SGLT2i and KNO3 in HFpEF - The SAK HFpEF Trial

Study Overview
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Brief Summary
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This study will test whether pharmacologic agents that may improve mitochondrial function and energy fuel metabolism [Empagliflozin (Empa)], with and without additional supplements that increase perfusion and fatty acid oxidation [Potassium Nitrate (KNO3)], improve submaximal exercise endurance and skeletal muscle oxidative phosphorylation capacity (SkM OxPhos) in participants with Heart Failure with Preserved Ejection Fraction (HFpEF).

Detailed Description
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This study will test whether Empagliflozin (Empa), with and without Potassium Nitrate (KNO3), improves submaximal exercise endurance, skeletal muscle oxidative phosphorylation capacity (SkM OxPhos), intramuscular perfusion, and changes in the skeletal muscle metabolome, proteome, and respiration in participants with Heart Failure with Preserved Ejection Fraction (HFpEF).

Official Title
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SGLT2i and KNO3 in HFpEF - The SAK HFpEF Trial

Conditions
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Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: Empagliflozin + Potassium Chloride
* Drug: Empagliflozin + Potassium Nitrate
* Drug: Potassium Chloride + Placebo for Empagliflozin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: 3 interventions will be randomized and administered in a double-blind fashion
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Empagliflozin + Potassium Chloride (KCl)<br>Empagliflozin (10 mg daily) + Potassium Chloride (6 mmol three times daily) Active arm will be 6 weeks in duration followed by a 2 week washout period. | Drug: Empagliflozin + Potassium Chloride<br>* Empagliflozin is the active intervention that may improve mitochondrial function and energy fuel metabolism in skeletal muscle. KCl is an active control.<br>* Other names: Jardiance + KCl;|
| Active Comparator: Empagliflozin + Potassium Nitrate (KNO3)<br>Empagliflozin (10 mg daily) + Potassium Nitrate (6 mmol three times daily) Active arm will be 6 weeks in duration followed by a 2 week washout period. | Drug: Empagliflozin + Potassium Nitrate<br>* Empagliflozin + KNO3 is the active intervention that may improve mitochondrial function and energy fuel metabolism in skeletal muscle, as well as increase skeletal muscle perfusion during exercise.<br>* Other names: Jardiance + KNO3;|
| Placebo Comparator: Potassium Chloride (KCl) + Placebo for Empa<br>Potassium Chloride (6 mmol three times daily) + Placebo for Empagliflozin Placebo arm will be 6 weeks in duration followed by a 2 week washout period. | Drug: Potassium Chloride + Placebo for Empagliflozin<br>* Active control.<br>* Other names: KCl + Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Submaximal Exercise Endurance | Time to exhaustion while exercising at 75% peak workload | Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intramuscular Perfusion | MRI assessment of skeletal muscle perfusion | Week 6 | 
| VO2 Kinetics | Assess the impact of interventions on the kinetics of oxygen consumption (VO2 kinetics) during exercise and recovery. On and Off kinetics will be modeled during the submaximal exercise transient. | Week 6 | 
| VO2 Efficiency | Assess the impact of interventions on the efficiency of oxygen consumed above basal metabolic rate compared to total work performed | Week 6 | 
| Vasodilatory Reserve | Percent change in systemic vascular resistance (SVR) at baseline vs SVR at 4 minutes of exercise at end of each intervention period | Week 6 | 
| Venous Substrate Concentration | Change in venous substrate concentrations at 4 minutes of exercise at end of each intervention period | Week 6 | 
| Respiratory Exchange Ratio | Change in RER at 4 minutes of exercise at end of each intervention period | Week 6 | 
| KCCQ Overall Summary Score | Assess impact of interventions on quality of life based on Kansas City Cardiomyopathy Questionnaire overall summary score | Week 6 | 
| Ambulatory Physical Activity | Use actigraphy to document the average steps per day taken during the final week of each interventional period | Week 6 | 
| Muscle Tissue Respirometry | Measure tissue rates of substrate metabolism and mitochondrial content | Week 6 | 
| Muscle Proteome | Measure relative abundances of proteins related to fatty acid and ketone oxidation as well as proteins related to mitochondrial biogenesis. | Week 6 | 
| Muscle Metabolome | Perform targeted quantitative metabolomics to assess changes in substrate metabolism | Week 6 | 
| Skeletal Muscle Oxidative Capacity | MRI assessment of skeletal muscle oxidative phosphorylation capacity | Week 6 |