Dapagliflozin effects on exercise, cardiac remodeling, biomarkers, and renal and pulmonary function in heart failure patients: not as good as expected?

Background: Sodium-glucose cotransporter-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 remodeling, cardiac biomarkers, fluid retention, and 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, and laboratory and echocardiographic assessments at baseline (T = 0), after 2–4 weeks (T1), and after 6 months of treatment (T2). Results: None of the patients interrupted SGLT2-i for adverse events albeit follow-up was completed by 67 of 75 enrolled patients. At T2, mean LVEF increased (from 34.6 ± 7.8 to 37.5 ± 9.2%; p < 0.001) while end-diastolic (EDV) and end-systolic (ESV) volumes decreased [EDV: 186 (145–232) vs. 177 (129–225) mL, ESV: 113 (87–163) 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]. Mean hemoglobin 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=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 < 0.001). Conclusions: Dapagliflozin induced positive LV remodeling, improvement of exercise ventilatory efficiency, and NYHA class but without peakVO2 fluid status and cardiac biomarkers changes.