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

Abstract

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.

Keywords: HFrEF; SGLT2-i; cardiopulmonary exercise testing (CPET); dapagliflozin; heart failure; reverse remodeling.

Figure 1

Study design. Scheduled activities at each study point. KCCQ, Kansas City Cardiomyopathy Questionnaire; PFT, pulmonary function test; CPET, cardiopulmonary exercise test; BIVA, bioelectrical impedance vector analysis; TTE, transthoracic echocardiography.

Figure 2

Biomarkers analysis. Biomarker variations at each study point. Orange = baseline; yellow = 2–4 weeks (T1); green = 6 months (T2). Nt-proBNP, N-terminal pro B-type natriuretic peptide; ST-2, suppression of tumorigenicity 2; hs-TNI, high-sensitivity troponin I; hsCRP, high-sensitivity C-reactive protein.

Figure 3

Functional and quality of life evaluation. Top: peak oxygen uptake (VO₂/kg) on the left, and ventilatory efficiency (VE/VCO₂ slope), on the right. Bottom: New York Heart Association (NYHA) class and Kansas City Cardiomyopathy Questionnaire results are reported on the left and right respectively. T0 = baseline, T2 = 6 months.

Figure 4

Effect of dapagliflozin on prognosis estimation by MECKI score. Schematic representation of the six variables constituting the MECKI score, which assesses prognosis. Left: variables that remained unchanged in our study; right: variables that significantly improved after 6 months with dapagliflozin. Na+, sodium; eGFR, estimated glomerular filtration rate calculated by modification of diet in renal disease (MDRD) formula; MECKI, Metabolic Exercise test data combined with Cardiac and Kidney Index; pVO₂ (%pred), peak oxygen uptake expressed as_% of predicted; LVEF, left ventricular ejection fraction; Hb, hemoglobin; VE/VCO₂s, ventilatory efficiency.