0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Research Letter |

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

James H. Flory, MD, MSCE1; Sean Hennessy, PharmD, PhD2
[+] 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.
Text Size: A A A
Published online

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%.

Place holder to copy figure label and caption
Figure.
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.

Graphic Jump Location

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.

Table Graphic Jump LocationTable.  Number of Patients Taking Oral Diabetes Medication and Percentage of Metformin Use in Each Category of Estimated Glomerular Filtration Rate (eGFR)a

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.

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

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.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
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.
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.
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.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
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.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Number of Patients Taking Oral Diabetes Medication and Percentage of Metformin Use in Each Category of Estimated Glomerular Filtration Rate (eGFR)a

References

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.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
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.
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.
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.
PubMed   |  Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

4,428 Views
4 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs
JAMAevidence.com

Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed
Clarifying Your Question

Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed
Three Examples of Question Clarification