Biguanides

BIGUANIDES

The structure of metformin is shown below. Phenformin (an older biguanide) was discontinued in the USA because of its association with lactic acidosis and because there was no documentation of any long-term benefit from its use.

Mechanisms of Action

A full explanation of the mechanism of action of the biguanides remains elusive, but their primary effect is to reduce hepatic glu-cose production through activation of the enzyme AMP-activated protein kinase (AMPK). Possible minor mechanisms of action include impairment of renal gluconeogenesis, slowing of glucose absorption from the gastrointestinal tract, with increased glucose to lactate conversion by enterocytes, direct stimulation of glycoly-sis in tissues, increased glucose removal from blood, and reduction of plasma glucagon levels. The biguanide blood glucose-lowering action does not depend on functioning pancreatic beta cells. Patients with type 2 diabetes have considerably less fasting hyper-glycemia as well as lower postprandial hyperglycemia after admin-istration of biguanides; however, hypoglycemia during biguanide therapy is essentially unknown. These agents are therefore more appropriately termed “euglycemic” agents.

Metabolism & Excretion

Metformin has a half-life of 1.5–3 hours, is not bound to plasma proteins, is not metabolized, and is excreted by the kidneys as the active compound. As a consequence of metformin’s blockade of gluconeogenesis, the drug may impair the hepatic metabolism of lactic acid. In patients with renal insufficiency, biguanides accu-mulate and thereby increase the risk of lactic acidosis, which appears to be a dose-related complication.

Clinical Use

Biguanides are recommended as first-line therapy for type 2 dia-betes. 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 land-mark 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.

The dosage of metformin is from 500 mg to a maximum of 2.55 g daily, with the lowest effective dose being recommended. Depending on whether the primary abnormality is fasting hyper-glycemia or postprandial hyperglycemia, metformin therapy can be initiated as a once-daily dose at bedtime or before a meal. A common schedule for fasting hyperglycemia would be to begin with a single 500-mg tablet at bedtime for a week or more. If this is tolerated without gastrointestinal discomfort and if hyperglyce-mia persists, a second 500-mg tablet may be added with the eve-ning meal. If further dose increases are required, an additional 500-mg tablet can be added to be taken with breakfast or the midday meal, or the larger (850-mg) tablet can be prescribed twice daily or even three times daily (the maximum recommended dosage) if needed. Dosage should always be divided because inges-tion of more than 1000 mg at any one time usually provokes sig-nificant gastrointestinal adverse effects.

Epidemiologic studies suggest that metformin use may dra-matically 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.

Toxicities

The most common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea), which occur 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. Absorption of vitamin B₁₂ appears to be reduced during long-term metformin therapy, and annual screening of serum vitamin B₁₂ levels and red blood cell parame-ters has been encouraged by the manufacturer to determine the need for vitamin B₁₂ injections. In the absence of hypoxia or renal or hepatic insufficiency, lactic acidosis is less common with met-formin therapy than with phenformin therapy.

Biguanides are contraindicated in patients with renal disease, alcoholism, hepatic disease, or conditions predisposing to tissue anoxia (eg, chronic cardiopulmonary dysfunction) because of the increased risk of lactic acidosis induced by these drugs.