SGLT2i and KNO3 in HFpEF - The SAK HFpEF Trial

Heart Failure With Preserved Ejection Fraction Clinical Trial

Official title:

SGLT2i and KNO3 in HFpEF - The SAK HFpEF Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05138575
• Other study ID #: 849401
• Status: Recruiting
• Phase: Phase 2
• Start date: January 24, 2022
• Est. completion date: March 1, 2026

Study information

• Verified date: March 2024
• Source: University of Pennsylvania
• Contact: Gabrielle Grosso
• Phone: 267-776-3138
• Email: Gabrielle.Grosso[@]Pennmedicine.upenn.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 oxidative phosphorylation capacity (SkM OxPhos) in participants with Heart Failure with Preserved Ejection Fraction (HFpEF).

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 53
• Est. completion date: March 1, 2026
• Est. primary completion date: March 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

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 follows:

1. 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)

2. Mitral E/e' ratio > 14 at rest or during exercise

3. 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)

4. 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

16. Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin < 3.0 g/dL)

17. eGFR < 30 mL/min/1.73m^2.

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. 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)

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, 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).

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Preserved Ejection Fraction

Intervention

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.
• 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.
• Potassium Chloride + Placebo for Empagliflozin
Active control.

Locations

Country	Name	City	State
United States	University of Pennsylvania Health System	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
University of Pennsylvania

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Intramyocardial Filling Pressure	Assess impact of interventions on intramyocardial filling pressures during submaximal exercise	Week 6
Primary	Submaximal Exercise Endurance	Time to exhaustion while exercising at 75% peak workload	Week 6
Secondary	Intramuscular Perfusion	MRI assessment of skeletal muscle perfusion	Week 6
Secondary	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
Secondary	VO2 Efficiency	Assess the impact of interventions on the efficiency of oxygen consumed above basal metabolic rate compared to total work performed	Week 6
Secondary	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
Secondary	Venous Substrate Concentration	Change in venous substrate concentrations at time of fatigue at end of each intervention period	Week 6
Secondary	Respiratory Exchange Ratio	Change in RER at 4 minutes of exercise at end of each intervention period	Week 6
Secondary	KCCQ Overall Summary Score	Assess impact of interventions on quality of life based on Kansas City Cardiomyopathy Questionnaire overall summary score	Week 6
Secondary	Ambulatory Physical Activity	Use actigraphy to document the average steps per day taken during the final week of each interventional period	Week 6
Secondary	Muscle Tissue Respirometry	Measure tissue rates of substrate metabolism and mitochondrial content	Week 6
Secondary	Muscle Proteome	Measure relative abundances of proteins related to fatty acid and ketone oxidation as well as proteins related to mitochondrial biogenesis.	Week 6
Secondary	Muscle Metabolome	Perform targeted quantitative metabolomics to assess changes in substrate metabolism	Week 6
Secondary	Skeletal Muscle Oxidative Capacity	MRI assessment of skeletal muscle oxidative phosphorylation capacity	Week 6
Secondary	Arteriovenous O2 content difference	quotient of VO2 to cardiac output	Week 6