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Rationale and Design of Prospective, Multicenter, Double-Arm Clinical Trial to Investigate the Efficacy of Tofogliflozin on Left Ventricular Diastolic Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus (TOP-HFPEF Trial)

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Abstract

Background

Recent large clinical trials have revealed that sodium–glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes not only in patients with heart failure with reduced ejection fraction, but also in patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF). However, the effect of SGLT2 inhibitors on left ventricular (LV) diastolic function is still controversial.

Methods and Results

The TOP-HFPEF trial (Efficacy of Tofogliflozin on Left Ventricular Diastolic Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus) is a multicenter, double-arm, open-label, confirmatory, investigator-initiated clinical study to investigate the effect of SGLT2 inhibitor on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus. The participants are randomly assigned (1:1) to the tofogliflozin group (20 mg once daily) or the control group (administration or continuation of antidiabetic drugs other than SGLT2 inhibitors). The estimated number of patients to be enrolled in this trial is 90 in total (45 in each group). The participants are followed up for 52 weeks with tofogliflozin or control drugs. The primary endpoint is the change in E/e′ assessed by echocardiography from the baseline to the end of this study (52 weeks). This trial will also evaluate the effects of tofogliflozin on cardiovascular events, biomarkers, other echocardiographic parameters, the occurrence of atrial fibrillation, and renal function.

Conclusions

The TOP-HFPEF trial will clarify the efficacy of an SGLT2 inhibitor, tofogliflozin, on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus.

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Data Availability

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Acknowledgements

We gratefully acknowledge Ms. Yumiko Ikeno and Ms. Ena Tsujita at Hanwa Memorial Hospital for their secretarial work, Ms. Kinuyo Ishida and Ms. Megumi Miyazaki for the construction of electrical case report form at National Cerebral and Cardiovascular Center.

Funding

This work was supported by Kowa Company, Limited.

Author information

Author notes

  1. Shin Ito and Yuri Nakajima contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Suita, Japan

    Shin Ito & Yuri Nakajima

  2. Department of Heart Failure and Transplant, National Cerebral and Cardiovascular Center, Suita, Japan

    Shin Ito & Chisato Izumi

  3. Cardiovascular Center, Medical Research Institute KITANO HOSPITAL, PIIF Tazuke-Kofukai, Osaka, Japan

    Hiroki Fukuda & Moriaki Inoko

  4. Department of Cardiology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan

    Gaku Nakazawa

  5. Department of Cardiology, Baba Memorial Hospital, Sakai, Japan

    Hajime Yamashita

  6. Department of Cardiovascular Medicine, Sakai City Medical Center, Sakai, Japan

    Hideo Matsuhisa

  7. Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan

    Shigeru Toyoda

  8. Department of Cardiology, Higashi Takarazuka Satoh Hospital, Takarazuka, Japan

    Shin Takiuchi

  9. Division of Cardiology, Bell Land General Hospital, Sakai, Japan

    Toru Kataoka

  10. Department of Cardiovascular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan

    Yasuhiro Izumiya

  11. Department of Cardiology, Osaka City General Hospital, Osaka, Japan

    Yukio Abe

  12. Department of Information and Computer Technology, Faculty of Engineering, Tokyo University of Science, Tokyo, Japan

    Takashi Sozu

  13. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    Yasushi Sakata

  14. Department of Metabolism, Endocrinology and Molecular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan

    Masanori Emoto

  15. Japan Red Cross Society, Nasu Red Cross Hospital, Otawara, Japan

    Teruo Inoue

  16. Hanwa Memorial Hospital, 3-5-8 Minamisumiyoshi, Sumiyoshi-Ku, Osaka, 558-0041, Japan

    Masafumi Kitakaze

  17. Non-Profit Organization Think of Medicine in Science, Osaka, Japan

    Masafumi Kitakaze

  18. The Osaka Medical Research Foundation for Intractable Diseases, Osaka, Japan

    Masafumi Kitakaze

Authors
  1. Shin Ito
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Contributions

Study concept and design (SI, YN, HF, GN, MI, S Toyoda, S Takiuchi, TK, YI, YA, YS, ME, TI, MK); study conduction and patients’ recruitment (CI, GN, HY, HM, MI, S Toyoda, S Takiuchi, TK, YI, YA, MK); planned statistical analysis (SI, HF, TS, MK); writing (SI, YN, MK); figures and tables (SI, YN); advisor (YS, ME, TI). All authors read and approved this manuscript.

Corresponding author

Correspondence to Masafumi Kitakaze.

Ethics declarations

Ethical Approval

This study is conducted in compliance with the Declaration of Helsinki and Japan’s Clinical Trials Act. The study protocol was approved by the Certified Review Board of Osaka Metropolitan University, and written informed consent will be obtained from all patients before their enrollment.

Consent to Participate

All eligible participants are required to provide written informed consent before enrollment in this study.

Consent for Publication

All authors reviewed the manuscript and approved its submission.

Conflict of Interest

Kowa Company will not have any role in the analysis or interpretation of the results of this study.

SI reports receiving a lecture fee from Nippon Boehringer Ingelheim Co., Ltd. and a grant from the Japan Society for the Promotion of Science, outside the submitted work.

YN reports receiving a grant from the Osaka Medical Research Foundation for Intractable Diseases, outside the submitted work.

HF reports receiving funds from Kitano Cadet-Doctor program, outside the submitted work.

CI reports personal fees from AstraZeneca K.K.; Medtronic Japan Co., Ltd.; Novartis Pharma K.K.; Kowa Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Daiichi Sankyo Co., Ltd.; Bayer Yakuhin, Ltd.; Otsuka Pharmaceutical Co., Ltd.; Pfizer Japan Inc.; Sumitomo Pharma Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Edwards Lifesciences Corp.; Nippon Boehringer Ingelheim Co., Ltd.; Tsumura & Co.; Philips Japan, Ltd.; Eisai Co., Ltd.; Canon Medical Systems Corp.; Alnylam Japan K.K.; Janssen Pharmaceutical K.K.; Kyowa Kirin Co., Ltd.; Abbott Medical Japan LLC; Eli Lilly Japan K.K.; Astellas Pharma Inc.; Nihon Medi-Physics Co., Ltd.; and Japan Lifeline Co., Ltd., outside the submitted work.

GN has nothing to disclose.

HY has nothing to disclose.

HM has nothing to disclose.

MI reports receiving scholarship funds and personal fees from Daiichi Sankyo Co., Ltd.; Novartis Pharma K.K.; Nippon Shinyaku Co., Ltd.; Bayer Yakuhin, Ltd.; Mitsubishi Tanabe Pharma Corp.; Nippon Boehringer Ingelheim Co., Ltd.; and Otsuka Pharmaceutical Co., Ltd.; receiving scholarship funds from Teijin Pharma, Ltd.; Public Research Center; Nihon Medi-Physics Co., Ltd.; and Mochida Pharmaceutical Co., Ltd.; receiving joint research funds from Mie University, Research Institute for Production Development Japan, Janssen Pharmaceutical K.K., Nihon Kohden Corp., Nara Medical University, National Cerebral and Cardiovascular Center, and IQVIA Japan K.K.; receiving joint research funds and personal fees from Amgen Inc.; receiving personal fees from Kowa Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; AstraZeneca K.K.; Pfizer Japan Inc.; Eli Lilly Japan K.K.; Ono Pharmaceutical Co., Ltd.; and Sumitomo Dainippon Pharma Co., Ltd., outside the submitted work.

S Toyoda reports receiving funds from Assist Japan Inc.; Abbott Vascular Japan Co., Ltd.; Abbott Medical Japan LLC; EP-CRSU Co., Ltd.; Next Japan Medicalnext Co., Ltd..; GE Healthcare Pharma Ltd.; CVQuest K.K.; Cmic Co., Ltd.; Sumitomo Electric Group CSR Foundation; Life Science Institute, Inc.; Teijin Pharma, Ltd.; Terumo Corp.; Nipro Corp.; Japan Heart Foundation; Next Japan Medicalnext Co., Ltd.; Japan Lifeline Co., Ltd.; Boston Scientific Japan K.K.; and Roche Diagnostics K.K.; receiving funds and lecture fees from Astellas Pharma Inc.; Otsuka Pharmaceutical Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Kyowa Kirin Co., Ltd.; Kowa Co., Ltd.; Sanofi K.K.; Daiichi Sankyo Co., Ltd.; Sumitomo Pharma Co., Ltd.; Mitsubishi Tanabe Pharma Corp.; Tsumura & Co.; Abiomed Japan K.K.; Eli Lilly Japan K.K.; Nippon Shinyaku Co., Ltd.; Nippon Boehringer Ingelheim Co., Ltd.; Medtronic Japan Co., Ltd.; Novartis Pharma K.K.; and Mochida Pharmaceutical Co., Ltd.; and receiving lecture fees from Bayer Yakuhin, Ltd.; Viatris Inc.; Novo Nordisk Pharma, Ltd.; AstraZeneca K.K.; Takeda Pharmaceutical Co., Ltd.; Janssen Pharmaceutical K.K.; Fukuda Denshi Co., Ltd.; Protea Japan Co., Ltd.; Eisai Co., Ltd.; Edwards Lifesciences Corp.; Zeria Pharmaceutical Co., Ltd.; Pfizer Japan Inc.; Bristol Myers Squibb K.K.; MSD Inc.; Amicus Therapeutics Inc.; and Toa Eiyo, Ltd., outside the submitted work.

S Takiuchi has nothing to disclose.

TK reports receiving personal fees from Kaneka Corp. and Philips Japan, Ltd., and receiving lecture fees from Kowa Co., Ltd.; Otsuka Pharmaceutical Co., Ltd.; Novartis Pharma K.K.; Nippon Boehringer Ingelheim Co., Ltd.; Daiichi Sankyo Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Tsumura & Co.; Toa Eiyo, Ltd.; AstraZeneca K.K.; Bayer Yakuhin, Ltd.; Boston Scientific Japan K.K.; Terumo Corp.; Nipro Corp.; and Abbott Medical Japan LLC, outside the submitted work.

YI reports receiving lecture fees from Pfizer Japan Inc.; Nippon Boehringer Ingelheim Co., Ltd.; Sanofi K.K.; Medtronic Japan Co., Ltd.; AstraZeneca K.K.; Toa Eiyo, Ltd.; Bayer Yakuhin, Ltd.; Takeda Pharmaceutical Co.; Ltd.; Sumitomo Pharma Co., Ltd.; Janssen Pharmaceutical K.K.; Otsuka Pharmaceutical Co., Ltd.; Kowa Co., Ltd.; Novartis Pharma K.K.; Mitsubishi Tanabe Pharma Corp.; Viatris Inc.; Nippon Shinyaku Co., Ltd.; Kyowa Kirin Co., Ltd.; Alnylam Japan K.K.; Eli Lilly Japan K.K.; JCR Pharmaceuticals Co., Ltd.; Amicus Therapeutics Inc.; Ono Pharmaceutical Co., Ltd.; Abbott Japan LLC; and GlaxoSmithKline Consumer Healthcare Japan K.K.; and receiving grants from Daiichi Sankyo Co., Ltd., outside the submitted work.

YA reports receiving personal fees from Abbott Medical Japan LLC; Astellas Pharma Inc.; AstraZeneca K.K.; Bayer Yakuhin, Ltd.; Daiichi Sankyo Co., Ltd.; Edwards Lifesciences Corp.; Eli Lilly Japan K.K.; GE Healthcare Japan Corp.; Mallinckrodt Pharma K.K.; Nippon Boehringer Ingelheim Co., Ltd.; Novartis Pharma K.K.; Ono Pharmaceutical Co., Ltd.; Otsuka Pharmaceutical Co., Ltd.; and Toa Eiyo, Ltd., outside the submitted work.

TS has nothing to disclose.

YS reports receiving personal fees from Daiichi Sankyo Co., Ltd.; Novartis Pharma K.K.; Nippon Boehringer Ingelheim Co., Ltd.; Otsuka Pharmaceutical Co., Ltd.; AstraZeneca K.K.; and Bayer Yakuhin, Ltd., outside the submitted work.

ME reports receiving grants from Mitsubishi Tanabe Pharma Corp.; Eisai Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; and Bayer Yakuhin, Ltd.; receiving personal lecture fees from Novo Nordisk Pharma, Ltd.; Sanofi K.K.; AstraZeneca K.K.; MSD Inc.; Kowa Co., Ltd.; Teijin Pharma, Ltd.; Sanwa Co., Ltd.; Eli Lilly Japan K.K.; and Astellas Pharma Inc.; and receiving grants and personal lecture fees from Nippon Boehringer Ingelheim Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Sumitomo Pharma Co., Ltd.; and Kyowa Kirin Co., Ltd., outside the submitted work.

TI reports personal fees from Kowa Co., Ltd.; Ono Pharmaceutical Co., Ltd.; Daiichi Sankyo Co., Ltd.; Mochida Pharmaceutical Co., Ltd.; Otsuka Pharmaceutical Co., Ltd.; AstraZeneca K.K.; Eisai Co., Ltd.; Mitsubishi Tanabe Pharma Corp.; Novo Nordic Pharma, Ltd.; and receiving grants from Fukuda Denshi Co., Ltd., outside the submitted work.

MK reports receiving personal fees from Daiichi Sankyo Co., Ltd.; Viatris Inc.; Otsuka Pharmaceutical Co., Ltd.; and Eli Lilly Japan K.K.; receiving grants and personal fees from Ono Pharmaceutical Co., Ltd.; Mitsubishi Tanabe Pharma Corp.; AstraZeneca K.K.; and Nippon Boehringer Ingelheim Co., Ltd.; receiving grants from Novartis Pharma K.K.; Takeda Pharmaceutical Co., Ltd.; and Kowa Co., Ltd., outside the submitted work.

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Ito, S., Nakajima, Y., Fukuda, H. et al. Rationale and Design of Prospective, Multicenter, Double-Arm Clinical Trial to Investigate the Efficacy of Tofogliflozin on Left Ventricular Diastolic Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus (TOP-HFPEF Trial). Cardiovasc Drugs Ther (2024). https://doi.org/10.1007/s10557-024-07576-y

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