Metformin – Some Background Information

Two drugs from the biguanide class, metformin, and phenformin, were developed in 1957. Metformin was eventually found to be 20 times less likely to cause lactic acidosis, but it was tainted by the history of its phenformin.

Two drugs from the biguanide class, metformin, and phenformin, were developed in 1957. Unfortunately, phenformin reached the U.S. market first and resulted in several deaths from lactic acidosis. When this risk surfaced, phenformin was pulled from drugstore shelves worldwide. Metformin was eventually found to be 20 times less likely to cause lactic acidosis, but it was tainted by the history of its cousin. Metformin first became available in France in 1979 and has been widely used in Europe since then, but it was not cleared for use in Type 2 diabetes in the U.S. until 1994.


Target Organ: Liver, secondary effects on muscle, and fat.

Action: Lower glucose production by the liver, increase the number of insulin receptors
on muscle and fat cells

Lowers HbA1c by 1.5% to 2.0%

Time to reach maximum effect: 2-4 hrs
Taken: with meal

Drug Acts Over Dose Range Doses/Day
8-12 hrs 500 – 2550 mg 2-3
Glucophage XR
24 hrs 500 – 2250 mg 1
+ glyburide)
12-18 hrs 250/1.25 to
2000/20 mg
Side Effects: bloating, fullness, nausea, cramping, diarrhea, vitamin B12 deficiency, headache, metallic taste, agitation, lactic acidosis
Contraindications: DKA, alcoholism, binge drinking, kidney or liver disease, congestive heart failure, pregnancy, use of contrast media, surgery, heart attack, age > 80

Metformin is a chemical kin to the French lilac plant, which was noted in the early 1900s to lower the blood sugar. However, French lilac, like phenformin, turned out to be too toxic for use in humans. Metformin, with a much shorter action time than phenformin, has a much lower risk for severe side effects and is quite safe for use by anyone who is otherwise healthy. In fact, in the major UKPDS study, it was the only drug that reduced diabetes-related death rates, heart attacks, and strokes. It should not be used by those who use more than two ounces or two drinks of alcohol a day, who have congestive heart failure, or who have significant kidney, liver, or lung disease.

Metformin lowers fasting blood glucose levels by an average of 25% (17 to 37%), postprandial blood glucose up to 44.5%, and the A1c by an average of 1.5% (0.8 to 3.1%). Metformin reduces raised plasma insulin levels in cases of metabolic syndrome by as much as 30% and reduces the need for injected insulin in Type 2s by 15 to 32%.

Metformin is available under the trade name Glucophage, or as an extended-release tablet called Glucophage XR. It works well when combined with sulfonylureas. A combination of glyburide and metformin is available as Glucovance. Combined therapy leads to a greater reduction in blood sugar than can be attained by either class alone. Generic metformin is available at a reduced cost.

Metformin possesses some distinct advantages in treating diabetes. Excess glucose produced by the liver is the major source of high blood sugars in Type 2 diabetes and is typically the reason for high blood sugars on waking in the morning. Metformin reduces this overproduction of glucose. It helps in lowering the blood sugar, especially after eating, with no risk of hypoglycemia when used alone. Modest improvement in cholesterol levels is also seen. The 10-year UKPDS Study of over 3,000 people with Type 2 diabetes found that those who were placed on metformin had a 36% decrease in overall mortality and a 39% decrease in heart attacks.

Because metformin shuts off the liver’s excess production of glucose, it reduces the amount of injected insulin needed to control the blood sugar in both Type 1 and Type 2 diabetes. People with Type 2 diabetes who are on insulin usually are advised to lower their insulin doses prior to starting metformin. The full improvement in glycemic control and cholesterol levels may not be seen until 4 to 6 weeks of use have passed.

Side effects from metformin include a change in taste, loss of appetite, nausea or vomiting, abdominal bloating or gas, diarrhea, or skin rash. These may occur during the first few weeks of taking the medication but are seldom long-lasting. Taking the medication with food and starting out with a low dose help reduce side effects. The dosage can be gradually increased as side effects diminish.

Lactic acidosis, the serious but rare side effect originally seen with phenformin, results when a buildup of lactic acid occurs due to an inability to clear metformin from the system. Lactic acidosis occurs very rarely, only once in every 30,000 person-years of use. It almost always occurs in older people who have another major health problem, especially one that may impair breathing or circulation. Warning signs of lactic acidosis include fast and shallow breathing, diarrhea, severe muscle aches, cramping, unusual weakness or tiredness, or feeling cold. Because lactic acidosis has a mortality rate of about 40%, anyone who has significant lung disease, congestive heart failure, or kidney disease should never take this drug.

Because drinking alcohol while taking metformin may also trigger lactic acidosis when other health risks are present, be sure to ask your doctor about alcohol consumption if you are taking this drug. Be aware that Tagamet, a gastrointestinal medication, may enhance the effects of metformin. Therefore, the dose of metformin may need to be lower if you already take Tagamet.

Although not yet FDA approved, metformin is now in clinical trials for the treatment of teens who have developed Type 2 diabetes. Some pediatricians also prescribe it, on occasion, to help control a strong Dawn Phenomenon seen in a growing teen with Type 1 diabetes. This use is also not approved. It also helps lower insulin resistance in women with polycystic ovary disease. One side-effect for these women, sometimes the desired outcome, is a greater likelihood of pregnancy.