We recently learned of an important change in the prescribing information for metformin, previously contraindicated in patients with type 2 diabetes accompanied by heart failure (HF) requiring pharmacological therapy. The contraindication was introduced to the label soon after the drug's U.S. release, when case reports emerged of HF patients taking metformin who developed lactic acidosis. It was never clear, however, whether either the HF or the medication were contributing factors. Subsequent analyses revealed a miniscule risk of lactic acidosis associated with metformin therapy, as compared with that of an earlier biguanide, phenformin (1).

In 2005, two studies (2,3) suggested that metformin was safe and may also provide advantages in the very patients in whom the drug was not to be used. These observational studies found significantly lower mortality risks in type 2 diabetic patients treated with metformin compared with other agents, after adjustment for differences in patient mix. With this information, the Food and Drug Administration (FDA) alerted metformin manufacturers that a label change was appropriate. Over the ensuing months, the prescribing information for all generic products was updated, eliminating the HF contraindication. In November 2006, the final package insert (Glucophage) was likewise modified.

For years, the wisdom of metformin's HF contraindication had been challenged, since it was essentially based on case reports in the absence of clinical trial validation and since glucose-lowering options for such patients were otherwise limited. Moreover, there was biological plausibility of benefit, particularly in patients with insulin resistance (4). The recent FDA endorsement increases the oral pharmacotherapy choices in HF patients with diabetes. Renal dysfunction and metabolic acidosis remain contraindications; HF is still in the label's “Warnings” section; it should obviously not be used in those with acute or unstable symptoms.

We bring this information to your readership's attention because we ourselves were surprised to hear of this major label change, with significant implications for patient care. After discussions with our colleagues, it was clear that we were not alone in our ignorance. We conducted an informal poll of 118 endocrinologists and diabetes educators 10 months after the label change was finalized; of 101 respondents, 95 (94%) were similarly unaware. This episode raises concerns regarding clinician notification when prescribing information is updated after patents expire—in stark contrast to the recent thiazolidinedione label changes, which were widely disseminated.

Misbin RI: The phantom of lactic acidosis due to metformin in patients with diabetes.
Diabetes Care
Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM: Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure.
Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA: Improved clinical outcomes associated with metformin in patients with diabetes and heart failure.
Diabetes Care
Masoudi FA, Inzucchi SE: Diabetes mellitus and heart failure.
Am J Cardiol

This letter is being simultaneously published in 2007 in Diabetes Care and the American Heart Journal. Copyright 2007 by the American Diabetes Association, Inc., and Elsevier.