Biguanides are recommended as first-line therapy for type 2 diabetes. Because metformin is an insulin-sparing agent and does not increase body weight or provoke hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia in such persons. The UKPDS reported that metformin therapy decreases the risk of macrovascular as well as microvascular disease; this is in contrast to the other therapies, which only modified microvascular morbidity. Biguanides are also indicated for use in combination with insulin secretagogues or thiazolidinediones in type 2 diabetics in whom oral monotherapy is inadequate. Metformin is useful in the prevention of type 2 diabetes; the landmark Diabetes Prevention Program concluded that metformin is efficacious in preventing the new onset of type 2 diabetes in middle-aged, obese persons with impaired glucose tolerance and fasting hyperglycemia. It is interesting that metformin did not prevent diabetes in older, leaner prediabetics.
Although the recommended maximal dosage is 2.55 g daily, little benefit is seen above a total dosage of 2000 mg daily. Treatment is initiated at 500 mg with a meal and increased gradually in divided doses. Common schedules would be 500 mg once or twice daily increased to 1000 mg twice daily. The maximal dosage is 850 mg three times a day. Epidemiologic studies suggest that metformin use may reduce the risk of some cancers. These data are still preliminary, and the speculative mechanism of action is a decrease in insulin (which also functions as a growth factor) levels as well as direct cellular effects mediated by AMPK. Other studies suggest a reduction in cardiovascular deaths in humans and an increase in longevity in mice (see Chapter 60).
The most common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea), occurring in up to 20% of patients. They are dose related, tend to occur at the onset of therapy, and are often transient. However, metformin may have to be discontinued in 3–5% of patients because of persistent diarrhea.
Metformin interferes with the calcium-dependent absorption of vitamin B12–intrinsic factor complex in the terminal ileum, and vitamin B12 deficiency can occur after many years of metformin use. Periodic screening for vitamin B12 deficiency should be considered, especially in patients with peripheral neuropathy or macrocytic anemia. Increased intake of calcium may prevent the metformin-induced B12 malabsorption.
Lactic acidosis can sometimes occur with metformin therapy. It is more likely to occur in conditions of tissue hypoxia when there is increased production of lactic acid and in renal failure when there is decreased clearance of metformin. Almost all reported cases have involved patients with associated risk factors that should have contraindicated its use (kidney, liver, or cardiorespiratory insufficiency; alcoholism). Acute kidney failure can occur rarely in certain patients receiving radiocontrast agents.
Metformin therapy should therefore be temporarily halted on the day of radiocontrast administration and restarted a day or two later after confirmation that renal function has not deteriorated. Renal function should be checked at least annually in patients on metformin therapy, and lower doses should be used in the elderly who may have limited renal reserve and in those with eGFR between 30 and 45 mL/min per 1.73 m2.