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

Abstract

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 VO₂ and VE/VCO₂ slope between the two groups (P = .083 and P = .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 VO₂ 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 VO₂ or VE/VCO₂ slope compared to sitagliptin, while showing favourable trends observed on several additional surrogate endpoints such as lean peak VO₂ , VAT and quality of life.

Keywords: DPP4 inhibitors; SGLT2 inhibitors; cardiorespiratory fitness; diabetes mellitus; heart failure.