Metformin: A review of its metabolic effects

Metformin is a biguanide that has been used worldwide for the treatment of type 2 diabetes for the past 4 decades. It improves glycemic control by enhancing insulin sensitivity in liver and muscle. Metformin does not stimulate insulin secretion and therefore is not associated with hypoglycemia. Improved metabolic control with metformin does not induce weight gain and may cause weight loss. Metformin also has a beneficial effect on several cardiovascular risk factors including dyslipidemia, elevated plasminogen activator inhibitor 1 levels, other fibrinolytic abnormalities, hyperinsulinemia, and insulin resistance. While metformin reduces insulin resistance, the cellular mechanism of action is incompletely understood. Metformin enhances muscle and adipocyte insulin receptor number and/or affinity, increases insulin receptor tyrosine kinase activity, stimulates glucose transport and glycogen synthesis, and reduces both hepatic gluconeogenesis and glycogenolysis. In addition, metformin has been reported to decrease lipid oxidation and plasma free fatty acid levels, leading to an inhibition of an overactive Randle cycle. Metformin monotherapy decreases the fasting plasma glucose concentration by ~ 60-70 mg/dl and HbA(1c) by 1.5-2.0% in patients with type 2 diabetes. The biguanide is completely additive to sulfonylureas and vice versa, as well as to acarbose and probably troglitazone. In insulin-treated type 2 diabetic patients, the addition of metformin improves insulin sensitivity and glycemic control while allowing a reduction in the daily insulin dose. Side effects of metformin are primarily confined to the gastrointestinal tract (abdominal discomfort and diarrhea). These side effects can be minimized by slow titration and administration with food. Lactic acidosis is rare, with an incidence of ~ 3 cases per 100,000 patient-years of therapy. Most reported cases of lactic acidosis occur in patients with contraindications, particularly impaired renal function (> 90% of cases). In summary, metformin is an effective and safe therapeutic agent for the treatment of type 2 diabetes. Its ability to improve insulin sensitivity and the cardiovascular risk profile of type 2 diabetic patients has enhanced its clinical use as first-line therapy. In the U.K. Prospective Diabetes Study, metformin was the only medication that reduced diabetes-related death, heart attacks, and stroke. Metformin recently has been approved for use in poorly controlled, insulin-treated type 2 diabetic subjects. In the future, its indications may expand to insulin-resistant patients at a high risk of developing type 2 diabetes or with other components of the insulin resistance syndrome.