The primary purpose of this study is to evaluate the impact of dapagliflozin, as compared with placebo, on heart failure, disease specific biomarkers, symptoms, health status and quality of life in patients with chronic heart failure with preserved systolic function.

A 12-week randomized, double-blind, placebo-controlled trial to evaluate the effects of once-daily dapagliflozin 10 mg on heart failure disease-specific biomarkers (NTproBNP and BNP), symptoms, health status, and quality of life in patients with chronic heart failure with preserved systolic function. An imaging substudy will also be conducted to explore the effects of dapagliflozin vs. placebo on various echocardiographic parameters.

Inclusion Criteria:

1. Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
2. Ejection fraction (EF) ≥ 45% as determined on imaging study within 24 months of enrolment with no change in clinical status suggesting potential for deterioration in systolic function
3. Elevated NT-proBNP (≥ 225 pg/ml) or BNP (≥ 75 pg/ml). For patients with permanent atrial fibrillation inclusion thresholds will be BNP ≥ 100 pg/mL or NTproBNP ≥ 375 pg/mL
4. Stable medical therapy for heart failure for 15 days as defined by: i. No addition or removal of ACE, angiotensin receptor blockers (ARBs), valsartan/sacubitril, beta-blockers, calcium channel blockers (CCBs) or aldosterone antagonists; ii.No substantial change in dosage (100% or greater increase or decrease from baseline dose) of ACE, ARBs, beta-blockers, CCBs or aldosterone antagonists
5. On a diuretic ≥15 days prior to screening visit and a stable diuretic therapy for 7 days
6. At least one of the following: i. Hospitalization for decompensated HF in the last 12 months; ii. Acute treatment for HF with intravenous loop diuretic or hemofiltration in the last 12 months; iii. Mean pulmonary capillary wedge pressure ≥15 mmHg or LV end diastolic pressure (LVEDP) ≥15 mmHg documented during catheterization at rest, or pulmonary capillary wedge pressure or LVEDP ≥25 mmHg documented during catheterization with exercise; iv. Structural heart disease evidenced by at least one of the following echo findings (any local measurement made within the 24 months prior to screening visit): a) left atrial (LA) enlargement defined by at least one of the following: LA width ≥3.8cm or LA length ≥5.0 cm or LA area ≥20 cm2 or LA volume ≥55 mL or LA volume index ≥29 mL/m2 b) or left ventricular hypertrophy (LVH) defined by septal thickness or posterior wall thickness ≥1.1 cm.

Exclusion Criteria:

1. Decompensated heart failure (hospitalization for heart failure within 7 days prior to screening)
2. History of type 1 diabetes
3. History of diabetic ketoacidosis
4. Estimated glomerular filtration rate (eGFR) < 20 at the screening visit by modified MDRD equation GFR (mL/min/1.73 m2 ) = 175 x (Scr) -1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if African American)
5. Admission for an acute coronary syndrome (ST-elevation MI, non-ST-elevation MI, or unstable angina), percutaneous coronary intervention, or cardiac surgery within 30 days prior to the screening visit.
6. Admission for cardiac resynchronization therapy (CRT) within 90 days prior to the screening visit.
7. Planned cardiovascular revascularization (percutaneous intervention or surgical) or major cardiac surgery (coronary artery bypass grafting, valve replacement, ventricular assist device, cardiac transplantation, or any other surgery requiring thoracotomy, or transcatheter aortic valve replacement) or CRT within the 90 days after the screening visit.
8. Participation in any interventional clinical trial (with an investigational drug or device) that is not an observational registry within 15 days of the screening visit.
9. History of hypersensitivity to dapagliflozin
10. For women of child-bearing potential: Current or planned pregnancy or currently lactating.
11. Life expectancy <1 year at the screening visit
12. Patients who are volume depleted based upon physical examination at the time of the screening or randomization visit
13. BNP <75 pg/mL and NTproBNP<225 pg/mL at the screening visit. For patients with permanent atrial fibrillation exclusion thresholds will be BNP<100 pg/mL and NTproBNP<375pg/mL.
14. Patients currently being treated with any SGLT-2 inhibitor (dapagliflozin, canagliflozin, empagliflozin, ertugliflozin) or having received treatment with any SGLT-2 inhibitor within the 12 weeks prior to the screening visit.
15. Average supine systolic BP <100 mmHg at the screening or randomization visit
16. Current history of bladder cancer
17. Donation of blood or bone marrow 12 weeks prior to the screening visit and no planned donations during the study period
18. Heart failure due to restrictive/infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, severe stenotic valve disease, and HOCM (hypertrophic obstructive cardiomyopathy).
19. Heart failure due to severe aortic or mitral regurgitation
20. Severe COPD thought to be a primary contributor to dyspnea
21. Isolated right heart failure due to pulmonary disease
22. Active and significant ischemia thought to be a primary contributor to dyspnea
23. Documentation of previous EF < 45%, under stable conditions, within the past 36 months
24. Complex congenital heart disease
25. Uncontrolled hypertension, defined as systolic blood pressure ≥200 mmHg during the screening visit (average value of three blood pressure measurements obtained in supine position)
26. Any other condition that in the judgment of the investigator would jeopardize the patient's participation in the study or that may interfere with the interpretation of study data or if the patient is considered unlikely to comply with study procedures, restrictions and requirements
27. Bariatric surgery within the past 6 months or planned bariatric surgery within the study time course.
28. CardioMems device implantation within previous 4 weeks or planned CardioMems implantation during study period
29. For echo substudy only: patients with ventricular paced rhythm or left bundle branch block on the most recent clinically available 12-lead electrocardiogram.
30. For echo substudy only: permanent atrial fibrillation