SGLT2i and KNO3 in HFpEF – The SAK HFpEF Trial

Inclusion Criteria:

NYHA Class II-III symptoms
Left ventricular ejection fraction >= 50%
Stable medical therapy for at least 1 month, defined as: no addition/removal/changes in antihypertensive medications or beta-blockers in the preceding 30 days and continuation of a stable diuretic regimen, if applicable

Prior or current evidence for elevated filling pressures as follows:

Mitral early (E)/septal tissue annular (e') velocity ratio > 8, in the context of a septal e' velocity <=7 cm/s or a lateral e' <= 10 cm/s, in addition to one of the following: i. Large left atrium (LA volume index > 34 mL/m2), ii. Chronic loop diuretic use for control of symptoms, iii. Elevated natriuretic peptides within the past year (e.g. NTproBNP > 125 pg/mL in sinus rhythm or > 375 pg/mL if in atrial fibrillation)
Mitral E/e' ratio > 14 at rest or during exercise
Elevated invasively-determined filling pressures previously (resting left ventricular end-diastolic pressure >= 16 mm Hg or pulmonary capillary wedge pressure >= 15 mmHg; or PCWP/LVEDP >= 25 mmHg with exercise)
Prior episode of acute heart failure requiring IV diuretics

Exclusion Criteria:

Age <18 years old
Pregnancy: Women of childbearing potential will undergo a urine pregnancy test during the screening visit. We note that the advanced age of HFpEF subjects (median age of 78 in the Get With the Guidelines-HF program) will make it unlikely that pre-menopausal females will be enrolled.
Treatment with organic nitrates or phosphodiesterase inhibitors that cannot be interrupted
Uncontrolled atrial fibrillation, as defined by a resting heart rate > 100 beats per minute at the time of the baseline assessment
Hemoglobin < 10 g/dL
Subject inability/unwillingness to exercise
Moderate or greater left sided valvular disease (mitral regurgitation, aortic stenosis, aortic regurgitation), mild or greater mitral stenosis, severe right-sided valvular disease
Known hypertrophic, infiltrative, 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 Stage III or greater GOLD criteria (FEV1<50%), 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 on the echocardiographic assessment during the baseline maximal effort cardiopulmonary exercise test will also be exclusionary
Left ventricular ejection fraction < 45% on a prior echocardiogram or cardiac MRI
Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin < 3.0 g/dL)
eGFR < 45 mL/min/1.73m^2. We note that while the FDA packing insert suggests a lower limit of 45 mL/min/1.73 m2 for Empa, the EMPERIOR Reduced trial enrolled HFrEF participants with an eGFR >= 20 mL/min/1.73m2.(59)
Methemoglobin > 5%
Serum potassium > 5.0 mEq/L on baseline testing
Type I Diabetes
History of ketoacidosis
Current use of or prior intolerance to an SGLT2i
Ongoing maintenance of a 'Ketogenic Diet' (low carbohydrate, high fat)
Allergy to beets
Severe right ventricular dysfunction
Baseline resting seated systolic blood pressure > 180 mmHg or < 100 mmHg
Orthostatic blood pressure response to the transition from supine to standing (>20 mmHg reduction in systolic blood pressure 2-3 minutes after standing, or a fall in SBP to < 90 mmHg)
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).
Contraindications to MRI