The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: TheCANA-HFstudy

Background Canagliflozin reduces hospitalizations for heart failure (HF) in type 2 diabetes mellitus (T2DM). Its effect on cardiorespiratory fitness and cardiac function in patients with established HF with reduced ejection fraction (HFrEF) is unknown. Methods We conducted a double-blind randomized controlled trial of canagliflozin 100 mg or sitagliptin 100 mg daily for 12 weeks in 88 patients, and measured peak oxygen consumption (VO2) and minute ventilation/carbon dioxide production (VE/VCO2) slope (co-primary endpoints for repeated measure ANOVA time_x_group interaction), lean peak VO2, ventilatory anaerobic threshold (VAT), cardiac function and quality of life (ie, Minnesota Living with Heart Failure Questionnaire [MLHFQ]), at baseline and 12-week follow-up. Results The study was terminated early due to the new guidelines recommending canagliflozin over sitagliptin in HF: 17 patients were assigned to canagliflozin and 19 to sitagliptin, total of 36 patients. There were no significant changes in peak VO(2)and VE/VCO(2)slope between the two groups (P= .083 andP= .98, respectively). Canagliflozin improved lean peak VO2(+2.4 mL kg(LM)(-1)min(-1),P= .036), VAT (+1.5 mL kg(-1)min(-1),P= .012) and VO(2)matched for respiratory exchange ratio (+2.4 mL Kg(-1)min(-1),P= .002) compared to sitagliptin. Canagliflozin also reduced MLHFQ score (-12.1,P= .018). Conclusions In this small and short-term study of patients with T2DM and HFrEF, interrupted early after only 36 patients, canagliflozin did not improve the primary endpoints of peak VO(2)or VE/VCO(2)slope compared to sitagliptin, while showing favourable trends observed on several additional surrogate endpoints such as lean peak VO2, VAT and quality of life.