. If gastrointestinal side effects occur, the dose should be cut back and built up more slowly.

As with every diabetic treatment plan, the goal is to completely normalize glycemic control. This includes normalizing fasting and after-meal glucoses, and glycosylated hemoglobins. Metformin is certainly not a panacea in this regard and use of the drug is no guarantee that insulin treatment will not be necessary.

DI: What if the patient is already taking insulin?

DE: If the patient is a candidate for metformin use, doctors need to taper insulin while increasing the dosage of metformin. Since metformin is no more efficient as a single agent than sulfonylureas, a combination of the two will likely be needed to take advantage of the drugs’ ability to work together. Using metformin just to lower the insulin dose is controversial.

DI: What precautions should be taken with metformin?

DE: The development of lactic acidosis is the major concern. This is very rare and occurs almost exclusively in patients with contraindications (see below). The overall incidence is less than 3 per 100,000. The symptoms of lactic acidosis are non-specific, but include malaise, muscle pain, and respiratory distress with elevated lactic acid levels in the blood. In the past lactic acidosis was fatal, but today, with prompt treatment patients usually recover fully.

DI: What are some drawbacks of metformin?

DE: Metformin may be more expensive, especially considering that most of the sulfonylureas are now available in generic form. It usually requires at least two doses per day and may have some gastrointestinal side-effects including loss of appetite, nausea, or diarrhea. These can be minimized by starting with a low dosage and building up slowly.

In addition to these side-effects, there may be a 7% decrease in vitamin B12 and folic acid levels.

DI: Who should not be taking metformin?

DE: Patients who should not take metformin include males with serum creatinine levels greater than 1.5 and females with a level higher than 1.4. Physicians should recall that creatinines must be corrected for age and for diabetes itself. Elderly people with diabetes may have markedly diminished kidney function which may make them unable to exrete the metformin, even with creatinines that are at the upper limit of normal. Other patients for whom metformin is not recommended are:

• Patients with type I diabetes
• Those who have or are at risk for cardiovascular disease
• Those at increased risk for severe infection, such as patients receiving chemotherapy
• Alcoholics or binge drinkers (even though metformin is not processed by the liver)
• Those with kidney or liver disease
• Patients receiving IV contrast agents such as those used for angiograms or some kidney x-rays
• Children and pregnant women
• Any patient who enters the hospital with a rapidly deteriorating medical condition

DI: What is the current treatment recommendation for type 2 diabetes?

DE: The current approach continues to focus first on the best possible attempt at diet, exercise, and self-monitoring. If that fails to produce normal glycemic control and a normal glycohemoglobin, a regimen of either a sulfonylurea or metformin is prescribed. If single drug therapy fails, then combining metformin with sulfonylureas is appropriate. If that combination fails, insulin therapy is considered.

Dr. Einhorn is Director of the Sharp Healthcare Diabetes Treatment and Research Center in San Diego. He is a member of the Medical Advisory Board for Diabetes Interview and is involved in research with new oral agents for type 2 diabetes, including metformin.