Effect of Dapagliflozin on Submaximal Exercise Tolerance in Heart Failure

Inclusion Criteria:

Diagnosis of HFrEF with NYHA Class II-III functional class, which has been present for at least two months
Left ventricular ejection fraction ≤ 40%
Stable medical therapy for at least 1 month
Plasma NT-proBNP level of: ≥ 200pg/mL; OR ≥ 125pg/mL if they were hospitalized for HF within the past 12 months; or ≥ 250 pg/mL if patient had atrial fibrillation/flutter on baseline ECG

Exclusion Criteria:

Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrollment or previous intolerance of an SGLT2 inhibitor
Type 1 diabetes mellitus
Age <18 years old
Pregnancy: Women of childbearing potential will undergo a urine pregnancy test during the screening visit.
Uncontrolled atrial fibrillation, as defined by a resting heart rate > 100 beats per minute at the time of the baseline assessment
Paroxysmal atrial fibrillation (Afib) or flutter with >1 hour of continuous Afib documented within the previous 6 months (prior to screening or randomization), direct-current (DC) cardioversion or ablation procedure for Afib within 6 months, or plan to attempt to restore sinus rhythm (with drug therapy, ablation, or DC cardioversion) within 6 months of randomization. Subjects with persistent Afib and no sinus rhythm documented in the prior 6 months are permitted.
Hemoglobin < 10 g/dL
eGFR < 25 mL/min/1.73m^2, or unstable or rapidly progressing renal disease at the time of randomization
Subject inability/unwillingness to exercise
Greater than moderate left sided valvular disease (mitral regurgitation, aortic stenosis, aortic regurgitation), moderate or greater mitral stenosis, severe right-sided valvular disease
Known hypertrophic, infiltrative, restrictive or inflammatory cardiomyopathy
Clinically significant pericardial disease, as per investigator judgment
Current angina due to clinically significant epicardial coronary disease, as per investigator judgment
Acute coronary syndrome or coronary intervention within the past 2 months
Primary pulmonary artery hypertension (WHO Group 1 Pulmonary Arterial Hypertension)

Clinically significant lung disease as defined by: Chronic Obstructive Pulmonary Disease meeting Stage III or greater GOLD criteria (FEV1<50% predicted), treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease, current use of supplemental oxygen aside from nocturnal oxygen for the treatment of obstructive sleep apnea.

- Desaturation to <90% on the baseline maximal effort cardiopulmonary exercise test will also be grounds for exclusion

Clinically-significant ischemia, as per investigator's judgement, on stress testing without either (1) subsequent revascularization, (2) an angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgment; (3) a follow-up 'negative' stress test, particularly when using a more specific technique (i.e., a negative perfusion imaging test following a 'positive' ECG stress test)

- Exercise induced regional wall motion abnormalities suggestive of ongoing ischemia during the baseline maximal effort cardiopulmonary exercise test will be exclusionary

Implantation of a CRT device within 12 weeks prior to enrollment or intent to implant a CRT device during the study period
Previous cardiac transplantation or implantation of a ventricular assist device, or implantation expected after randomization
Symptomatic bradycardia or second- or third-degree heart block, in the absence of a pacemaker
Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin < 3.0 g/dL)
Severe right ventricular dysfunction
Baseline resting seated systolic blood pressure > 180 mmHg or <90 mmHg
Orthostatic blood pressure response to the transition from supine to standing (>20 mmHg reduction in systolic blood pressure 2-3 minutes after standing)
Active participation in another study that utilizes an investigational agent (observational studies/registries allowed)

Any condition that, in the opinion of the investigator, will interfere with the completion of the study. This may include comorbid or psychiatric conditions that may impede successful completion of the protocol, or logistical concerns (e.g. inability to travel to the exercise unit).

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