Short-term Effects of Dapagliflozin on Peak VO2 in HFrEF

This study will be a double-blind multicenter randomized study (1:1) to evaluate the effect of dapagliflozin 10 mg per day or placebo on short-term functional capacity evaluated through changes in peak oxygen consumption.

This study will be a double-blind multicenter randomized study (1:1) to evaluate the effect of dapagliflozin 10 mg per day or placebo on short-term functional capacity evaluated through changes in peak oxygen consumption. This trial will include patients with stable symptomatic heart failure with reduced ejection fraction (HFrEF). Efficacy endpoints will be evaluated at 3 time points: 1) baseline (before dapagliflozin/placebo administration), 2) 30 days after randomization, and, 3) 90 days after randomization. An intermediate clinical visit will be performed one week after study initiation.

Pre-and post-treatment evaluations (at baseline, 30 and 90 days) will include clinical assessment, cardiopulmonary exercise stress test, echocardiography, 6-minute walk test (6MWT), and quality of life indicators (Minnesota Living with Heart Failure Questionnaire -MLHFQ).

The investigators postulate that dapagliflozin 10 mg/day improves short-term functional capacity of patients with symptomatic HFrEF through multifactorial mechanisms, such as diuretic effect and improvement in myocardial energetic efficiency.

Eligibility Criteria:
Inclusion Criteria:

* The participant or his legal representative is willing and able to give informed consent for participation in the study.
* Male or female, aged ≥18 years.
* Established documented diagnosis of symptomatic HF (NYHA functional class II-III), which has been present for at least 2 months.
* LVEF ≤40% documented in the last 3 months by echocardiography or cardiac magnetic resonance.
* NT-proBNP ≥600 pg/ml.
* Patients should receive background standard of care for HFrEF at judgment of the investigator.
* Estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73m2 (DMRD formula) at enrolment.

Exclusion Criteria:

* Inability to perform a valid (respiratory exchange ratio -RER- ≥1.05) baseline cardiopulmonary exercise test (CPET)
* Patients receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrolment, or previous intolerance of an SGLT2 inhibitor
* Type 1 diabetes
* Symptomatic hypotension or systolic blood pressure \<95 mmHg
* Current acute decompensated HF or hospitalization due to decompensated HF \<4 weeks prior to enrolment
* Myocardial infarction, unstable angina, stroke, or transient ischemic attack within 12 weeks prior to enrolment
* Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or cardiac valve repair/replacement within 12 weeks prior to enrolment, or planned to undergo any of these operations after randomization
* Implantation of a cardiac resynchronization therapy (CRT) device within 12 weeks prior to enrolment or intent to implant a CRT device
* Previous cardiac transplantation or implantation of a ventricular assistance device or similar device, or implantation expected after randomization
* HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, or uncorrected severe primary cardiac valve disease
* Symptomatic bradycardia or second or third-degree heart block without a pacemaker
* Severe renal dysfunction (eGFR\<30 ml/min/1.73m2) or prior admission for acute renal failure in the last 4 weeks.
* Pregnant or lactating women
* Woman of childbearing age, unless they are using highly effective contraceptive methods.
* Patients with severe hepatic impairment (Child-Pugh class C).