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Effects of Teneligliptin on the Progressive Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes Mellitus in Open-Label, Marker-Stratified Randomized, Parallel-Group Comparison, Standard Treatment-Controlled Multicenter Trial (TOPLEVEL Study): Rationale and Study Design

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Abstract

Background and Aims

Diabetes mellitus (DM) can cause left ventricular (LV) diastolic dysfunction, leading to heart failure with preserved ejection fraction (HFpEF). Dipeptidyl peptidase IV (DPP-IV) inhibitors have failed to reduce hospitalization due to HF in type 2 DM (T2D) patients in a large-scale clinical trial, despite their cardiovascular protective effects. Therefore, it is important to investigate whether DPP-IV inhibitors can improve LV diastolic dysfunction in T2D patients. The aim of the study was to evaluate whether teneligliptin, the strongest of the DPP-IV inhibitors, improves LV dysfunction or prevents the worsening of LV diastolic function in T2D patients.

Methods

The TOPLEVEL study is designed as an open-labeled, marker-stratified randomized, parallel-group comparison, standard treatment-controlled multicenter study. TOPLEVEL includes two marker-defined subgroups to give treatment recommendations for T2D patients with normal (E/e′ < 8) or impaired LV diastolic function (E/e′ ≥ 8), where E/e′ is the ratio of peak velocity of early transmitral diastolic filling by echocardiography to early diastolic mitral annular velocity by tissue Doppler echocardiography as LV diastolic function. Patients are randomly assigned to either teneligliptin (20 or 40 mg) or the standard treatment group. All patients are followed up for 2 years. The primary endpoint measure is the change in E/e′ from baseline and 2 years after enrollment.

Conclusion and Perspectives

TOPLEVEL is a clinical trial of teneligliptin targeting LV diastolic dysfunction in T2D patients. This study demonstrates the effectiveness of DPP-IV inhibitors on LV diastolic dysfunction, an important surrogate endpoint to predict the cardiovascular outcomes of HFpEF (UMIN000014589).

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Availability of Data and Materials

To avoid potential bias of the analysis, the data set supporting the conclusions of this article will not be available until the final report of this trial is published.

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Acknowledgments

We gratefully acknowledge Ms. M. Yoda, Ms. M. Takahashi, Ms. R. Umezawa, and Ms. M. Saida for their secretarial assistance.

Funding

This study was conducted with funding provided by the Mitsubishi Tanabe Pharma Corporation.

Author information

Author notes

  1. Atsushi Nakano

    Present address: Department of Medical Affairs Division, GlaxoSmithKline K.K, 1-8-1 Akasaka, Minato-ku, Tokyo, 107-0052, Japan

Authors and Affiliations

  1. Department of Clinical Medicine and Development, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565, Japan

    Miki Imazu, Atsushi Nakano, Shin Ito & Masafumi Kitakaze

  2. Department of Data Science, National Cerebral and Cardiovascular Center, Suita, Japan

    Toshimitsu Hamasaki

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  1. Miki Imazu
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Consortia

On behalf of the TOPLEVEL investigators and study coordinators

Contributions

MI conceived the study. MI and SI wrote the manuscript. TH performed statistical analyses and provided the biostatistical study design. MK conceived and supervised the study and is the Principal Investigator on the grant. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Masafumi Kitakaze.

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Conflict of Interest

Persons from Mitsubishi Tanabe Pharma Corporation were not involved in conducting this study and analysis, and the intentions of Mitsubishi Tanabe Pharma Corporation are not reflected in the results or interpretations of this study.

Disclosure

Drs. Imadu, Ito, and Hamasaki have nothing to disclose. Dr. Nakano is now an employee of GlaxoSmithKline K.K. Dr. Kitakaze reports receiving grants from the Japanese government during the course of the study: grants from the Japanese government, grants from the Japan Heart Foundation, grants from the Japan Cardiovascular Research Foundation, grants and personal fees from Asteras, personal fees from Daiichi-sankyo, grants and personal fees from Pfizer, grants and personal fees from Ono, personal fees from Bayer, grants from Novartis, grants and personal fees from Mitubishi Tanabe Pharma, personal fees from Kowa, personal fees from MSD, grants from Nihon Kohden, personal fees from Shionogi, personal fees from AstraZeneca, grants and personal fees from AstraZeneca, personal fees from Taisho-Toyama, personal fees from Toyama-Kagaku, grants and personal fees from Kureha, and personal fees from Toaeiyo, outside of the currently proposed work.

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Imazu, M., Nakano, A., Ito, S. et al. Effects of Teneligliptin on the Progressive Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes Mellitus in Open-Label, Marker-Stratified Randomized, Parallel-Group Comparison, Standard Treatment-Controlled Multicenter Trial (TOPLEVEL Study): Rationale and Study Design. Cardiovasc Drugs Ther 33, 363–370 (2019). https://doi.org/10.1007/s10557-019-06871-3

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