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Efficacy and safety of metformin and sitagliptin based triple antihyperglycemic therapy (STRATEGY): a multicenter, randomized, controlled, non-inferiority clinical trial

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Abstract

Despite the current guideline’s recommendation of a timely stepwise intensification therapy, the “clinical inertia”, termed as the delayed treatment intensification, commonly exists in the real world, which may be partly due to the relatively little substantial evidence and no clear consensus regarding the efficacy and safety of triple oral agents in patients inadequately controlled with dual therapy. In this clinical trial performed in 237 centers in China, 5,535 type 2 diabetic patients inadequately controlled by previous therapies were treated with a stable metformin/sitagliptin dual therapy for 20 weeks. The patients who did not reach the glycated hemoglobin A1c (HbA1c) goal were then further randomized into glimepiride, gliclazide, repaglinide, or acarbose group for an additional 24-week triple therapy. A mean HbA1c reduction of 0.85% was observed when sitagliptin was added to the patients inadequately controlled with metformin in 16 weeks. Further HbA1c reductions in the 24-week triple therapy stage were 0.65% in glimepiride group, 0.70% in gliclazide group, 0.61% in repaglinide group, and 0.45% in acarbose group. The non-inferiority criterion for primary hypotheses was met for gliclazide and repaglinide, but not for acarbose, compared with glimepiride, when added to metformin/sitagliptin dual therapy. The incidences of adverse events (AEs) were 29.2% in the dual therapy stage and 30.3% in the triple therapy stage. Metformin/sitagliptin as baseline therapy, with the addition of a third oral antihyperglycemic agent, including glimepiride, gliclazide, repaglinide, or acarbose, was effective, safe and well-tolerated for achieving an HbA1c <7.0% goal in type 2 diabetic patients inadequately controlled with previous therapies. The timely augmentation of up to three oral antihyperglycemic agents is valid and of important clinical benefit to prevent patients from exposure to unnecessarily prolonged hyperglycemia.

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Acknowledgements

We acknowledge the Chinese Medical Association for overseeing the ethical obligations of this study and for its kind support in communication with all the participating 237 centers, and Sun Yat-sen University for providing good clinical practice training to all the investigators. We would like to thank Prof. John B. Buse from University of North Carolina School of Medicine, USA for his constructive discussion of the manuscript preparation, and thank Prof. Rury R. Holman from University of Oxford, Oxford, United Kingdom for kind advice concerning trial conduct and constructive discussions with respect to the study results. The authors thank Zengyu Wen from MacroStat for his statistical assistance of the current work, and are grateful to the patients enrolled and the investigators participating in this study for their dedication to the study (the list seen in Text S3 in Supporting Information).This work was supported by Merck & Co., Inc., Kenilworth, NJ, the 5010 Project of Sun Yat-sen University, and Program for Changjiang Scholars and Innovative Research Team in University (to Jianping Weng).

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-Sen University; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, 510630, China

    Wen Xu, Bin Yao, Longyi Zeng & Jianping Weng

  2. Department of Endocrinology, Chinese People’s Liberation Army General Hospital, Beijing, 100853, China

    Yiming Mu & Juming Lu

  3. Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021, China

    Jiajun Zhao

  4. Department of Endocrinology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China

    Dalong Zhu & Yan Bi

  5. Department of Endocrinology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Qiuhe Ji

  6. Institute of Metabolism and Endocrinology, The Second Xiangya Hospital and the Diabetes Center, Key Laboratory of Diabetes Immunology, Ministry of Education Central South University, National Clinical Research Center for Metabolic Diseases, Changsha, 410011, China

    Zhiguang Zhou

  7. Merck Sharp & Dohme China, Shanghai, 200020, China

    Anhua Mao & Bin Zhao

  8. Merck & Co, Inc., Kenilworth, NJ, 07033, USA

    Samuel S. Engel

  9. Department of Endocrinology, West China Hospital, Sichuan University, Chengdu, 610041, China

    Xingwu Ran

  10. Department of Endocrinology, Peking University People’s Hospital, Beijing, 100044, China

    Linong Ji

  11. Department of Endocrinology, China-Japan Friendship Hospital, Beijing, 100029, China

    Wenying Yang

  12. Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Weiping Jia

Authors
  1. Wen Xu
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  2. Yiming Mu
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  3. Jiajun Zhao
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  4. Dalong Zhu
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  5. Qiuhe Ji
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  6. Zhiguang Zhou
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  7. Bin Yao
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  8. Anhua Mao
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  9. Samuel S. Engel
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  10. Bin Zhao
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  11. Yan Bi
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  12. Longyi Zeng
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  13. Xingwu Ran
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  14. Juming Lu
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  15. Linong Ji
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  16. Wenying Yang
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  17. Weiping Jia
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  18. Jianping Weng
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Corresponding authors

Correspondence to Yiming Mu, Weiping Jia or Jianping Weng.

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Prof. Jianping Weng is a professor of the Department of Endocrinology at the Third Affiliated Hospital, Sun Yat-sen University in Guangdong, China. He is the director of Guangdong Provincial Key Laboratory of Diabetology. Dr Weng received his Bachelor degree at the former Nanjing Railway Medical College, Master and Ph.D degrees at the former Sun Yat-sen University of Medical Science. He was a research fellow of the Department of Endocrinology at Malmö University Hospital in Lund, Sweden. Dr Weng’s research interests focus on endocrinology, metabolic disease and genetics in diabetes. He has published over 110 scientific articles in international peer-reviewed journals including the Lancet, Molecular Endocrinology, Endocrinology, Human Genetics, Diabetes, Diabetes Care. His research has been funded by National Natural Science Foundation of China (NSFC), Hi-tech Research and Development Program of China (863 program), National Health and Family Planning Commission and Ministry of Education. He is the Editor-in-Chief of the Chinese Journal of Diabetes Mellitus, and the Associate Editor-in-Chief of the Chinese Medical Journal. He is also a board editor of the Diabetes and of the Journal of Internal Medicine. Dr Weng was the President of the Chinese Diabetes Society 2012−2015. Over the years, he has garnered much recognition and accolade from the scientific community, including being named an Outstanding Young Scholar by the NSFC in 2010, and a Changjiang Scholar professor by the Ministry of Education in 2012. He was also a winner of the Support Program for 100 Outstanding Talents in Guangdong in 2013.

Prof. Yiming Mu is Professor and Chief of the Department of Endocrinology, Chinese PLA General Hospital, in Beijing. He also holds the post of the President of Chinese Society of Endocrinology (CSE) and Vice President of the Chinese Endocrinologist Association. He received the Distinguished Contribution Award of the CSE in 2014. Professor Mu completed his basic medical education in China and then went to Japan to hone his skills on the principles of molecular research and obtained a Ph.D degree from the Kyushu University in Japan. His broad research interests are reflected in more than 400 publications to date in diverse fields including diabetes, glucose metabolism and pancreatic beta-cell biology and stem cell biology.

Prof. Weiping Jia is now Professor of Division of Endocrinology & metabolism at Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Director of Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory for Diabetes and Shanghai Diabetes Institute. Dr. Jia is now president of Chinese Diabetes Society, and Chief Editor of Chinese Journal of Internal Medicine as well as editorial board members of Lancet Diabetes Endocrinology and Diabetes. Her research interest involved various aspects of diabetes, obesity and metabolic disorders from genetic and molecular biology to disease management, especially the translational research on the disease. She has published more than 400 papers and over 100 research articles in international scientific journals, including British Medical Journal, Journal of the American College of Cardiology, Diabetes, Diabetes Care, Diabetologia, Journal of Clinical Endocrinology and Metabolism, American Journal of Psychiatry, and Obesity Review, etc. Her research has been funded by National Natural Science Foundation of China (NSFC), National Basic Research Program of China (973 program), Hi-tech Research and Development Program of China (863 program), and European Association for the Study of Diabetes (EASD). She is the Co-PI of research projects funded by the National Institute of Health (NIH) in USA.

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Xu, W., Mu, Y., Zhao, J. et al. Efficacy and safety of metformin and sitagliptin based triple antihyperglycemic therapy (STRATEGY): a multicenter, randomized, controlled, non-inferiority clinical trial. Sci. China Life Sci. 60, 225–238 (2017). https://doi.org/10.1007/s11427-016-0409-7

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