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Effects of Sodium Glucose Co-Transporter 2 Inhibitor Canagliflozin in Patients with Type 2 Diabetes and Chronic Heart Failure (CANDLE): An Open-Label, Randomized Controlled Trial

48 Pages Posted: 2 Mar 2019

See all articles by Atsushi Tanaka

Atsushi Tanaka

Saga University - Department of Cardiovascular Medicine

Itaru Hisauchi

Saitama University - Department of Cardiology

Isao Taguchi

Saitama University - Department of Cardiology

Akira Sezai

Nihon University

Shigeru Toyoda

Dokkyo Medical University

Masataka Sata

Tokushima University

Yasunori Sato

Keio University

Shinichiro Ueda

University of Ryukyu

Jun-ichi Oyama

Saga University - Department of Cardiovascular Medicine

Masafumi Kitakaze

National Cerebral and Cardiovascular Centre - Department of Clinical Research and Development

Toyoaki Murohara

Nagoya University - Department of Cardiology

Koichi Node

Saga University - Department of Cardiovascular Medicine

CANDLE Trial Investigators

More...

Abstract

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce heart failure (HF)-related outcome risk in patients with type 2 diabetes (T2D). However, little is known about the safety and efficacy of SGLT2 inhibitors in patients with T2D and concomitant HF.

Methods: CANDLE was an open-label, randomized, parallel-group, multicentre trial at 34 centers in Japan. We randomly assigned (1:1) patients with T2D and New York Heart Association class I-III stable HF to canagliflozin 100 mg once daily or glimepiride (initiation: 0*5 or 1*0 mg daily) by using a computer-generated, dynamic balancing method, stratified by age, HbA1c, and left ventricular ejection fraction, and treated for 24 weeks. Neither patients nor investigators were masked to group assignment, but assessors for the primary endpoint were blinded. The primary endpoint was the non-inferiority of canagliflozin versus glimepiride, with a non-inferiority margin 1*1 in the group ratio of the percentage change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to 24 weeks.

Findings: Between August 10, 2015 and June 30, 2017, 122 patients were assigned to canagliflozin and 123 to glimepiride: 113 in the canagliflozin group and 120 in the glimepiride group were included in the primary endpoint analysis. The group ratio of NT-proBNP percentage changes was 0*48 (95% CI, -0*13 to 1*59, p=0*226). Meanwhile, a group difference in the NT-proBNP absolute change from baseline to 24 weeks was significant (canagliflozin: -107*0 ± 597*8 pg/mL; glimepiride 21*7 ± 252*8, p=0*047). Canagliflozin was well tolerated with adverse events comparable to those of glimepiride.

Interpretation: Although the trial did not meet the primary endpoint, canagliflozin significantly reduced NT-proBNP, compared to glimepiride, in patients with T2D and HF. Our data suggest clinical benefits of SGLT2 inhibitors in that population.

Trial Registry Number: This study is registered with the University Medical Information Network Clinical Trial Registry, 000017669.

Funding Statement: Mitsubishi Tanabe Pharma Corporation.

Declaration of Interests: AT has received modest honoraria from Astellas, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, MSD, Mitsubishi Tanabe, Novo Nordisk, Taisho Toyama, and Takeda. IT has received grants and personal fees from Mitsubishi Tanabe, AstraZeneca, Bristol-Myers Squibb, Bayer, Takeda, Daiichi Sankyo, Otsuka, MSD, Shionogi, Kowa, Sumitomo Dainippon, Boehringer Ingelheim, Mitsubishi Tanabe, and Mochida. MS has received grants and personal fees from Mitsubishi Tanabe, Takeda, Daiichi Sankyo, Astellas, Pfizer, Novartis, Boehringer Ingelheim, Bayer, MSD, Kowa, and AstraZeneca. SU has received grants from Kowa, Bristol-Myers Squibb, Bayer, honoraria from MSD, Boehringer Ingelheim, and Chugai. JO belongs to the endowed department of Fukuda Denshi. MK has received grants from Japanese government, Japan Heart Foundation, Japan Cardiovascular Research Foundation, Novartis, Nihon Kohden, and Kureha, grants and personal fees from Astellas, Pfizer, Ono, Mitsubishi Tanabe, and AstraZeneca, personal fees from Daiichi Sankyo. TM has received grants from Mitsubishi Tanabe, and Boehringer Ingelheim, personal fees from Mitsubishi Tanabe, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Ono, and Kowa. KN has received grants from Mitsubishi Tanabe, during the conduct of the study; personal fees from MSD, Astellas, Amgen Astellas, AstraZeneca, Eli Lilly, Otsuka, Daiichi Sankyo, Takeda, Boehringer Ingelheim, Bayer, Pfizer, Ono, and Mitsubishi Tanabe, grants from Asahi Kasei, Astellas, Mitsubishi Tanabe, Teijin, Terumo, Boehringer Ingelheim, and Bayer, scholarship from Bayer, Daiichi Sankyo, Teijin, Astellas, Takeda, and Bristol-Myers Squibb. All other authors declare no competing interests.

Ethics Approval Statement: The trial was approved by individual sites’ institutional review boards or independent ethics committees, in compliance with the Declaration of Helsinki and the current legal regulations in Japan.

Suggested Citation

Tanaka, Atsushi and Hisauchi, Itaru and Taguchi, Isao and Sezai, Akira and Toyoda, Shigeru and Sata, Masataka and Sato, Yasunori and Ueda, Shinichiro and Oyama, Jun-ichi and Kitakaze, Masafumi and Murohara, Toyoaki and Node, Koichi and Investigators, CANDLE Trial, Effects of Sodium Glucose Co-Transporter 2 Inhibitor Canagliflozin in Patients with Type 2 Diabetes and Chronic Heart Failure (CANDLE): An Open-Label, Randomized Controlled Trial (February 27, 2019). Available at SSRN: https://ssrn.com/abstract=3343659 or http://dx.doi.org/10.2139/ssrn.3343659

Atsushi Tanaka

Saga University - Department of Cardiovascular Medicine

1 本庄町 Saga
Saga Prefecture, 840-8502
Japan

Itaru Hisauchi

Saitama University - Department of Cardiology

Japan

Isao Taguchi

Saitama University - Department of Cardiology

Japan

Akira Sezai

Nihon University

Tokyo
Japan

Shigeru Toyoda

Dokkyo Medical University

Japan

Masataka Sata

Tokushima University

Tokushima
Japan

Yasunori Sato

Keio University

2-15-45 Mita
Minato-ku
Tokyo, 108-8345
Japan

Shinichiro Ueda

University of Ryukyu

Okinawa
Japan

Jun-ichi Oyama

Saga University - Department of Cardiovascular Medicine

1 本庄町 Saga
Saga Prefecture, 840-8502
Japan

Masafumi Kitakaze

National Cerebral and Cardiovascular Centre - Department of Clinical Research and Development ( email )

Japan

Toyoaki Murohara

Nagoya University - Department of Cardiology

Japan

Koichi Node (Contact Author)

Saga University - Department of Cardiovascular Medicine ( email )

1 本庄町 Saga
Saga Prefecture, 840-8502
Japan

No contact information is available for CANDLE Trial Investigators

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