The biguanide metformin (dimethylbiguanide) was initially introduced for the treatment of type 2 diabetes mellitus in the late 1950s. Today, this drug is considered to be the first-choice agent and the “gold standard” for most people with type 2 diabetes. It has been estimated that the annual number of people receiving prescriptions for metformin worldwide is more than 120 million.
The efficacy and benefits of metformin treatment in type 2 diabetes have been confirmed by large-scale studies and recognized by many consensus statements. Still, a large list of contraindications may increase the incidence of serious adverse effects, which precludes many patients from taking metformin.
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Intolerance and contraindications to metformin
Three particular contraindications to the use of metformin have been suggested. These include renal impairment with elevated serum creatine levels (i.e. more than 136 mmol/l in men and 124 mmol/l in women) or abnormal creatinine clearance, congestive heart failure requiring pharmacologic treatment, and advanced age (more than 80 years of age).
Renal impairment represents a contraindication to metformin usage due to the increased risk of lactic acidosis, which is a form of metabolic acidosis due to the inadequate clearance of lactic acid from the blood. Although lactic acidosis linked to metformin is a rare condition, with an estimated prevalence of one to five cases per 100,000 population, it has a reported mortality of 30-50%.
However, recent studies have suggested that metformin can be used safely, unless the estimated glomerular filtration rate, which is the volume of fluid that is filtered from the capillaries of the glomeruli into the kidney tubules per unit time, falls below 30 ml/min. Moreover, a dose reduction is advised at 45 ml/min.
Congestive heart failure is typically considered to be a contraindication for metformin treatment, thus the drug is withheld from large numbers of patients with type 2 diabetes and coincident cardiac failure. More recent studies suggest that metformin may not be absolutely contraindicated and could be beneficial in such patients.
The drug label states that metformin treatment should not be initiated in patients older than 80 years of age unless their creatinine clearance is normal. Still, several studies of patients with type 2 diabetes, including those over 70 years of age, have shown that metformin treatment is not associated with significantly increased plasma lactate levels.
Therefore, a reasonable approach is to start with a low dose of about 250 mg twice a day and increase the dose weekly, based on tolerance and effect of the drug on the surrogate endpoint of blood glucose level, to a maximum dose of 2,000-2,500 mg per day. Metformin therapy should be interrupted if acute changes in renal function arise.
Guidelines for the clinical use
The consensus statement of the European Association for the Study of Diabetes and the American Dental Association recommends that metformin be initiated together with diet and exercise when patients have been diagnosed with type 2 diabetes. Additional antihyperglycemic agents are selected on the basis of clinically relevant issues, such as glucose-lowering effectiveness, risk of hypoglycemia, and effect on body weight.
Metformin remains the drug of choice for pharmacological treatment in insulin-resistant and obese diabetic individuals. Still, as the antihyperglycemic effects of metformin are similar in lean and obese subjects, it can also be recommended as a first-line treatment even without obesity.
The addition of metformin to insulin is advantageous compared to insulin alone. Furthermore, the addition of metformin to sulfonylureas in patients with secondary sulfonylurea failure is reasonable in view of their synergistic mechanisms of action. All these favorable effects have led to the widespread recommendation in evidence-based guidelines of many countries to use metformin as a first-line agent.