Metformin's contraindications: needed for now

© 2005 CMA Media Inc. or its licensors Appropriate drug prescribing is an ongoing challenge and may at times generate controversy. Whether we have adequate and reliable data to alter our prescribing of the antihyperglycemic agent metformin for type 2 diabetes mellitus is addressed in this commentary. Metformin is currently recommended as an agent of choice for the treatment of type 2 diabetes, particularly in obese patients. Its effectiveness in lowering blood glucose concentrations as a consequence of inhibiting hepatic glucose production and insulin resistance is well established. More recent data from the UK Prospective Diabetes Study (UKPDS) indicated that obese patients with newly diagnosed type 2 diabetes who received metformin had a significant (7% absolute) reduction in the rate of diabetes-related death and a 10% reduction in overall mortality after 10 years of follow-up compared with patients following a prescribed diet only and those given a sulfonylurea, despite similar glycemic control in the latter group. This apparent protection against vascular complications independent of glucose control presents a novel attribute to an oral antihyperglycemic agent and has stimulated the prescribing of metformin. As with all pharmacologic agents, there are limitations and contraindications to the use of metformin. Although gastrointestinal side effects may render the drug intolerable or limit the dose, the main concern with metformin is lactic acidosis. The drug is a biguanide. In the 1960s and early 1970s, other biguanides (phenformin and buformin) were available to treat type 2 diabetes. Despite their efficacy as glucose-lowering agents, they were removed from the market because their use was associated with an unacceptably high incidence of lactic acidosis, a condition with a 40%–50% death rate. The safety record of metformin is much better. Monitoring in Canada from 1972 to 1983 revealed only 36 cases of lactic acidosis after 56 000 patient-years of use. More recent retrospective analyses have reported that lactic acidosis occurs as frequently among patients with type 2 diabetes not taking metformin as among those taking the drug. These findings have caused some clinicians to question whether metformin can cause or contribute to lactic acidosis and whether it is necessary to maintain current contraindications to its use (severe liver disease, congestive heart failure, age ≥ 80 years and renal impairment). From our knowledge of the mechanism of action of metformin, increased lactic acid production is possible. Similar to all biguanides, metformin acts in the mitochondria to inhibit either the Krebs (tricarboxylic acid) cycle or oxidative phosphorylation, or both. Recent discoveries indicate that the enzyme AMP (adenosine monophosphate)-kinase is activated. AMP-kinase is activated under physiologic conditions by elevation in cellular AMP concentration, which occurs during exercise or fasting. The degree of mitochondrial inhibition by metformin may be less than that by the other biguanides, but the most important factor that accounts for metformin’s relative safety is that, in contrast to phenformin, it does not require hepatic metabolism and instead is excreted unchanged by the kidney. Thus, renal function is a key determinant of safety: although lactic acidosis has occurred because of ingestion of toxic amounts of metformin in a few cases, most cases of metformin-associated lactic acidosis involved patients with impaired renal function. The current contraindications revolve around the concerns of clearance of lactate (liver), predisposition to lactic acidosis (congestive heart failure, severe liver disease, uremia) and renal impairment (elevated serum creatinine level, congestive heart failure and advanced age). Are the safety record and potential vascular protection reasons enough to remove or modify these contraindications to extend metformin’s use in type 2 diabetes? The first issue to address in order to answer this question is whether patients with type 2 diabetes who receive metformin despite having contraindications to it are at increased risk of lactic acidosis. Such a study has not been performed and would probably be ethically difficult given the high mortality rate associated with lactic acidosis. Also, because lactic acidosis is uncommon, obtaining reliable data would require a large study population. Thus, we are left with retrospective reports of outcomes among patients given metformin in a “contraindicated” setting. Another Metformin’s contraindications: needed for now