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.
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
- Conditions the study is for
- Heart Failure With Preserved Ejection Fraction
- 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.
Cassandra Demastus, CRNP contact
United States1 site, 1 recruiting
- Recruiting
University of Pennsylvania Health System
Philadelphia, Pennsylvania, 19104
Cassandra J Demastus, Cassandra.Demastus@Pennmedicine.upenn.edu
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 group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: Drug: Potassium Chloride + Placebo for Empagliflozin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Submaximal Exercise Endurance
Time to exhaustion while exercising at 75% peak workload
Measured: Week 6
Secondary outcomes (14)
Intramuscular Perfusion
MRI assessment of skeletal muscle perfusion
Measured: 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.
Measured: Week 6
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
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
Venous Substrate Concentration
Change in venous substrate concentrations at time of fatigue at end of each intervention period
Measured: Week 6
Respiratory Exchange Ratio
Change in RER at 4 minutes of exercise at end of each intervention period
Measured: Week 6
KCCQ Overall Summary Score
Assess impact of interventions on quality of life based on Kansas City Cardiomyopathy Questionnaire overall summary score
Measured: Week 6
Ambulatory Physical Activity
Use actigraphy to document the average steps per day taken during the final week of each interventional period
Measured: Week 6
Muscle Tissue Respirometry
Measure tissue rates of substrate metabolism and mitochondrial content
Measured: Week 6
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
Muscle Metabolome
Perform targeted quantitative metabolomics to assess changes in substrate metabolism
Measured: Week 6
Skeletal Muscle Oxidative Capacity
MRI assessment of skeletal muscle oxidative phosphorylation capacity
Measured: Week 6
Arteriovenous O2 content difference
quotient of VO2 to cardiac output
Measured: Week 6
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.
- First posted1 Dec 2021
- Study start24 Jan 2022
- Primary completion31 May 2027 (estimated)
- Study completion31 May 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Heart Failure With Preserved Ejection FractionStudies of the same condition, open and under way.
- More trials run by University of PennsylvaniaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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)
Sponsor and investigators
- Lead sponsor
- University of Pennsylvania
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Payman Zamani, MD, University of Pennsylvania
- Investigators
- Payman Zamani, MD, Principal investigator, University of Pennsylvania
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.
Study at a glance
From the registry record, last updated by the sponsor on 16 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- SGLT2i and KNO3 in HFpEF - The SAK HFpEF Trial
- ClinicalTrials.gov ID
- NCT05138575
- Acronym / sponsor ID
- SAK / 849401
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 53 participants (estimated)
- Lead sponsor
- University of PennsylvaniaUniversity, hospital or other
- Study start
- 24 Jan 2022 (actual)
- Primary completion
- 31 May 2027 (estimated)
- Study completion
- 31 May 2027 (estimated)
- First posted
- 1 Dec 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- 3 interventions will be randomized and administered in a double-blind fashion
| Arm | Type | Receives |
|---|---|---|
| Empagliflozin + Potassium Chloride (KCl) | Active comparator | Drug: Empagliflozin + Potassium ChlorideEmpagliflozin (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. |
| Empagliflozin + Potassium Nitrate (KNO3) | Active comparator | Drug: Empagliflozin + Potassium NitrateEmpagliflozin (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. |
| Potassium Chloride (KCl) + Placebo for Empa | Placebo comparator | Drug: Potassium Chloride + Placebo for EmpagliflozinPotassium Chloride (6 mmol three times daily) + Placebo for Empagliflozin Placebo arm will be 6 weeks in duration followed by a 2 week washout period. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- 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
Key exclusion criteria (31 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Empagliflozin + Potassium ChlorideAlso: Jardiance + KClEmpagliflozin is the active intervention that may improve mitochondrial function and energy fuel metabolism in skeletal muscle. KCl is an active control. | Drug | Empagliflozin + Potassium Chloride (KCl) |
| Empagliflozin + Potassium NitrateAlso: Jardiance + KNO3Empagliflozin + 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. | Drug | Empagliflozin + Potassium Nitrate (KNO3) |
| Potassium Chloride + Placebo for EmpagliflozinAlso: KCl + PlaceboActive control. | Drug | Potassium Chloride (KCl) + Placebo for Empa |
Primary outcome
Submaximal Exercise Endurance
Time frame: Week 6
Time to exhaustion while exercising at 75% peak workload
14 secondary outcomes
Intramuscular Perfusion
Time frame: Week 6
VO2 Kinetics
Time frame: Week 6
VO2 Efficiency
Time frame: Week 6
Vasodilatory Reserve
Time frame: Week 6
Venous Substrate Concentration
Time frame: Week 6
Respiratory Exchange Ratio
Time frame: Week 6
KCCQ Overall Summary Score
Time frame: Week 6
Ambulatory Physical Activity
Time frame: Week 6
Muscle Tissue Respirometry
Time frame: Week 6
Muscle Proteome
Time frame: Week 6
Muscle Metabolome
Time frame: Week 6
Skeletal Muscle Oxidative Capacity
Time frame: Week 6
Arteriovenous O2 content difference
Time frame: Week 6
Peak VO2 during Submaximal Exercise
Time frame: Week 6
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Apr 2026.
- Individual participant dataSharing planned: 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Cassandra Demastus, CRNP contact
Payman Zamani, MD principal investigator
University of Pennsylvania
1 site in 1 country: see every site and its status.
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?
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.