Abstract

Introduction

Type 2 diabetes (T2DM) is associated with cardiovascular death, including sudden cardiac death due to arrhythmias. Patients with an implantable cardioverter-defibrillator (ICD) are also at high risk of developing a clinically significant ventricular arrhythmia. It has been reported that sodium–glucose cotransporter 2 (SGLT2) inhibitors can reduce cardiovascular deaths; however, the physiological mechanisms of this remain unclear. It is, however, well known that SGLT2 inhibitors increase blood ketone bodies, which have been suggested to have sympatho-suppressive effects. Empagliflozin (EMPA) is an SGLT2 inhibitor. The current clinical trial titled “Placebo-controlled, double-blind study of empagliflozin (EMPA) and implantable cardioverter-defibrillator (EMPA-ICD) in patients with type 2 diabetes (T2DM)” was designed to investigate the antiarrhythmic effects of EMPA.

Methods

The EMPA-ICD study is a prospective, multicenter, placebo-controlled, double-blind, randomized, investigator-initiated clinical trial currently in progress. A total of 210 patients with T2DM (hemoglobin A1c 6.5–10.0%) will be randomized (1:1) to receive once-daily placebo or EMPA, 10 mg, for 24 weeks. The primary endpoint is the number of clinically significant ventricular arrhythmias for 24 weeks before and 24 weeks after study drug administration, as documented by the ICD. The secondary endpoints of the study are the change from baseline concentrations in blood ketone and catecholamine 24 weeks after drug treatment.

Conclusion

The EMPA-ICD study is the first clinical trial to assess the effect of an SGLT2 inhibitor on clinically significant ventricular arrhythmias in patients with T2DM and an ICD.

Trial registration

Unique trial number, jRCTs031180120 (https://jrct.niph.go.jp/latest-detail/jRCTs031180120).

Details

Title
Placebo-Controlled, Double-Blind Study of Empagliflozin (EMPA) and Implantable Cardioverter-Defibrillator (EMPA-ICD) in Patients with Type 2 Diabetes (T2DM): Rationale and Design
Author
Fujiki, Shinya 1 ; Iijima, Kenichi 1 ; Okabe, Masaaki 2 ; Niwano, Shinichi 3 ; Tsujita, Kenichi 4 ; Naito, Shigeto 5 ; Ando, Kenji 6 ; Kusano, Kengo 7 ; Kato, Ritsushi 8 ; Nitta, Junichi 9 ; Miura, Tetsuji 10 ; Mitsuhashi, Takeshi 11 ; Kario, Kazuomi 12 ; Kondo, Yusuke 13 ; Ieda, Masaki 14 ; Hagiwara, Nobuhisa 15 ; Murohara, Toyoaki 16 ; Takahashi, Kazuyoshi 17 ; Tomita, Hirofumi 18 ; Takeishi, Yasuchika 19 ; Anzai, Toshihisa 20 ; Shimizu, Wataru 21 ; Watanabe, Masafumi 22 ; Morino, Yoshihiro 23 ; Kato, Takeshi 24 ; Tada, Hiroshi 25 ; Nakagawa, Yoshihisa 26 ; Yano, Masafumi 27 ; Maemura, Koji 28 ; Kimura, Takeshi 29 ; Yoshida, Hisako 30 ; Ota, Keiko 31 ; Tanaka, Takahiro 32 ; Kitamura, Nobutaka 32 ; Node, Koichi 33 ; Aizawa, Yoshifusa 2 ; Shimizu, Ippei 34 ; Izumi, Daisuke 1 ; Ozaki, Kazuyuki 1 ; Minamino, Tohru 35   VIAFID ORCID Logo  ; Takahashi, Minoru; Kitazawa, Hitoshi; Ikeda, Yoshio; Fujita, Satoru; Fuse, Koichi; Nasuno, Akimitsu; Sato, Akinori; Yuasa, Sho; Ota, Yusuke; Goto, Sonoka; Ando, Ryota; Fukaya, Hidehira; Kishihara, Jun; Oikawa, Jun; Ishizue, Naruya; Shirakawa, Yuki; Ishii, Shunsuke; Nabeta, Takeru; Kawano, Hiroaki; Kaikita, Koichi; Soejima, Hirofumi; Yamamoto, Eiichiro; Suzuki, Satoru; Sakamoto, Kenji; Nakamura, Taishi; Usuku, Hiroki; Araki, Satoshi; Arima, Yuichiro; Takashio, Seiji; Kanazawa, Hisanori; Sueta, Daisuke; Hoshiyama, Tadashi; Fujisue, Koichiro; Ito, Miwa; Oike, Fumi; Sato, Ryota; Takae, Masafumi; Nishi, Masato; Yamanaga, Kenshi; Komorita, Takashi; Kawahara, Yusei; Morioka, Mami; Kubota, Yuji; Nakamura, Kohki; Sasaki, Takehito; Hiroshima, Kenichi; Nagashima, Michio; Fukunaga, Masato; Hirokami, Jun; Noda, Takashi; Inoue, Yuko; Ishibashi, Kouhei; Wada, Mitsuru; Kamakura, Tsukasa; Yamagata, Kenichiro; Miyamoto, Koji; Nakajima, Kenzaburo; Ueda, Nobuhiko; Hosoda, Kiminori; Makino, Hisashi; Ohata, Yoko; Tamanaha, Tamiko; Koezuka, Ryo; Matsubara, Masaki; Shiba, Mariko Harada; Son, Cheol; Tomita, Tsutomu; Noguchi, Michio; Nakajima, Yoshie; Ikeda, Yoshifumi; Tsutsui, Kenta; Umemura, Jun; Inoue, Kanki; Nagahara, Daigo; Umemoto, Tomio; Ugata, Yusuke; Yamamoto, Shingo; Akashi, Naoyuki; Komori, Takahiro; Kabutoya, Tomoyuki; Kobayashi, Yoshio; Igarashi, Miyako; Yamasaki, Hiro; Komatsu, Yuki; Kimata, Akira; Shoda, Morio; Suzuki, Atsushi; Inden, Yasuya; Hosaka, Yukio; Sasaki, Shingo; Horiuchi, Daisuke; Ishida, Yuji; Kinjo, Takahiko; Nishizaki, Kimitaka; Kaneshiro, Takashi; Yamada, Shinya; Hijioka, Naoko; Watanabe, Masaya; Koya, Taro; Nakao, Motoki; Iwasaki, Yu-ki; Yodogawa, Kenji; Hayashi, Hiroshi; Kubota, Yoshiaki; Eiichiro, Oka; Takamura, Masayuki; Furusho, Hiroshi; Hayashi, Kenshi; Tsuda, Toyonobu; Niwa, Satoru; Usuda, Keisuke; Ozawa, Tomoya; Okuyama, Yusuke; Fukae, Satoki; Doi, Yoshiyuki; Arakawa, Shuji; Hasegawa, Kanae; Mukai, Moe; Arimoto, Takanori; Kutsuzawa, Daisuke; Fukuda, Masakazu; Yoshiga, Yasuhiro; Kato, Takayoshi; Owada, Shingen; Yoshizawa, Reisuke; Komatsu, Takashi; Sawa, Yohei; Yamashita, Yugo; Saikawa, Takashi; Watanabe, Tohru; Kayamori, Hiromi; Onoda, Hiroshi; Kumaki, Takayuki; Hirayama, Sho; Hayashi, Hidemori; Tabuchi, Haruna; Tokano, Takashi; Odagiri, Fuminori

1  Niigata University Graduate School of Medical and Dental Sciences, Department of Cardiovascular Biology and Medicine, Niigata, Japan (GRID:grid.260975.f) (ISNI:0000 0001 0671 5144) 
2  Tachikawa General Hospital, Department of Cardiology, Nagaoka, Niigata, Japan (GRID:grid.416822.b) (ISNI:0000 0004 0531 5386) 
3  Kitasato University, Cardiovascular Medicine, Sagamihara, Japan (GRID:grid.410786.c) (ISNI:0000 0000 9206 2938) 
4  Kumamoto University, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto, Japan (GRID:grid.274841.c) (ISNI:0000 0001 0660 6749) 
5  Gunma Prefectural Cardiovascular Center, Division of Cardiology, Maebashi, Japan (GRID:grid.418349.3) 
6  Kokura Memorial Hospital, Department of Cardiology, Kitakyushu, Fukuoka, Japan (GRID:grid.415432.5) (ISNI:0000 0004 0377 9814) 
7  National Cerebral and Cardiovascular Center, Department of Cardiovascular Medicine, Suita, Osaka, Japan (GRID:grid.410796.d) (ISNI:0000 0004 0378 8307) 
8  Saitama Medical University International Medical Center, Department of Cardiology, Hidaka, Saitama, Japan (GRID:grid.412377.4); Saitama Medical University International Medical Center, Department of Arrhythmia, Hidaka, Saitama, Japan (GRID:grid.412377.4) 
9  Sakakibara Heart Institute, Department of Cardiology, Fuchu, Tokyo, Japan (GRID:grid.413411.2) 
10  Sapporo Medical University School of Medicine, Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo, Japan (GRID:grid.263171.0) (ISNI:0000 0001 0691 0855) 
11  Jichi Medical University Saitama Medical Center, Department of Cardiology, Saitama, Japan (GRID:grid.415020.2) (ISNI:0000 0004 0467 0255) 
12  Jichi Medical University School of Medicine, Division of Cardiovascular Medicine, Department of Medicine, Shimotsuke, Tochigi, Japan (GRID:grid.410804.9) (ISNI:0000000123090000) 
13  Chiba University Graduate School of Medicine, Department of Cardiovascular Medicine, Chiba, Japan (GRID:grid.136304.3) (ISNI:0000 0004 0370 1101) 
14  University of Tsukuba, Department of Cardiology, Faculty of Medicine, Tsukuba, Ibaraki, Japan (GRID:grid.20515.33) (ISNI:0000 0001 2369 4728) 
15  Tokyo Women’s Medical University, Department of Cardiology, Tokyo, Japan (GRID:grid.410818.4) (ISNI:0000 0001 0720 6587) 
16  Nagoya University Graduate School of Medicine, Department of Cardiology, Nagoya, Japan (GRID:grid.27476.30) (ISNI:0000 0001 0943 978X) 
17  Niigata City General Hospital, Department of Cardiology, Niigata, Japan (GRID:grid.416205.4) (ISNI:0000 0004 1764 833X) 
18  Hirosaki University Graduate School of Medicine, Department of Cardiology and Nephrology, Hirosaki, Japan (GRID:grid.257016.7) (ISNI:0000 0001 0673 6172) 
19  Fukushima Medical University, Department of Cardiovascular Medicine, Fukushima, Japan (GRID:grid.411582.b) (ISNI:0000 0001 1017 9540) 
20  Hokkaido University Graduate School of Medicine, Department of Cardiovascular Medicine, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691) 
21  Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan (GRID:grid.410821.e) (ISNI:0000 0001 2173 8328) 
22  Yamagata University Faculty of Medicine, Department of Cardiology, Pulmonology, and Nephrology, Yamagata, Japan (GRID:grid.268394.2) (ISNI:0000 0001 0674 7277) 
23  Iwate Medical University, Division of Cardiology, Department of Internal Medicine, Morioka, Japan (GRID:grid.411790.a) (ISNI:0000 0000 9613 6383) 
24  Kanazawa University, Department of Cardiology, Graduate School of Medical Science, Kanazawa, Ishikawa, Japan (GRID:grid.9707.9) (ISNI:0000 0001 2308 3329) 
25  University of Fukui, Department of Cardiovascular Medicine, Faculty of Medical Sciences, Fukui, Japan (GRID:grid.163577.1) (ISNI:0000 0001 0692 8246) 
26  Shiga University of Medical Science, Department of Cardiovascular Medicine, Otsu, Japan (GRID:grid.410827.8) (ISNI:0000 0000 9747 6806) 
27  Yamaguchi University Graduate School of Medicine, Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi, Japan (GRID:grid.268397.1) (ISNI:0000 0001 0660 7960) 
28  Nagasaki University Graduate School of Biomedical Sciences, Department of Cardiovascular Medicine, Nagasaki, Japan (GRID:grid.174567.6) (ISNI:0000 0000 8902 2273) 
29  Kyoto University Graduate School of Medicine, Department of Cardiovascular Medicine, Kyoto, Japan (GRID:grid.258799.8) (ISNI:0000 0004 0372 2033) 
30  Osaka City University, Graduate School of Medicine, Department of Medial Statistics, Osaka, Japan (GRID:grid.261445.0) (ISNI:0000 0001 1009 6411) 
31  Osaka City University Hospital, Data Management Group, Department of Clinical Research Support, Center for Clinical Research and Innovation, Osaka, Japan (GRID:grid.470114.7) 
32  Niigata University Medical and Dental Hospital, Clinical and Translational Research Center, Niigata, Japan (GRID:grid.412181.f) (ISNI:0000 0004 0639 8670) 
33  Saga University, Department of Cardiovascular Medicine, Saga, Japan (GRID:grid.412339.e) (ISNI:0000 0001 1172 4459) 
34  Niigata University Graduate School of Medical and Dental Sciences, Department of Cardiovascular Biology and Medicine, Niigata, Japan (GRID:grid.260975.f) (ISNI:0000 0001 0671 5144); Niigata University Graduate School of Medical and Dental Sciences, Divisiont of Molecular Aging and Cell Biology, Niigata, Japan (GRID:grid.260975.f) (ISNI:0000 0001 0671 5144) 
35  Niigata University Graduate School of Medical and Dental Sciences, Department of Cardiovascular Biology and Medicine, Niigata, Japan (GRID:grid.260975.f) (ISNI:0000 0001 0671 5144); Juntendo University Graduate School of Medicine, Department of Cardiovascular Biology and Medicine, Tokyo, Japan (GRID:grid.258269.2) (ISNI:0000 0004 1762 2738); Japan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, Tokyo, Japan (GRID:grid.480536.c) (ISNI:0000 0004 5373 4593) 
Pages
2739-2755
Publication year
2020
Publication date
Nov 2020
Publisher
Springer Nature B.V.
ISSN
18696953
e-ISSN
18696961
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1007/s13300-020-00924-9
ProQuest document ID
2512385001
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.