Dapagliflozin effects on Exercise, Cardiac Remodeling, Biomarkers, Renal and Pulmonary Function in heart failure patients. Not as good as expected?

Massimo Mapelli ^1* Irene Mattavelli ¹ Elisabetta Salvioni ¹ Nicolò Capra ¹ Valentina Mantegazza ¹ Anna Garlaschè ¹ Jeness Campodonico ¹ Filippo Maria Rubbo ² Chiara Paganin ¹ Teresa Maria Capovilla ² Alessandro Alberto Nepitella ¹ Rebecca Caputo ¹ Paola Gugliandolo ¹ Carlo Vignati ¹ Beatrice Pezzuto ^1,2 Fabiana De Martino ³ Giulia Grilli ¹ Marco Scatigna ¹ Alice Bonomi ¹ Gianfranco Sinagra ² Manuela Muratori ¹ Piergiuseppe Agostoni ¹

• ¹ Monzino Cardiology Center (IRCCS), Milan, Italy
• ² University of Trieste, Trieste, Friuli-Venezia Giulia, Italy
• ³ Casa di Cura Tortorella Spa, Salerno, Italy

Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2-i) are standard therapy for heart failure (HF). We performed a holistic evaluation of dapagliflozin including its effects on exercise performance, left ventricle (LV) reverse remodelling, cardiac biomarkers, fluid retention, renal and pulmonary function.Methods: We enrolled HF reduced ejection fraction (LVEF) outpatients (EF <40%) eligible for SGLT2-i and performed cardiopulmonary exercise tests (CPET), pulmonary function tests, bioelectrical impedance vector analysis (BIVA), laboratory and echocardiographic assessments at baseline (T=0), after 2-4 weeks (T1) and 6 months of treatment (T2).Results: None of the patients interrupted SGLT2-i for adverse events albeit follow-up was completed by 67 out of 75 enrolled patients. At T2 LVEF increased (from 34.6±7.8 to 37.5±9.2%; p<0.001) while end-diastolic (EDV) and end-systolic (ESV) volumes reduced vs. 177 vs. 110[76-145] mL; p<0.001). Peak oxygen intake was unchanged (peakVO2 16.2[13.4-18.7] vs. 16.0[13.3-18.9] mL/kg/min, p=0.297), while exercise ventilatory efficiency (VE/VCO2 slope) improved (from 34.2[31.1-39.2] to 33.7[30.2-37.6], p=0.006). Haemoglobin increased (from 13.8±1.5 to 14.6±1.7 g/dL, (p<0.001), while renal function did not change after a transient worsening at T1. NT-proBNP, ST-2, and hs-TNI did not change as overall body fluids and quality of life assessed by KCCQ. NYHA class improved (p-value=0.002), paralleled by a decrease of MECKI (Metabolic Exercise test data combined with Cardiac and Kidney Indexes) score, from 3.3%[1.9-8.0] to 2.8%[1.2-5.7], suggestive of a positive impact on 2 years prognosis (p-value< 0.001).Conclusions: Dapagliflozin induced positive LV remodelling, improvement of exercise ventilatory efficiency, and NYHA class but without peakVO2 fluid status and cardiac biomarkers changes.