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Heart Failure With Preserved Ejection FractionPhase 2SAKNCT05138575

SGLT2i and KNO3 in HFpEF - The SAK HFpEF Trial

A Phase 2 study testing Empagliflozin + Potassium Chloride and Empagliflozin + Potassium Nitrate in people with Heart Failure With Preserved Ejection Fraction, run by University of Pennsylvania at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Empagliflozin + Potassium Chloride and Empagliflozin + Potassium Nitrate
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
53 participants
Where
1 siteUnited States
Study dates
24 Jan 2022to 31 May 2027
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
  • 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

Who cannot join

  • 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
Show all 31Show fewer
  • 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, 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
  • Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin < 3.0 g/dL)
  • eGFR < 30 mL/min/1.73m2.
  • 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
  • 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
  • Active participation in another study that utilizes an investigational agent (observational studies/registries allowed)
  • 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).

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Melissa Fernando contact

2672536141

fernand@Pennmedicine.upenn.edu

Cassandra Demastus, CRNP contact

Cassandra.Demastus@Pennmedicine.upenn.edu

United States1 site, 1 recruiting

  • University of Pennsylvania Health System

    Philadelphia, Pennsylvania, 19104

    Cassandra J Demastus, Cassandra.Demastus@Pennmedicine.upenn.edu

    Recruiting

Other trials in United States

About this study

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).

Read the 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).

Being tested
Empagliflozin + Potassium Chloride, Empagliflozin + Potassium Nitrate, Potassium Chloride + Placebo for Empagliflozin

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Empagliflozin + Potassium ChlorideDrug

    Also called Jardiance + KCl

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

    KCl is an active control.

  • Empagliflozin + Potassium NitrateDrug

    Also called Jardiance + KNO3

    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.

  • Potassium Chloride + Placebo for EmpagliflozinDrug

    Also called KCl + Placebo

    Active control.

Study groups in NCT05138575
Study groupRoleWhat they receive
Empagliflozin + Potassium Chloride (KCl)Active comparatorEmpagliflozin (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.
Receives: Drug: Empagliflozin + Potassium Chloride
Empagliflozin + Potassium Nitrate (KNO3)Active comparatorEmpagliflozin (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.
Receives: Drug: Empagliflozin + Potassium Nitrate
Potassium Chloride (KCl) + Placebo for EmpaPlacebo comparatorPotassium Chloride (6 mmol three times daily) + Placebo for Empagliflozin Placebo arm will be 6 weeks in duration followed by a 2 week washout period.
Receives: Drug: Potassium Chloride + Placebo for Empagliflozin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Submaximal Exercise Endurance

    Time to exhaustion while exercising at 75% peak workload

    Measured: Week 6

Secondary outcomes (14)

  1. Intramuscular Perfusion

    MRI assessment of skeletal muscle perfusion

    Measured: Week 6

  2. 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.

    Measured: Week 6

  3. VO2 Efficiency

    Assess the impact of interventions on the efficiency of oxygen consumed above basal metabolic rate compared to total work performed

    Measured: Week 6

  4. Vasodilatory Reserve

    Percent change in systemic vascular resistance (SVR) at baseline vs SVR at 4 minutes of exercise at end of each intervention period

    Measured: Week 6

  5. Venous Substrate Concentration

    Change in venous substrate concentrations at time of fatigue at end of each intervention period

    Measured: Week 6

  6. Respiratory Exchange Ratio

    Change in RER at 4 minutes of exercise at end of each intervention period

    Measured: Week 6

  7. KCCQ Overall Summary Score

    Assess impact of interventions on quality of life based on Kansas City Cardiomyopathy Questionnaire overall summary score

    Measured: Week 6

  8. Ambulatory Physical Activity

    Use actigraphy to document the average steps per day taken during the final week of each interventional period

    Measured: Week 6

  9. Muscle Tissue Respirometry

    Measure tissue rates of substrate metabolism and mitochondrial content

    Measured: Week 6

  10. Muscle Proteome

    Measure relative abundances of proteins related to fatty acid and ketone oxidation as well as proteins related to mitochondrial biogenesis.

    Measured: Week 6

  11. Muscle Metabolome

    Perform targeted quantitative metabolomics to assess changes in substrate metabolism

    Measured: Week 6

  12. Skeletal Muscle Oxidative Capacity

    MRI assessment of skeletal muscle oxidative phosphorylation capacity

    Measured: Week 6

  13. Arteriovenous O2 content difference

    quotient of VO2 to cardiac output

    Measured: Week 6

  14. Peak VO2 during Submaximal Exercise

    Assess the impact of interventions on the peak oxygen consumption achieved during submaximal exercise

    Measured: Week 6

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Dec 2021
  2. Study start24 Jan 2022
  3. Primary completion31 May 2027 (estimated)
  4. Study completion31 May 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Model description
3 interventions will be randomized and administered in a double-blind fashion
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
53 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05138575
Sponsor's protocol ID
849401
Acronym
SAK
Status last verified
Apr 2026
First submitted
3 Nov 2021
Last updated
16 Apr 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: 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.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Empagliflozin + Potassium Chloride and Empagliflozin + Potassium Nitrate in people with Heart Failure With Preserved Ejection Fraction, run by University of Pennsylvania at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 16 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Melissa Fernando (2672536141, fernand@Pennmedicine.upenn.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Submaximal Exercise Endurance (time frame: Week 6). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05138575.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Apr 2026; AzTrials last refreshed its copy on 7 Nov 2026.

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