Calculated using National Health and Nutrition Examination Survey data from 2011 to 2012.
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Flory JH, Hennessy S. Metformin Use Reduction in Mild to Moderate Renal Impairment: Possible Inappropriate Curbing of Use Based on Food and Drug Administration Contraindications. JAMA Intern Med. 2015;175(3):458–459. doi:10.1001/jamainternmed.2014.6936
Metformin hydrochloride is the first-line drug for type 2 diabetes mellitus (T2DM)1 and is the only oral diabetes drug with evidence for improved cardiovascular outcomes. Despite this, half of the patients with T2DM do not take metformin. Even in patients who are taking other oral T2DM drugs, only about 70% use metformin.2
One likely explanation for this shortfall is the avoidance of metformin use in renal insufficiency. The drug carries a contraindication against use when serum creatinine levels exceed 1.4 mg/dL in women or 1.5 mg/dL in men based on fears about lactic acidosis (to convert creatinine level to micromoles per liter, multiply by 88.4). This contraindication has been widely criticized as overly conservative.1,3 Professional societies support metformin use at estimated glomerular filtration rates (eGFRs), a better measure of renal function than the serum creatinine level, of 45 or even 30 mL/min (which typically equates to a serum creatinine level of about 2 mg/dL).1 Because this contraindication may inappropriately discourage metformin use in patients with mild renal impairment, US Food and Drug Administration (FDA) citizen petitions4,5 were filed in 2012 and 2013, respectively, requesting that the contraindication be relaxed and reframed in terms of the more modern eGFR measure, although the FDA has provided no substantive response.
To quantify the potential public health importance of this issue, we examined 2007 to 2012 data from the National Health and Nutrition Examination Survey to assess how much metformin nonuse may be attributable to excessive concern about safety in renal insufficiency. Analysis was restricted to participants using oral diabetes drugs. Patients who reported heart or liver failure, which are also potential contraindications to metformin use, were excluded. Sex, age, race/ethnicity, serum creatinine level, and eGFR6 were examined as predictors of metformin use. Analysis was conducted using statistical software (R; http://www.r-project.org/).
In 2011-2012, the rate of metformin use in patients with an eGFR exceeding 90 mL/min was 90.4% (Figure). At eGFRs greater than 60 to 90 mL/min, at which renal function is mildly impaired but the serum creatinine level is typically below the contraindication cutoff, the rate was 80.6%. At eGFRs of 30 to 60 mL/min, at which metformin use is usually formally contraindicated but professional guidelines1 support cautious use, rates were 48.6% to 57.4%. At eGFRs below 30 mL/min, at which metformin use is discouraged, the rate was 17.9%.
An estimate of the influence of renal contraindications on metformin use is summarized in the Table. If the 90.4% use rates listed above for an eGFR exceeding 90 mL/min were seen with an eGFR greater than 60 to 90 mL/min, approximately 425 000 additional patients would take metformin. If these rates were extended down to an eGFR of 30 mL/min, the number of patients taking metformin would increase by about an additional 560 000. Most important, these figures do not include patients who are receiving no oral diabetes agents, so they are almost certainly underestimates. However, a lower eGFR may be associated with other factors (eg, undocumented heart failure) that might account for some portion of this shortfall.
These findings are relevant to clinical care and health policy because they indicate that exaggerated concerns about the safety of metformin use in renal impairment may unnecessarily prevent its use in hundreds of thousands of patients, even at eGFRs exceeding 60 mL/min. The approximately 50% rate of metformin nonuse in patients with eGFRs between 30 and 60 mL/min has multiple potential causes, but one likely contributing factor is the inconsistency between professional society guidelines1 and the FDA label. The FDA is overdue to revisit the contraindication to metformin use in patients with renal insufficiency, which may be worsening the care of almost 1 million patients with T2DM in the United States.
Corresponding Author: James H. Flory, MD, MSCE, Division of Endocrinology, Weill Cornell Medical College, 525 E 68th St, 20th Floor, Baker Pavilion, New York, NY 10021 (firstname.lastname@example.org).
Published Online: January 5, 2015. doi:10.1001/jamainternmed.2014.6936.
Author Contributions: Dr Flory had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Flory.
Critical revision of the manuscript for important intellectual content: Hennessy.
Statistical analysis: Flory.
Conflict of Interest Disclosures: Dr Hennessy reports consulting for Abbott Laboratories, Hoffmann-La Roche Ltd, Novartis Pharmaceuticals, Bayer Healthcare LLC, AstraZeneca, and Bristol-Myers Squibb; receiving research support from AstraZeneca and Bristol-Myers Squibb; and receiving institutional support from Pfizer Inc and Sanofi to support pharmacoepidemiology training. No other disclosures were reported.
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