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

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.