SGLT2i and KNO3 in HFpEF - The SAK HFpEF Trial

NCT05138575 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 849401
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Heart Failure With Preserved Ejection Fraction

Outcome Measures

Primary Outcomes (1)

• Submaximal Exercise Endurance

  Time to exhaustion while exercising at 75% peak workload

  Week 6

Secondary Outcomes (14)

• Intramuscular Perfusion

  Week 6

• VO2 Kinetics

  Week 6

• VO2 Efficiency

  Week 6

• Vasodilatory Reserve

  Week 6

• Venous Substrate Concentration

  Week 6

Other Outcomes (1)

• Intramyocardial Filling Pressure

  Week 6

Study Arms (3)

Empagliflozin + Potassium Chloride (KCl)

ACTIVE COMPARATOR

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 + Potassium Nitrate (KNO3)

ACTIVE COMPARATOR

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

Potassium Chloride (KCl) + Placebo for Empa

PLACEBO COMPARATOR

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

Interventions

Empagliflozin + Potassium Nitrate DRUG

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.

Also known as: Jardiance + KNO3

Empagliflozin + Potassium Nitrate (KNO3)

Potassium Chloride + Placebo for Empagliflozin DRUG

Active control.

Also known as: KCl + Placebo

Potassium Chloride (KCl) + Placebo for Empa

Empagliflozin + Potassium Chloride DRUG

Empagliflozin is the active intervention that may improve mitochondrial function and energy fuel metabolism in skeletal muscle. KCl is an active control.

Also known as: Jardiance + KCl

Empagliflozin + Potassium Chloride (KCl)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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

You may not qualify if:

• Age \<18 years old
• Pregnancy: Women of childbearing potential will undergo a urine pregnancy test during the screening visit.
• Treatment with organic nitrates or phosphodiesterase inhibitors that cannot be interrupted
• Uncontrolled atrial fibrillation, as defined by a resting atrial fibrillation 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.
• 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)
• 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

Sponsors & Collaborators

• University of Pennsylvania: lead

Study Sites (1)

University of Pennsylvania Health System

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

MeSH Terms

Interventions

empagliflozin; Potassium Chloride; potassium nitrate

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Potassium Compounds

Study Officials

• Payman Zamani, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Melissa Fernando

CONTACT

2672536141; fernand@Pennmedicine.upenn.edu

Cassandra Demastus, CRNP

CONTACT

Cassandra.Demastus@Pennmedicine.upenn.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: All personnel will be masked except for the IDS pharmacist dispensing the drugs.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Model Details: 3 interventions will be randomized and administered in a double-blind fashion

Study Record Dates

• First Submitted: November 3, 2021
• First Posted: December 1, 2021
• Study Start: January 24, 2022
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): May 31, 2027
• Last Updated: April 16, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)