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Original Research
13 October 2015

Effects on Clinical Outcomes of Adding Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas to Metformin Therapy in Patients With Type 2 Diabetes Mellitus

Authors: Shuo-Ming Ou, MD, Chia-Jen Shih, MD, Pei-Wen Chao, MD, Hsi Chu, MD, Shu-Chen Kuo, MD, PhD, Yi-Jung Lee, MD, Shuu-Jiun Wang, MD, … Show All … , Chih-Yu Yang, MD, PhD, Chih-Ching Lin, MD, PhD, Tzeng-Ji Chen, MD, PhD, Der-Cherng Tarng, MD, PhD, Szu-Yuan Li, MD, PhD, and Yung-Tai Chen, MDAuthor, Article, & Disclosure Information
Publication: Annals of Internal Medicine
Volume 163, Number 9
https://doi.org/10.7326/M15-0308
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Abstract

Background:

Recent studies concluded that dipeptidyl peptidase-4 (DPP-4) inhibitors provide glycemic control but also raised concerns about the risk for heart failure in patients with type 2 diabetes mellitus (T2DM). However, large-scale studies of the effects on cardiovascular outcomes of adding DPP-4 inhibitors versus sulfonylureas to metformin therapy remain scarce.

Objective:

To compare clinical outcomes of adding DPP-4 inhibitors versus sulfonylureas to metformin therapy in patients with T2DM.

Design:

Nationwide study using Taiwan's National Health Insurance Research Database.

Setting:

Taiwan.

Patients:

All patients with T2DM aged 20 years or older between 2009 and 2012. A total of 10 089 propensity score–matched pairs of DPP-4 inhibitor users and sulfonylurea users were examined.

Measurements:

Cox models with exposure to sulfonylureas and DPP-4 inhibitors included as time-varying covariates were used to compare outcomes. The following outcomes were considered: all-cause mortality, major adverse cardiovascular events (MACEs) (including ischemic stroke and myocardial infarction), hospitalization for heart failure, and hypoglycemia. Patients were followed until death or 31 December 2013.

Results:

DPP-4 inhibitors were associated with lower risks for all-cause death (hazard ratio [HR], 0.63 [95% CI, 0.55 to 0.72]), MACEs (HR, 0.68 [CI, 0.55 to 0.83]), ischemic stroke (HR, 0.64 [CI, 0.51 to 0.81]), and hypoglycemia (HR, 0.43 [CI, 0.33 to 0.56]) compared with sulfonylureas as add-on therapy to metformin but had no effect on risks for myocardial infarction and hospitalization for heart failure.

Limitation:

Observational study design.

Conclusion:

Compared with sulfonylureas, DPP-4 inhibitors were associated with lower risks for all-cause death, MACEs, ischemic stroke, and hypoglycemia when used as add-ons to metformin therapy.

Primary Funding Source:

None.

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Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 163 • Number 9 • 3 November 2015
Pages: 663 - 672

History

Published online: 13 October 2015
Published in issue: 3 November 2015

Keywords

  1. Hazard ratio
  2. Health insurance
  3. Heart failure
  4. Hospital medicine
  5. Hospitalizations
  6. Hypoglycemia
  7. Hypoglycemics
  8. Ischemic stroke
  9. Longitudinal studies
  10. Myocardial infarction

Copyright

© 2015 American College of Physicians.

Authors

Affiliations

Shuo-Ming Ou, MD
From National Yang-Ming University, Taipei Veterans General Hospital, Taipei Medical University, Taipei City Hospital, Ren Ai Branch, and Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan; and National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
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Chia-Jen Shih, MD
From National Yang-Ming University, Taipei Veterans General Hospital, Taipei Medical University, Taipei City Hospital, Ren Ai Branch, and Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan; and National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
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Pei-Wen Chao, MD
From National Yang-Ming University, Taipei Veterans General Hospital, Taipei Medical University, Taipei City Hospital, Ren Ai Branch, and Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan; and National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
View all articles by this author
Hsi Chu, MD
From National Yang-Ming University, Taipei Veterans General Hospital, Taipei Medical University, Taipei City Hospital, Ren Ai Branch, and Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan; and National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
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Shu-Chen Kuo, MD, PhD
From National Yang-Ming University, Taipei Veterans General Hospital, Taipei Medical University, Taipei City Hospital, Ren Ai Branch, and Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan; and National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
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Yi-Jung Lee, MD
From National Yang-Ming University, Taipei Veterans General Hospital, Taipei Medical University, Taipei City Hospital, Ren Ai Branch, and Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan; and National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
View all articles by this author
Shuu-Jiun Wang, MD
From National Yang-Ming University, Taipei Veterans General Hospital, Taipei Medical University, Taipei City Hospital, Ren Ai Branch, and Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan; and National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
View all articles by this author
Chih-Yu Yang, MD, PhD
From National Yang-Ming University, Taipei Veterans General Hospital, Taipei Medical University, Taipei City Hospital, Ren Ai Branch, and Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan; and National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
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Chih-Ching Lin, MD, PhD
From National Yang-Ming University, Taipei Veterans General Hospital, Taipei Medical University, Taipei City Hospital, Ren Ai Branch, and Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan; and National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
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Tzeng-Ji Chen, MD, PhD
From National Yang-Ming University, Taipei Veterans General Hospital, Taipei Medical University, Taipei City Hospital, Ren Ai Branch, and Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan; and National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
View all articles by this author
Der-Cherng Tarng, MD, PhD
From National Yang-Ming University, Taipei Veterans General Hospital, Taipei Medical University, Taipei City Hospital, Ren Ai Branch, and Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan; and National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
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Szu-Yuan Li, MD, PhD
From National Yang-Ming University, Taipei Veterans General Hospital, Taipei Medical University, Taipei City Hospital, Ren Ai Branch, and Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan; and National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
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Yung-Tai Chen, MD
From National Yang-Ming University, Taipei Veterans General Hospital, Taipei Medical University, Taipei City Hospital, Ren Ai Branch, and Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan; Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan; and National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan.
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Note: Drs. Li and Y.T. Chen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Disclaimer: This study was based in part on data from the NHIRD provided by the Bureau of National Health Insurance of the Department of Health and managed by the National Health Research Institutes. The conclusions presented in this study are those of the authors and do not necessarily reflect the views of the Bureau of National Health Insurance, the Department of Health, or the National Health Research Institutes.
Disclosures: Dr. Wang reports grants from the Ministry of Science and Technology, Taipei Veterans General Hospital, and National Yang-Ming University and personal fees from GlaxoSmithKline (Taiwan), Eli Lilly and Company (Taiwan), MSD Taiwan, Allergan, Eli Lilly and Company, and Daiichi Sankyo outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=M15-0308.
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.
Reproducible Research Statement: Study protocol and data set: Not available. Statistical code: Available from Dr. Yung-Tai Chen (e-mail, [email protected]).
Corresponding Author: Szu-Yuan Li, MD, PhD, Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Road, Beitou District, Taipei, Taiwan (e-mail, [email protected]), or Yung-Tai Chen, MD, Division of Nephrology, Department of Medicine, Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan (e-mail, [email protected]).
Current Author Addresses: Drs. Ou, Yang, Lin, Tarng, and Li: Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Road, Beitou District, Taipei, Taiwan.
Dr. Shih: Department of Medicine, Taipei Veterans General Hospital, Yuanshan Branch, No. 386, Rongguang Road, Yuanshan Township, Yilan, Taiwan.
Dr. Chao: Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, No. 111, Section 3, Xinglong Road, Wenshan District, Taipei, Taiwan.
Dr. Chu: Division of Respiratory Medicine, Department of Chest, Taipei City Hospital, Heping Fuyou Branch, No. 33, Section 2, Zhonghua Road, Wanhua District, Taipei, Taiwan.
Dr. Kuo: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, No. 35, Keyan Road, Zhunan Township, Miaoli, Taiwan.
Dr. Lee: Division of Neurology, Department of Medicine, Taipei City Hospital, Ren Ai Branch, No. 10, Section 4, Ren'ai Road, Da'an District, Taipei, Taiwan.
Dr. Wang: Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Road, Beitou District, Taipei, Taiwan.
Dr. T.J. Chen: Department of Family Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Road, Beitou District, Taipei, Taiwan.
Dr. Y.T. Chen: Division of Nephrology, Department of Medicine, Taipei City Hospital, Heping Fuyou Branch, No. 33, Section 2, Zhonghua Road, Wanhua District, Taipei, Taiwan.
Author Contributions: Conception and design: S.M. Ou, C.J. Shih, C.C. Lin, T.J. Chen, S.Y. Li, Y.T. Chen.
Analysis and interpretation of the data: S.M. Ou, C.J. Shih, H. Chu, S.J. Wang, C.C. Lin, T.J. Chen, S.Y. Li, Y.T. Chen.
Drafting of the article: S.M. Ou, C.J. Shih, P.W. Chao, S.C. Kuo, Y.T. Chen.
Critical revision of the article for important intellectual content: S.M. Ou, H. Chu, Y.J. Lee, C.Y. Yang, C.C. Lin, D.C. Tarng, Y.T. Chen.
Final approval of the article: S.M. Ou, C.J. Shih, P.W. Chao, H. Chu, S.C. Kuo, Y.J. Lee, S.J. Wang, C.Y. Yang, C.C. Lin, T.J. Chen, D.C. Tarng, S.Y. Li, Y.T. Chen.
Provision of study materials or patients: S.M. Ou, Y.T. Chen.
Statistical expertise: S.M. Ou, S.C. Kuo, Y.T. Chen.
Administrative, technical, or logistic support: S.M. Ou, P.W. Chao, S.C. Kuo, S.J. Wang, S.Y. Li, Y.T. Chen.
Collection and assembly of data: S.M. Ou, C.J. Shih, S.Y. Li, Y.T. Chen.
* Drs. Ou and Shih contributed equally to this work.
This article was published online first at www.annals.org on 13 October 2015.

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Shuo-Ming Ou, Chia-Jen Shih, Pei-Wen Chao, et al. Effects on Clinical Outcomes of Adding Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas to Metformin Therapy in Patients With Type 2 Diabetes Mellitus. Ann Intern Med.2015;163:663-672. [Epub 13 October 2015]. doi:10.7326/M15-0308

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