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Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial

Nature Medicine volume 28, pages 965–973 (2022)Cite this article

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Abstract

Improving glucose sensitivity remains an unmet medical need in treating type 2 diabetes (T2D). Dorzagliatin is a dual-acting, orally bioavailable glucokinase activator that enhances glucokinase activity in a glucose-dependent manner, improves glucose-stimulated insulin secretion and demonstrates effects on glycemic control in patients with T2D. We report the findings of a randomized, double-blind, placebo-controlled phase 3 clinical trial to evaluate the efficacy and safety of dorzagliatin in patients with T2D. Eligible drug-naïve patients with T2D (n = 463) were randomly assigned to the dorzagliatin or placebo group at a ratio of 2:1 for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin from baseline to week 24. Safety was assessed throughout the trial. At week 24, the least-squares mean change in glycated hemoglobin from baseline (95% confidence interval) was −1.07% (−1.19%, −0.95%) in the dorzagliatin group and −0.50% (−0.68%, −0.32%) in the placebo group (estimated treatment difference, −0.57%; 95% confidence interval: −0.79%, −0.36%; P < 0.001). The incidence of adverse events was similar between the two groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin group. In summary, dorzagliatin improved glycemic control in drug-naïve patients with T2D and showed a good tolerability and safety profile.

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Fig. 1: SEED study patient disposition.
Fig. 2: Primary and secondary efficacy endpoints.

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Data availability

Data from analyses in the SEED study are not publicly available due to the sponsor’s contractual obligations. We encourage researchers or parties interested in collaboration for noncommercial use to submit an application to the corresponding authors (lichen@huamedicine.com). Applications should specifically outline the data the parties are interested in receiving and how the data will be used; the use of the data must also comply with the Human Genetics Resources Administration requirements of China and other country-specific or region-specific regulations. All shared data will be de-identified and will be made available 2 years after the date of publication. A signed data access agreement with the sponsor is required before accessing the shared data. The study protocol and statistical analysis plan are provided with the paper.

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Acknowledgements

This study was sponsored by Hua Medicine. We thank J. Chen for medical writing and editing support, funded by Hua Medicine; L. Li, C. Geng and L. Yuan (Hua Medicine) for assistance with the efficacy data; A. Wang (Hua Medicine) for assistance with the safety data; X. Liu (Hua Medicine) for assistance with the statistical analyses; and G. Yu and F. Tang, who reviewed an earlier version of the manuscript on behalf of Hua Medicine. Hua Medicine participated in the design, conduct and data analysis and interpretation of the clinical study, the preparation of the manuscript, and were involved in making the decision to publish. The study was also funded in part, by grants from the National Major Scientific and Technological Special Project for Significant New Drug Development (2014ZX09101002004 and 2018ZX09711002–012–001), the Shanghai Science and Technology Innovation Action Project (14431908300, 15XD1520500, 17DZ1910200 and 19431905200), the Shanghai Pudong District Science and Technology Innovation Action Project (PKJ2014-S06) and the Shanghai Municipal Commission of Economy and Informatization Innovation Action Project (XC-ZXSJ-01-2015-02 and 18XI-18).

Author information

Author notes

  1. These authors contributed equally: Dalong Zhu, Xiaoying Li.

Authors and Affiliations

  1. Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China

    Dalong Zhu & Ping Li

  2. Zhongshan Hospital, Fudan University, Shanghai, China

    Xiaoying Li

  3. Nanjing First Hospital, Nanjing, China

    Jianhua Ma

  4. Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, China

    Jiao’e Zeng

  5. The First People’s Hospital of Changde City, Changde, China

    Shenglian Gan

  6. Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China

    Xiaolin Dong

  7. The First Hospital of Shanxi Medical University, Taiyuan, China

    Jing Yang

  8. Zhuzhou Central Hospital, Zhuzhou, China

    Xiaohong Lin

  9. The Second Hospital of Jilin University, Changchun, China

    Hanqing Cai

  10. Chenzhou First People’s Hospital, Chenzhou, China

    Weihong Song

  11. Taihe Hospital, Hubei University of Medicine, Shiyan, China

    Xuefeng Li

  12. Tongji Hospital of Tongji University, Shanghai, China

    Keqin Zhang

  13. The First Affiliated Hospital of Anhui Medical University, Hefei, China

    Qiu Zhang

  14. The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Yibing Lu

  15. Wuxi People’s Hospital, Wuxi, China

    Ruifang Bu

  16. Changsha Central Hospital, Changsha, China

    Huige Shao

  17. The First Hospital of Jilin University, Changchun, China

    Guixia Wang

  18. Affiliated Hospital of Jiangsu University, Zhenjiang, China

    Guoyue Yuan

  19. West China Hospital, Sichuan University, Chengdu, China

    Xingwu Ran

  20. The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China

    Lin Liao

  21. The Affiliated Hospital of Qingdao University, Qingdao, China

    Wenjuan Zhao

  22. Siping Hospital of China Medical University, Siping, China

    Li Sun

  23. The Affiliated Hospital of Guizhou Medical University, Guiyang, China

    Lixin Shi

  24. The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, China

    Zhaoshun Jiang

  25. Southern Medical University Nanfang Hospital, Guangzhou, China

    Yaoming Xue

  26. The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China

    Hongwei Jiang

  27. PLA Rocket Force Characteristic Medical Center, Beijing, China

    Quanmin Li

  28. Sanya Central Hospital, Sanya, China

    Zongbao Li

  29. The Second Affiliated Hospital of Hainan Medical University, Haikou, China

    Maoxiong Fu

  30. Chongqing Red Cross Hospital, Chongqing, China

    Zerong Liang

  31. Chongqing University Three Gorges Central Hospital, Chongqing, China

    Lian Guo

  32. Tianjin Medical University General Hospital, Tianjin, China

    Ming Liu

  33. The Third Medical Center of PLA General Hospital, Beijing, China

    Chun Xu

  34. Peking Union Medical College Hospital, Beijing, China

    Wenhui Li

  35. Tongji Hospital, Tongji Medical College of HUST, Wuhan, China

    Xuefeng Yu

  36. The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Guijun Qin

  37. Jiangxi Pingxiang People’s Hospital, Pingxiang, China

    Zhou Yang

  38. The Second Hospital of Dalian Medical University, Dalian, China

    Benli Su

  39. The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Longyi Zeng

  40. Xuzhou Central Hospital, Xuzhou, China

    Houfa Geng

  41. Shanghai Changzheng Hospital, Shanghai, China

    Yongquan Shi

  42. Hua Medicine, Shanghai, China

    Yu Zhao, Yi Zhang & Li Chen

  43. China-Japan Friendship Hospital, Beijing, China

    Wenying Yang

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Contributions

D.Zhu and L.Chen led the design, conduct and analysis of the clinical study and the development of the manuscript. X.Li and W.Yang contributed to the protocol design, data analysis and manuscript draft as the study consultants. The trial was designed and overseen by representatives of Hua Medicine with input from selected site investigators. The site investigators collected the data, and the sponsor performed the data analyses. All of the authors interpreted the data and vouched for its accuracy and completeness and the fidelity of the trial to the protocol. The first author wrote the first draft of the manuscript with assistance from an independent medical writer funded by the sponsor. The manuscript was subsequently revised and approved by all authors, who agreed to submit the manuscript for publication.

Corresponding authors

Correspondence to Dalong Zhu, Wenying Yang or Li Chen.

Ethics declarations

Competing interests

L.Chen, Y. Zhao and Y. Zhang are employees of Hua Medicine. D.Zhu, X.Li and W.Yang served on the Diabetes Advisory Board for Hua Medicine. The remaining authors declare no competing interests.

Peer review

Peer review information

Nature Medicine thanks Victor Volovici, Naveed Sattar and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: Jennifer Sargent and Joao Monteiro, in collaboration with the Nature Medicine team.

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Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 SEED trial design.

The SEED trial design was shown in the Extended Data Fig. 1, in which it showed the process of T2D patients completing the SEED study. Selected drug naive T2D patients entered into a 4 week single-blinded placebo run-in period followed by a randomization into a 24-week double blinded placebo controlled treatment to evaluate the primary efficacy and safety endpoints. Upon completion of the double blinded period, patients entered into an open-label 28 week treatment to evaluate drug safety endpoints, followed by a 1-week end of study follow-up.

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Supplementary Information

Supplementary Tables 1–10, clinical study protocol and statistical analysis plan

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Zhu, D., Li, X., Ma, J. et al. Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med 28, 965–973 (2022). https://doi.org/10.1038/s41591-022-01802-6

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