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Frequency of Inappropriate Metformin Prescriptions
To the Editor: Metformin is commonly used in the management of type 2 diabetes. More than 25 million prescriptions for metformin were written in 2000, making it the most commonly prescribed branded diabetes medication in the United States.1 Metformin has been associated with the development of lactic acidosis, and since its initial marketing in 1995 the US Food and Drug Administration (FDA) has required a "black box" warning in the package insert.2-3 Labeled contraindications include renal dysfunction and congestive heart failure (CHF) requiring pharmacologic treatment.4 We sought to determine the frequency of metformin use in a sample of patients with these 2 primary contraindications to therapy.
Methods
We performed a retrospective chart review of patients receiving metformin through our outpatient pharmacy at an academic medical center. Institutional review board approval was obtained, and all patients with 2 or more prescriptions for metformin processed between January 1, 2000, and September 30, 2000, were identified. These patient records were randomized using a random number generator (SAS v6.12, SAS Institute Inc, Cary, NC).
The prevalence of inappropriate prescriptions for metformin was defined as the percent of patients receiving metformin who had documented CHF or renal dysfunction. Patients were considered to have CHF if the diagnosis was included in the medical problem list or clinic notes, and if they were taking medications for CHF (diuretics, angiotensin-converting enzyme inhibitors, digoxin). Renal dysfunction was defined as a serum creatinine greater than 1.5 mg/dL (132.6 µmol/L) for men and greater than 1.4 mg/dL (123.8 µmol/L) for women. Patient records were also reviewed for documentation of functional cardiac status or evidence that contraindications were considered.
Results
Pharmacy records identified 241 patients with 2 or more prescriptions for metformin; 100 of these were randomly selected for chart review. Twenty-two patients (22%; 95% confidence interval, 14%-30%) were found to have either CHF requiring medications or renal insufficiency. Of these 22 patients, 14 had CHF only, 5 had renal insufficiency only, and 3 had both. For patients with contraindications to metformin, the mean age was 60 years, 50% were women, and 50% were African American. These characteristics were similar for patients without contraindications. Patients with contraindications did have a significantly longer duration of diabetes (14.2 vs 6.4 years; P<.001).
Of the 17 patients with CHF, 4 patients had a documented New York Heart Association functional classification (class II: n = 2; class III: n = 2). Of the 8 patients with renal dysfunction, the mean serum creatinine was 1.8 mg/dL (159.1 µmol/L) and mean blood urea nitrogen was 27 mg/dL (9.639 mmol/L). Only 2 patients had documentation in the medical record that providers considered metformin contraindications.
Comment
In our review, almost one quarter of patients with a prescription for metformin had 1 or more absolute contraindications. Several recent studies in Europe have documented similar rates of inappropriate metformin prescribing.2, 5-6
Adverse event reports suggest the incidence of metformin-associated lactic acidosis is between 1 in 10 000 to 1 in 100 000 patient-years.7 In the first 14 months after its release in the United States, the FDA received 47 confirmed cases of lactic acidosis associated with metformin, with a 42% mortality rate. More than 90% of patients had relative or absolute contraindications to metformin.3
Because our assessment of the prevalence of contraindications to metformin use relies on a chart review, it may underestimate the frequency of contraindications and it is difficult to determine whether clinicians are aware they are prescribing metformin against a black-box warning. Nonetheless, our results suggest that metformin frequently may be inappropriately prescribed despite black-box contraindications. Documentation of this potential risk in the medical record is limited and health care providers should consider improving the documentation of the risk of lactic acidosis and provide appropriate counseling for patients who receive the drug.
Cheryl Horlen, PharmD
School of Pharmacy
Campbell University
Buies Creek, NC
Robb Malone, PharmD,CDE;
Betsy Bryant, PharmD,CDE
Department of Medicine
University of North Carolina
Chapel Hill
Betty Dennis, PharmD,MS,CDE
University of North Carolina Hospital Pharmacy
Chapel Hill
Tim Carey, MD,MPH;
Mike Pignone, MD,MPH;
Russell Rothman, MD,MPP
Department of Medicine
University of North Carolina
Chapel Hill
1. Top 200 drugs by retail sales in 2000. Drug Topics 2001. March 19, 2001.
2. Emslie-Smith AM, Boyle DI, Evans JM, Sullivan F, Morris AD. Contraindications to metformin therapy in patients with Type 2 diabetes: a population-based study of adherence to prescribing guidelines. Diabet Med. 2001;18:483-488.
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3. Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med. 1998;338:265-266.
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4. Glucophage. Princeton, NJ: Bristol-Myers Squibb; 2001.
5. Holstein A, Nahrwold D, Hinze S, Egberts EH. Contra-indications to metformin therapy are largely disregarded. Diabet Med. 1999;16:692-696.
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6. Sulkin TV, Bosman D, Krentz AJ. Contraindications to metformin therapy in patients with NIDDM. Diabetes Care. 1997;20:925-928.
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7. Howlett HC, Bailey CJ. A risk-benefit assessment of metformin in type 2 diabetes mellitus. Drug Saf. 1999;20:489-503.
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Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.
JAMA. 2002;287:2504-2505.
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