SGLT2i and KNO3 in HFpEF - The SAK HFpEF Trial (SAK)

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).

Study Overview

• Status: Recruiting
• Conditions: Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: Empagliflozin + Potassium Chloride; Drug: Empagliflozin + Potassium Nitrate; Drug: Potassium Chloride + Placebo for Empagliflozin

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Estimated): 53
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Cassandra Demastus, CRNP; Email: Cassandra.Demastus@Pennmedicine.upenn.edu
• Study Contact Backup: Name: Melissa Fernando; Phone Number: 2672536141; Email: fernand@Pennmedicine.upenn.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania Health System
      • Contact: Cassandra J Demastus; Email: Cassandra.Demastus@Pennmedicine.upenn.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion:

1. NYHA Class II-III symptoms 2. Left ventricular ejection fraction >= 50% 3. Stable medical condition for at least 2 weeks, as per investigator judgment 4. Prior or current evidence for elevated filling pressures, as evidenced by at least one of the following:

a. 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) b. Mitral E/e' ratio > 14 at rest or during exercise c. 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) d. Prior episode of acute heart failure requiring IV diuretics

Exclusion Criteria:

1. Age <18 years old
2. Pregnancy: Women of childbearing potential will undergo a urine pregnancy test during the screening visit.
3. Treatment with organic nitrates or phosphodiesterase inhibitors that cannot be interrupted
4. Uncontrolled atrial fibrillation, as defined by a resting atrial fibrillation heart rate > 100 beats per minute at the time of the baseline assessment
5. Hemoglobin < 10 g/dL
6. Subject inability/unwillingness to exercise
7. Moderate or greater left sided valvular disease (mitral regurgitation, aortic stenosis, aortic regurgitation), mild or greater mitral stenosis, severe right-sided valvular disease
8. Known hypertrophic, infiltrative, or inflammatory cardiomyopathy
9. Clinically significant pericardial disease, as per investigator judgment
10. Current angina due to clinically significant epicardial coronary disease, as per investigator judgment
11. Acute coronary syndrome or coronary intervention within the past 2 months
12. Primary pulmonary artery hypertension (WHO Group 1 Pulmonary Arterial Hypertension)

13. 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

14. 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

15. Left ventricular ejection fraction < 45% on a prior echocardiogram or cardiac MRI, unless the reduced LVEF occurred within the context of an uncontrolled supraventricular arrhythmia, with return of a normal ejection fraction following treatment of the arrhythmia
16. Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin < 3.0 g/dL)
17. eGFR < 30 mL/min/1.73m2.
18. Methemoglobin > 5%
19. Serum potassium > 5.0 mEq/L on baseline testing
20. Type I Diabetes
21. History of ketoacidosis
22. Current use of, or prior intolerance to, an SGLT2i
23. Ongoing maintenance of a 'Ketogenic Diet' (low carbohydrate, high fat)
24. Allergy to beets
25. Severe right ventricular dysfunction
26. Baseline resting seated systolic blood pressure > 180 mmHg or < 100 mmHg
27. Persistently low or high seated blood pressure or 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) at the baseline visit
28. Active participation in another study that utilizes an investigational agent (observational studies/registries allowed)
29. Any condition that, in the opinion of the investigator, may interfere with the completion/performance 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Empagliflozin + Potassium Chloride (KCl); 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; Empagliflozin is the active intervention that may improve mitochondrial function and energy fuel metabolism in skeletal muscle. KCl is an active control.; Other Names: Jardiance + KCl
Active Comparator: Empagliflozin + Potassium Nitrate (KNO3); 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; 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.; Other Names: Jardiance + KNO3
Placebo Comparator: Potassium Chloride (KCl) + Placebo for Empa; 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; Active control.; Other Names: KCl + Placebo

What is the study measuring?

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
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
Venous Substrate Concentration	Change in venous substrate concentrations at time of fatigue at end of each intervention period	Week 6
Arteriovenous O2 content difference	quotient of VO2 to cardiac output	Week 6
Peak VO2 during Submaximal Exercise	Assess the impact of interventions on the peak oxygen consumption achieved during submaximal exercise	Week 6

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intramyocardial Filling Pressure	Assess impact of interventions on intramyocardial filling pressures during submaximal exercise	Week 6

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Payman Zamani, MD, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2022
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): May 31, 2027

Study Registration Dates

• First Submitted: November 3, 2021
• First Submitted That Met QC Criteria: November 16, 2021
• First Posted (Actual): December 1, 2021

Study Record Updates

• Last Update Posted (Actual): April 16, 2026
• Last Update Submitted That Met QC Criteria: April 15, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; Inorganic Chemicals; Chlorine Compounds; Chlorides; Hydrochloric Acid; Potassium Compounds; empagliflozin; Potassium Chloride; potassium nitrate
• Other Study ID Numbers: 849401

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be maintained indefinitely in an electronic database. This will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by clinical sites and by the research staff will be secured and password protected. At the end of the study, all study databases will be de-identified and archived.

If any data or samples are shared with collaborators at UPenn or elsewhere, only de-identified samples/data will be given, without any linking information.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes