[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.204.247.205. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Download PDF
Figure.
Percentage of Metformin Use Among Patients Taking Oral Diabetes Medication vs Estimated Glomerular Filtration Rate (eGFR)
Percentage of Metformin Use Among Patients Taking Oral Diabetes Medication vs Estimated Glomerular Filtration Rate (eGFR)

Calculated using National Health and Nutrition Examination Survey data from 2011 to 2012.

Table.  
Number of Patients Taking Oral Diabetes Medication and Percentage of Metformin Use in Each Category of Estimated Glomerular Filtration Rate (eGFR)a
Number of Patients Taking Oral Diabetes Medication and Percentage of Metformin Use in Each Category of Estimated Glomerular Filtration Rate (eGFR)a
1.
Inzucchi  SE, Bergenstal  RM, Buse  JB,  et al.  Management of hyperglycaemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) [published correction appears in Diabetologia. 2013;56(3):680]. Diabetologia. 2012;55(6):1577-1596.
PubMedArticle
2.
Hampp  C, Borders-Hemphill  V, Moeny  DG, Wysowski  DK.  Use of antidiabetic drugs in the U.S., 2003-2012. Diabetes Care. 2014;37(5):1367-1374.
PubMedArticle
3.
Lipska  KJ, Bailey  CJ, Inzucchi  SE.  Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care. 2011;34(6):1431-1437.
PubMedArticle
4.
Notice & Comment. James Flory, M.D., et al (New York Presbyterian Hospital, Weill-Cornell): amendment re FDA-2012-P-1052-0003. http://www.noticeandcomment.com/James-Flory-M-D-et-al-New-York-Presbyterian-Hospital-Weill-Cornell-Amendment-re-FDA-2012-P-1052-0003-fn-6513.aspx. Accessed September 12, 2014.
5.
Notice & Comment. Request to revise the prescribing label for metformin: docket ID: FDA-2013-P-0298. http://www.noticeandcomment.com/FDA-2013-P-0298-fdt-9174.aspx. Accessed September 12, 2014.
6.
Levey  AS, Bosch  JP, Lewis  JB, Greene  T, Rogers  N, Roth  D; Modification of Diet in Renal Disease Study Group.  A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130(6):461-470.
PubMedArticle
Research Letter
March 2015

Metformin Use Reduction in Mild to Moderate Renal ImpairmentPossible Inappropriate Curbing of Use Based on Food and Drug Administration Contraindications

Author Affiliations
  • 1Division of Endocrinology and Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, New York
  • 2Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
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.

Methods

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/).

Results

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.

Discussion

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.

Back to top
Article Information

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 (jaf9052@nyp.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.

References
1.
Inzucchi  SE, Bergenstal  RM, Buse  JB,  et al.  Management of hyperglycaemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) [published correction appears in Diabetologia. 2013;56(3):680]. Diabetologia. 2012;55(6):1577-1596.
PubMedArticle
2.
Hampp  C, Borders-Hemphill  V, Moeny  DG, Wysowski  DK.  Use of antidiabetic drugs in the U.S., 2003-2012. Diabetes Care. 2014;37(5):1367-1374.
PubMedArticle
3.
Lipska  KJ, Bailey  CJ, Inzucchi  SE.  Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care. 2011;34(6):1431-1437.
PubMedArticle
4.
Notice & Comment. James Flory, M.D., et al (New York Presbyterian Hospital, Weill-Cornell): amendment re FDA-2012-P-1052-0003. http://www.noticeandcomment.com/James-Flory-M-D-et-al-New-York-Presbyterian-Hospital-Weill-Cornell-Amendment-re-FDA-2012-P-1052-0003-fn-6513.aspx. Accessed September 12, 2014.
5.
Notice & Comment. Request to revise the prescribing label for metformin: docket ID: FDA-2013-P-0298. http://www.noticeandcomment.com/FDA-2013-P-0298-fdt-9174.aspx. Accessed September 12, 2014.
6.
Levey  AS, Bosch  JP, Lewis  JB, Greene  T, Rogers  N, Roth  D; Modification of Diet in Renal Disease Study Group.  A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130(6):461-470.
PubMedArticle
×