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Benefit of Early Add-on of Linagliptin to Insulin in Japanese Patients With Type 2 Diabetes Mellitus: Randomized-Controlled Open-Label Trial (TRUST2)

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Abstract

Introduction

This trial was conducted to assess the long-term safety, efficacy, and benefit of early add-on of linagliptin to insulin in patients with type 2 diabetes mellitus (T2DM).

Methods

This trial enrolled 246 subjects. The subjects were randomized to the linagliptin group or the control group and were observed for 156 weeks. After week 16, subjects in the control group were also allowed to add linagliptin to evaluate the benefit of early add-on of linagliptin to insulin. The primary end point was a change in HbA1c from baseline to week 16. Secondary end points included fasting plasma glucose, daily insulin dose, and frequency of adverse events.

Results

HbA1c and fasting plasma glucose levels significantly decreased from baseline to week 16 in the linagliptin group compared with the control group. The significant improvement in HbA1c continued until week 52. The daily insulin dose significantly decreased in the linagliptin group compared with the control group. The frequency of hypoglycemia and adverse events was comparable in both groups.

Conclusions

Add-on of linagliptin to insulin was tolerated, improved glycemic control, and reduced the daily insulin dose. This study demonstrates the long-term safety, efficacy and benefit of early add-on of linagliptin to insulin in Japanese T2DM patients.

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Acknowledgements

Authors thank Mrs. Kumi Yagi for the collection and management of the clinical data. We thank all the participants in this study. Other members of the TRUST2 study group included H. Seino (Seino Internal Medical Clinic, Fukushima); S. Nakata (Nakata Clinic, Kanagawa); D. Uchida (Hotaruno Central Naika, Chiba), R. Komi, A. Ooka, and A. Tanaka (Shonankamakura General Hospital, Kanagawa); C. Nawa (Shinjuku Mitsui Building Clinic, Tokyo); M. Moriwaki (Moriwaki Clinic, Osaka); F. Haseda (First Towakai Hospital, Osaka); K. Murata (Suisyoukai Murata Hospital, Osaka); Y. Hiromine (Kindai University, Osaka); H. Nishimura (Kumanomae Nishimura Medical Clinic, Tokyo); S. Matsutani, T. Tsunoda, and H. Konya (Ashiya Municipal Hospital, Hyogo); S. Sakane (Hirakata City Hospital, Osaka); H. Ohashi (Oyama East Clinic, Tochigi); A. Nagao, A. Arimitsu, and S. Kurebayashi (Nishinomiya Municipal Central Hospital, Hyogo); H. Fujii (Tama Center Clinic Mirai, Tokyo); H. Imbe, M. Miyawaki, Y. Mishiba, M. Onishi, K. Tanimoto, and F. Nakatsuji (Osaka Medical College, Osaka); J. Kozawa, H. Iwahashi, and K. Fukui (Osaka University, Osaka); T. Yamamoto (Kansai Rosai Hospital, Hyogo); Y. Kojima, A. Aida, and T. Hiyoshi (Japanese Red Cross Medical Center, Tokyo); M. Menjyu (Menjyu Clinic, Osaka); I. Hayashi (Hayashi Clinic, Hyogo).

Funding

This study was financially supported by Boehringer Ingelheim. The journal’s Rapid Service Fee and fee for the technical assistance in the launch and execution of the study and the medical writing of the manuscript by Soiken Inc. were also financially supported by Boehringer Ingelheim.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authorship Contributions

Tomoyuki Katsuno analyzed the data and wrote, critically reviewed, and approved the final manuscript. Toshihiko Shiraiw, Shingo Iwasaki, Hyohun Park, Nobuaki Watanabe, Shizuka Kaneko, and Jungo Terasaki were involved in the coordination and conduct of the trial and wrote, critically reviewed, and approved the final manuscript. Jun-ichiro Miyagawa, Toshiaki Hanafusa, Akihisa Imagawa, Iichiro Shimomura, Hiroshi Ikegami, Hidenori Koyama, and Mitsuyoshi Namba were involved in the coordination and conduct of the trial and wrote, critically reviewed, and approved the final manuscript.

Medical writing, editorial, and other assistance

The authors thank Soiken Inc. for their technical assistance in the launch and execution of the study and support with the medical writing of the manuscript. This was financially supported by Boehringer Ingelheim.

Disclosures

Toshihiko Shiraiwa has received lecture fees from Takeda Pharmaceutical Co., Ltd., and Sanofi K.K. and grants from Novo Nordisk Pharma Ltd., Kowa Pharmaceutical Co., Ltd., Poxel SA, Daiichi Sankyo Co., Ltd., and Sanofi K.K. SK has received lecture fees from Sumitomo Dainippon Pharma Co., Ltd., Novo Nordisk Pharma Ltd., Eli Lilly and Company, AstraZeneca K.K., Mitsubishi Tanabe Pharma Co., and Boehringer Ingelheim Pharmaceuticals and grants from Eli Lilly and Company, Novo Nordisk Pharma Ltd., Daiichi Sankyo Co., Ltd., and Soiken Inc. Akihisa Imagawa has received lecture fees from Eli Lilly and Company, Ono Pharmaceutical Co., Ltd., and Astellas Pharma Inc. and grants from Astellas Pharma Inc., AstraZeneca K.K., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Soiken Inc., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., and Merck Biopharma Co. Ltd and scholarship contributions from Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Kyowa Kirin Co., Ltd., and Ono Pharmaceutical Co., Ltd. Iichiro Shimomura has received lecture fees from MSD K.K., Ono Pharmaceutical Co., Ltd., Kowa Pharmaceutical Co., Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho Co. Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eli Lilly and Company, and Novo Nordisk Pharma Ltd., grants from Kowa Pharmaceutical Co., Ltd., and ROHTO Pharmaceutical Co., Ltd., and scholarship contributions from Astellas Pharma Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Teijin Pharma Ltd., Novartis Pharma K.K., and Novo Nordisk Pharma Ltd. Hiroshi Ikegami has received lecture fees from Astellas Pharma Inc., MSD K.K., Terumo Co., Eli Lilly and Company, Novartis Pharma K.K., and Novo Nordisk Pharma Ltd. and scholarship contributions from Takeda Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., LifeScan Japan K.K., Otsuka Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Novo Nordisk Pharma Ltd., Abbott Japan Co., Ltd., Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Daiichi Sankyo Co., Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., and Bayer Yakuhin Ltd. Hidenori Koyama has received a lecture fee from Sanwa Kagaku Kenkyusho Co. Ltd., grant from AstraZeneca K.K. and Boehringer Ingelheim Pharmaceuticals, Inc., and scholarship contributions from Astellas Pharma Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Daiichi Sankyo Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Pharma Ltd., and Pfizer Japan Inc. All funding agencies played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Tomoyuki Katsuno, Shingo Iwasaki, Hyohun Park, Nobuaki Watanabe, Shizuka Kaneko, Jungo Terasaki, Toshiaki Hanafusa, Mitsuyoshi Namba, and Jun-ichiro Miyagawa have nothing to disclose.

Compliance With Ethics Guidelines

This study and its protocols were approved by the institutional review board of each participating institution, according to the Ethical Guidelines for Medical and Health Research Involving Human Subjects issued by the Ministry of Health, Labour and Welfare in Japan. This study was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) (registration number: UMIN000010830). The study was conducted in accordance with the Declaration of Helsinki, Ethical Guidelines for Medical and Health Research Involving Human Subjects as well as other relevant bylaws and regulations. The study protocol was first approved by Hyogo College of Medicine, Independent Ethics Committee, and then other ethics committees for all other institutions. The names of all participated research institutions and the names of ethics committees that have approved the study are listed in supplementary Table 1. Written informed consent was obtained prior to treatment from all enrolled patients who met the eligibility criteria.

Data Availability

The datasets generated during and/or analyzed during the current study are not publicly available due to the lack of a statement in the study protocol enabling data sharing with a third party after the end of the study and in the informed consent documents as well as lack of approval for data sharing by the institutional review board of each participating institution.

Author information

Authors and Affiliations

  1. Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan

    Tomoyuki Katsuno, Hidenori Koyama, Mitsuyoshi Namba & Jun-ichiro Miyagawa

  2. Department of Occupational Therapy, School of Rehabilitation, Hyogo University of Health Sciences, Hyogo, Japan

    Tomoyuki Katsuno

  3. Shiraiwa Medical Clinic, Osaka, Japan

    Toshihiko Shiraiwa

  4. Iwasaki Internal Medicine Clinic, Osaka, Japan

    Shingo Iwasaki

  5. Fukuda Clinic, Osaka, Japan

    Hyohun Park

  6. Watanabe Clinic, Hyogo, Japan

    Nobuaki Watanabe

  7. Takatsuki Red Cross Hospital, Osaka, Japan

    Shizuka Kaneko

  8. Department of Internal Medicine (I), Osaka Medical College, Takatsuki, Osaka, Japan

    Jungo Terasaki & Akihisa Imagawa

  9. Sakai City Medical Center, Osaka, Japan

    Toshiaki Hanafusa

  10. Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan

    Iichiro Shimomura

  11. Department of Endocrinology, Metabolism and Diabetes, Kindai University, Osaka, Japan

    Hiroshi Ikegami

  12. Takarazuka City Hospital, Hyogo, Japan

    Mitsuyoshi Namba

  13. Keiseikai Medical Corporation, Osaka, Japan

    Jun-ichiro Miyagawa

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  1. Tomoyuki Katsuno
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  2. Toshihiko Shiraiwa
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  9. Akihisa Imagawa
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  14. Jun-ichiro Miyagawa
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Consortia

For the TRUST2 study group

  • H. Seino
  • , S. Nakata
  • , D. Uchida
  • , R. Komi
  • , A. Ooka
  • , A. Tanaka
  • , C. Nawa
  • , M. Moriwaki
  • , F. Haseda
  • , K. Murata
  • , Y. Hiromine
  • , H. Nishimura
  • , S. Matsutani
  • , T. Tsunoda
  • , H. Konya
  • , S. Sakane
  • , H. Ohashi
  • , A. Nagao
  • , A. Arimitsu
  • , S. Kurebayashi
  • , H. Fujii
  • , H. Imbe
  • , M. Miyawaki
  • , Y. Mishiba
  • , M. Onishi
  • , K. Tanimoto
  • , F. Nakatsuji
  • , J. Kozawa
  • , H. Iwahashi
  • , K. Fukui
  • , T. Yamamoto
  • , Y. Kojima
  • , A. Aida
  • , T. Hiyoshi
  • , M. Menjyu
  •  & I. Hayashi

Corresponding author

Correspondence to Tomoyuki Katsuno.

Additional information

Other members of the TRUST2 study group due listed in the “Acknowledgements” section.

Supplementary Information

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Supplementary file1 (DOCX 17 KB)

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Katsuno, T., Shiraiwa, T., Iwasaki, S. et al. Benefit of Early Add-on of Linagliptin to Insulin in Japanese Patients With Type 2 Diabetes Mellitus: Randomized-Controlled Open-Label Trial (TRUST2). Adv Ther 38, 1514–1535 (2021). https://doi.org/10.1007/s12325-021-01631-y

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