The mechanisms underlying the effects of dapagliflozin in heart failure with reduced ejection fraction (HFrEF) are not yet fully understood. This study aims to evaluate the effect of the drug on cardiorespiratory function by assessing alveolar–capillary membrane characteristics, sleep apnea, pulmonary and cardiac performance in stable HFrEF patients. Seventy-three patients with stable HFrEF were enrolled, with 66 completing the six-month follow-up. Analyses included assessment of the alveolar–capillary membrane by diffusion capacity, including its membrane diffusion and capillary volume components and measurements of proSP-B in the blood, an emerging biomarker of alveolar–capillary membrane function. Pulmonary function tests, overnight respiratory monitoring, and echocardiographic parameter collection were also conducted. After 6 months, a reduction in circulating proSP-B levels was observed (32.65 ± 13.36 at baseline vs. 30.86 ± 12.45 AU at 6 months, p for trend 0.0092), accompanied by improvements in echocardiographic parameters (left ventricle ejection fraction and pulmonary pressures). Pulmonary function tests and overnight respiratory monitoring showed no significant changes in lung diffusion, spirometry, or obstructive sleep apnea (apnea hypopnea index from 5.0 [1.1–16.6] at baseline to 6.2 [0.7–13.8]/h; p = n.s.). A significant reduction in central sleep apnea (CSA) was noted in the 13 patients with at least one CSA at baseline (15 [3–48] vs. 0 [0–18.5]/h, p = 0.017). Dapagliflozin demonstrates both hemodynamic and non-hemodynamic effects, particularly improving alveolar–capillary membrane function. This study highlights the multifactorial benefits of dapagliflozin in patients with stable HFrEF and the potential of proSP-B as a sensitive marker for evaluating therapeutic response.

Background: Sodium/glucose cotransporter-2 inhibitors (SGLT2is), such as dapagliflozin and empagliflozin, are currently a standard therapy for heart failure (HF) patients. We report the real-world use of SGLT2is in a monocentric cohort of HF patients with reduced ejection fraction (HFrEF) and improved ejection fraction (HFimpEF), comparing patient characteristics and outcomes with those observed in large-scale randomized clinical trials (RCTs). Methods: We retrospectively analyzed a cohort of 370 stable patients with HFrEF or HFimpEF who initiated therapy with dapagliflozin or empagliflozin between June 2019 and November 2023. Baseline data, including medical history, concomitant diseases, therapy, laboratory tests, echocardiographic results and cardiopulmonary exercise tests (CPETs), were collected at the start of the therapy with SGLT2is. After a median period of 18 months, follow-up data on treatment adherence, adverse events, hospitalizations, and mortality were also reviewed. A comparison was made between patients taking dapagliflozin and those taking empagliflozin and then individual populations were compared with those from the trials. Results: Among 370 patients (81% HFrEF, 19% HFimpEF), 276 received dapagliflozin and 94 empagliflozin. Empagliflozin patients were older, had higher NYHA class and LVEF, and higher incidence of diabetes, while dapagliflozin users had greater use of sacubitril/valsartan and mineralocorticoid receptor antagonists. Both groups were older than the RCT cohorts. Dapagliflozin patients had LVEF comparable to DAPA-HF, while empagliflozin patients had higher LVEF than EMPEROR-Reduced. HF hospitalizations were more frequent in the real-world groups, but mortality was lower than in RCTs. The composite outcome of death and worsening HF was higher in the real-world dapagliflozin cohort vs. DAPA-HF but similar between the real-world empagliflozin cohort and EMPEROR-Reduced. Conclusions: In this real-world cohort, the use of empagliflozin was associated with cardio-nephro-metabolic comorbidities and dapagliflozin being prescribed more frequently for patients with isolated cardiac symptoms. While outcomes were generally favorable, they differed from those seen in RCTs, highlighting the importance of real-world data in understanding the practical application of these therapies.