The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA‐HF study

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 (VO(2)) and minute ventilation/carbon dioxide production (VE/VCO(2)) slope (co‐primary endpoints for repeated measure ANOVA time_x_group interaction), lean peak VO(2), 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 and P = .98, respectively). Canagliflozin improved lean peak VO(2) (+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 VO(2), VAT and quality of life.