Short-Term Effects of Dapagliflozin on Ventilatory Efficiency During Exercise and Cardiac Remodeling in Patients with Heart Failure with Reduced Ejection Fraction

Background. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, initially developed as glucose-lowering agents, showed a significant reduction in cardiovascular mortality, heart failure (HF) hospitalization and cardiac remodeling, inducing a significant improvement in quality of life and long-term prognosis. However, the acute impact on clinical status is not clear. Methods. Patients with a condition of HF with reduced ejection fraction (HFrEF) and optimal medical therapy fort at least 4 weeks were enrolled. Patients were evaluated at baseline and after 30±7 days of dapagliflozin administration. Baseline and follow-up visits included clinical evaluation, blood tests, trans-thoracic echocardiography, cardiopulmonary exercise test (CPET), and analysis of quality of life. The primary endpoint of the study was the evaluation of the short-term effects induced by dapagliflozin administration on functional capacity, defined as variation in CPET parameters and Kansas City Cardiomyopathies questionnaire (KCCQ). Results. A total of 20 patients were included. We observed that the addition of dapagliflozin induced an early improvement in ventilatory efficiency during exercise. Specifically, median ventilation/CO2 production (VE/VCO2) slope significantly decreased from 37.8 at baseline (interquartile range, IQR, 34.1;42.8) to 36.2 at follow-up (IQR 31.6;38) (p=0.003). Patients reported a significant improvement in their quality of life, as demonstrated by a significant increase in the final score of KCCQ (median difference, MD, 9 (IQR: 0;15.8), p=0.0003). After dapagliflozin administration, we showed a significant increase in EF (36%, IQR 36;46), while median global longitudinal strain (GLS) was similar (-11.2%, IQR -14.3; -7.5). Moreover, a significant improvement in right ventricle systolic function was observed: at 30±7 days follow- up, a raise in Systolic wave prime, S’, (MD 2 (IQR: 0;4), p=0.024) and TAPSE (MD 2 (IQR: 1;5), p=0.001) was obtained. In addition, we also observed a non-significant amelioration in diastolic function, left ventricle remodeling, inflammatory profile and NT-proBNP values. Conclusions. The addition of dapagliflozin on-top of optimal medical therapy may induce an early improvement of ventilatory efficiency, exercise tolerance and quality of life in patients with HFrEF.