METFORMIN - A REVIEW OF ITS METABOLIC EFFECTS

Metformin is a biguanide that has been used worldwide for the treatmen t of type 2 diabetes for the past 4 decades. It improves glycemic cont rol by enhancing insulin sensitivity in liver and muscle. Metformin do es not stimulate insulin secretion and therefore is not associated wit h hypoglycemia. Improved metabolic control with metformin does not ind uce weight gain and may cause weight loss. Metformin also has a benefi cial effect on several cardiovascular risk factors including dyslipide mia, elevated plasminogen activator inhibitor 1 levels, other fibrinol ytic abnormalities, hyperinsulinemia, and insulin resistance. While me tformin reduces insulin resistance, the cellular mechanism of action i s incompletely understood. Metformin enhances muscle and adipocyte ins ulin receptor number and/or affinity, increases insulin receptor tyros ine kinase activity, stimulates glucose transport and glycogen synthes is, and reduces both hepatic gluconeogenesis and glycogenolysis. In ad dition, metformin has been reported to decrease lipid oxidation and pl asma free fatty acid levels, leading to an inhibition of an overactive Randle cycle. Metformin monotherapy decreases the fasting plasma gluc ose concentration by similar to 60-70 mg/dl and HbA(1c) by 1.5-2.0% in patients with type 2 diabetes. The biguanide is completely additive t o sulfonylureas and vice versa, as well as to acarbose and probably tr oglitazone. In insulin-treated type 2 diabetic patients, the addition of metformin improves insulin sensitivity and glycemic control while a llowing a reduction in the daily insulin dose. Side effects of metform in are primarily confined to the gastrointestinal tract (abdominal dis comfort and diarrhea). These side effects can be minimized by slow tit ration and administration with food. Lactic acidosis is rare, with an incidence of similar to 3 cases per 100,000 patient-years of therapy. Most reported cases of lactic acidosis occur in patients with contrain dications, particularly impaired renal function (>90% of cases). In su mmary, metformin is an effective and safe therapeutic agent for the tr eatment of type 2 diabetes. Its ability to improve insulin sensitivity and the cardiovascular risk profile of type 2 diabetic patients has e nhanced its clinical use as first-line therapy. In the U.K. Prospectiv e Diabetes Study, metformin was the only medication that reduced diabe tes-related death, heart attacks, and stroke. Metformin recently has b een approved for use is poorly controlled, insulin-treated type 2 diab etic subjects. In the future, its indications may expand to insulin-re sistant patients at a high risk of developing type 2 diabetes or with other components of the insulin resistance syndrome.