The aim of prospective, open label, single center, randomized controlled trial is to investigate the efficacy of enavogliflozin on exercise performance, diastolic dysfunction, and quality of life in patients with heart failure with preserved ejection fraction (HFpEF).

HFpEF is a clinically heterogenous syndrome and has unique characteristics that differ from the other entities of heart failure. Cardiovascular and non-cardiovascular comorbidities are known to contribute to the pathogenesis of HFpEF, and consequently, the importance of HFpEF is increasingly emphasized as the population ages. In fact, HFpEF occurs in approximately 5% of the general population aged over 60 years and account for half of hospitalization for heart failure. Notwithstanding, no medication has been found to be effective for HFpEF. Only recently, Sodium glucose cotransporter 2 (SGLT2) inhibitors was proven effective in patients with HFpEF in two landmark trials, EMPEROR-Preserved and DELIVER trials. In both trials, SGLT2 inhibitor was consistently associated with reduced risk of composite outcome of cardiovascular death and hospitalization for heart failure. In this regard, 2023 focused update of the 2021 European Society of Cardiology (ESC) guidelines for heart failure recommends SGLT2 inhibitor as class 1A recommendation in patients with HFpEF.

Despite the solid evidence about the clinical benefit of SGLT2 inhibitor in patients with HFpEF, little is known about the mechanisms responsible for the beneficial cardiac effects of SGLT2 inhibitor. Patients with HFpEF are known to have impaired exercise and functional capacity, which lead to declined quality of life and debilitating symptoms. Along with unclear mechanisms responsible for the beneficial cardiac effect of SGLT2 inhibitor, the impacts of SGLT2 inhibitor on exercise and functional capacity in patients with HFpEF have also not been clearly evaluated. Therefore, this trial aim to evaluate the impact of SGLT2 inhibitor on exercise performance, diastolic function, and quality of life in patients with HFpEF using newly developed SGLT2 inhibitor, Enavogliflozin.

1. Inclusion Criteria:

1) Age ≥19 2) New York Heart Association (NYHA) II-III dyspnea 3) Diagnosis of HFpEF (Exams conducted within 6 months from screening) [must satisfy all (1), (2), and (3)]

1. Left ventricular ejection fraction (LVEF) ≥50%

2. NT-proBNP ≥220 pg/mL or BNP ≥80 pg/mL, if in sinus rhythm NT-proBNP ≥660 pg/mL or BNP ≥240 pg/mL, if in atrial fibrillation

3. Satisfying either noninvasive or invasive criteria I. Noninvasive: Echocardiography with at least one of the following criteria

   • LAVI ≥34 ml/m2

   • Lateral E/e' ≥9

   • LVMI ≥115 g/m2 if male or ≥95 g/m2 if female

   • LV wall thickness ≥12mm II. Invasive: LVEDP ≥16mmHg or pulmonary capillary wedge pressure(PCWP) ≥15mmHg 4) Stable/chronic ambulatory patients without hospitalization within the last 30 days due to heart failure decompensation episode 5) Patients taking heart failure medication without change for at least 3 weeks before screening

     2. Exclusion Criteria:

     1. Unwillingness or inability to comply with the procedures described in this protocol
     2. The ability to walk is, in the investigator's opinion, clearly limited by joint disease or other locomotor problems or lung diseases rather than by cardiorespiratory fitness
     3. NYHA IV dyspnea
     4. Type 1 diabetes mellitus
     5. Estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula)
     6. Anemia (Hb <7g/dL)
     7. Severe hepatic impairment (Child-Pugh class C)
     8. Acute myocardial infarction or unstable angina within 30 days before inclusion or planned coronary revascularization at the time of inclusion
     9. Significant left-sided valvular heart disease (moderate to severe stenosis and severe regurgitation)
     10. Heart failure due to any of the following: infiltrative cardiomyopathy (amyloidosis, sarcoidosis), active myocarditis, constrictive pericarditis, hypertrophic cardiomyopathy
     11. Symptomatic hypotension (systolic blood pressure <90mmHg)
     12. Severe chronic obstructive pulmonary disease (postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity(FVC) <70% and FEV1 <50%)
     13. Treated with sodium-glucose cotransporter-2 inhibitors (SGLT2i) within 30 days before inclusion
     14. History of diabetic ketoacidosis while in treatment with SGLT2i
     15. Recurrent genitourinary tract infections
     16. History of Hypersensitivity reaction to SGLT2i
     17. Non-cardiac co-morbid conditions are present with life expectancy <2 year or that may result in protocol non-compliance (per site investigator's medical judgment)
     18. Female patients who are currently or planning to become pregnant
     19. Female patients who are lactating
     20. Patients participating in other clinical trials

After publication of first manuscript and trial results, de-identified data will be shared upon reasonable request and with permission from the principal investigator.

After publication of first manuscript and trial results, de-identified data will be shared upon reasonable request and with permission from the principal investigator.

After publication of first manuscript and trial results, de-identified data will be shared upon reasonable request and with permission from the principal investigator.

Clinical outcome assessment will be performed under blinded assessment about the allocated treatment group.