Matthew J. Crowley, MD, MHS; Clarissa J. Diamantidis, MD, MHS; Jennifer R. McDuffie, PhD; C. Blake Cameron, MD, MBI; John W. Stanifer, MD, MSc; Clare K. Mock, MD; Xianwei Wang, MD; Shuang Tang, PhD; Avishek Nagi, MS; Andrzej S. Kosinski, PhD; John W. Williams, Jr., MD, MHS
Disclaimer: The views expressed in this article do not necessarily reflect the position of the Department of Veterans Affairs or Duke University.
Acknowledgment: The authors thank David D'Alessio, MD, for his critical review of this manuscript and Liz Wing, MA, for her editorial assistance.
Grant Support: This project was supported by the VHA Evidence-based Synthesis Program (project 09-009). Dr. Crowley is supported by a Career Development Award from VHA Health Services Research and Development (CDA 13-261). Dr. Diamantidis is supported by a Mentored Patient-Oriented Research Career Development Award from the National Institute of Diabetes and Digestive and Kidney Diseases (K23-DK099385).
Disclosures: Drs. Crowley, Kosinski, and Williams report grants from the Veterans Administration Quality Enhancement Research Initiative during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-1901.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: PROSPERO (CRD42016027708). Statistical code: See Methods; analytic data set (.csv files) and code are available from Dr. Crowley (e-mail, email@example.com). Data set: See Appendix and VHA report “Metformin Use in Patients With Historical Contraindications or Precautions” (www.hsrd.research.va.gov/publications/esp).
Requests for Single Reprints: Matthew J. Crowley, MD, MHS, Durham Veterans Affairs Medical Center, Health Services Research and Development (152), 508 Fulton Street, Durham, NC 27705; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Crowley: Durham Veterans Affairs Medical Center, Health Services Research and Development (152), 508 Fulton Street, Durham, NC 27705.
Drs. Diamantidis and Williams: 411 West Chapel Hill Street, Suite 500, Durham, NC 27701.
Dr. McDuffie: 411 West Chapel Hill Street, Suite 6, Durham, NC 27701.
Dr. Cameron: 2424 Erwin Road, Suite 605, Durham, NC 27705.
Dr. Stanifer: Duke Clinical Research Institute, 2400 Pratt Street, Durham, NC 27705.
Dr. Mock: University of North Carolina, Hillsborough Hospital, 430 Waterstone Drive, Hillsborough, NC 27278.
Dr. Wang: Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 6, Tiantan Xili, Dongcheng District, Beijing, China 100050.
Dr. Tang: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Mr. Nagi: Durham Veterans Affairs Medical Center, 508 Fulton Street, Durham, NC 27705.
Dr. Kosinski: Duke Clinical Research Institute, Room 7058, P.O. Box 17969, Durham, NC 27715.
Author Contributions: Conception and design: M.J. Crowley, C.J. Diamantidis, J.R. McDuffie, C.B. Cameron, J.W. Stanifer, J.W. Williams.
Analysis and interpretation of the data: M.J. Crowley, C.J. Diamantidis, J.R. McDuffie, C.B. Cameron, J.W. Stanifer, A.S. Kosinski, J.W. Williams.
Drafting of the article: M.J. Crowley, C.J. Diamantidis, J.R. McDuffie, C.B. Cameron, J.W. Stanifer.
Critical revision for important intellectual content: M.J. Crowley, C.J. Diamantidis, J.W. Stanifer, J.W. Williams.
Final approval of the article: M.J. Crowley, C.J. Diamantidis, J.R. McDuffie, C.B. Cameron, J.W. Stanifer, C.K. Mock, X. Wang, S. Tang, A. Nagi, A.S. Kosinski, J.W. Williams.
Statistical expertise: A.S. Kosinski, J.W. Williams.
Obtaining of funding: J.W. Williams.
Administrative, technical, or logistic support: J.R. McDuffie, A. Nagi.
Collection and assembly of data: M.J. Crowley, C.J. Diamantidis, J.R. McDuffie, C.B. Cameron, J.W. Stanifer, X. Wang, J.W. Williams.
Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron CB, Stanifer JW, Mock CK, et al. Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease: A Systematic Review. Ann Intern Med. [Epub ahead of print 3 January 2017]:. doi: 10.7326/M16-1901
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Published: Ann Intern Med. 2017.
Recent changes to the U.S. Food and Drug Administration boxed warning for metformin will increase its use in persons with historical contraindications or precautions. Prescribers must understand the clinical outcomes of metformin use in these populations.
To synthesize data addressing outcomes of metformin use in populations with type 2 diabetes and moderate to severe chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment.
MEDLINE (via PubMed) from January 1994 to September 2016, and Cochrane Library, EMBASE, and International Pharmaceutical Abstracts from January 1994 to November 2015.
English-language studies that: 1) examined adults with type 2 diabetes and CKD (with estimated glomerular filtration rate less than 60 mL/min/1.73 m2), CHF, or CLD with hepatic impairment; 2) compared diabetes regimens that included metformin with those that did not; and 3) reported all-cause mortality, major adverse cardiovascular events, and other outcomes of interest.
2 reviewers abstracted data and independently rated study quality and strength of evidence.
On the basis of quantitative and qualitative syntheses involving 17 observational studies, metformin use is associated with reduced all-cause mortality in patients with CKD, CHF, or CLD with hepatic impairment, and with fewer heart failure readmissions in patients with CKD or CHF.
Strength of evidence was low, and data on multiple outcomes of interest were sparse. Available studies were observational and varied in follow-up duration.
Metformin use in patients with moderate CKD, CHF, or CLD with hepatic impairment is associated with improvements in key clinical outcomes. Our findings support the recent changes in metformin labeling.
U.S. Department of Veterans Affairs. (PROSPERO: CRD42016027708)
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Cardiology, Endocrine and Metabolism, Gastroenterology/Hepatology, Nephrology, Diabetes.
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