SGLT2i and KNO3 in HFpEF - The SAK HFpEF Trial

Phase 2

Recruiting

• Conditions: Heart Failure With Preserved Ejection Fraction
• Interventions: Drug: Empagliflozin + Potassium Chloride; Drug: Empagliflozin + Potassium Nitrate; Drug: Potassium Chloride + Placebo for Empagliflozin

• Registration Number: NCT05138575
• Lead Sponsor: University of Pennsylvania

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).

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).

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2021-11-03
• Study First Submitted QC: 2021-11-16
• Study First Posted: 2021-12-01
• Study Start: 2022-01-24
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-25
• Last Update Posted: 2024-06-27
• Primary Completion: 2026-03-01
• Study Completion: 2026-03-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 53

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

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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).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Empagliflozin + Potassium Chloride (KCl)	Empagliflozin + Potassium Chloride	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.
Empagliflozin + Potassium Nitrate (KNO3)	Empagliflozin + Potassium Nitrate	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.
Potassium Chloride (KCl) + Placebo for Empa	Potassium Chloride + Placebo for Empagliflozin	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.

Primary Outcome Measures

Name	Time	Method
Submaximal Exercise Endurance	Week 6	Time to exhaustion while exercising at 75% peak workload

Secondary Outcome Measures

Name	Time	Method
Vasodilatory Reserve	Week 6	Percent change in systemic vascular resistance (SVR) at baseline vs SVR at 4 minutes of exercise at end of each intervention period
Ambulatory Physical Activity	Week 6	Use actigraphy to document the average steps per day taken during the final week of each interventional period
VO2 Efficiency	Week 6	Assess the impact of interventions on the efficiency of oxygen consumed above basal metabolic rate compared to total work performed
Venous Substrate Concentration	Week 6	Change in venous substrate concentrations at time of fatigue at end of each intervention period
KCCQ Overall Summary Score	Week 6	Assess impact of interventions on quality of life based on Kansas City Cardiomyopathy Questionnaire overall summary score
Intramuscular Perfusion	Week 6	MRI assessment of skeletal muscle perfusion
VO2 Kinetics	Week 6	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.
Respiratory Exchange Ratio	Week 6	Change in RER at 4 minutes of exercise at end of each intervention period
Muscle Tissue Respirometry	Week 6	Measure tissue rates of substrate metabolism and mitochondrial content
Muscle Proteome	Week 6	Measure relative abundances of proteins related to fatty acid and ketone oxidation as well as proteins related to mitochondrial biogenesis.
Muscle Metabolome	Week 6	Perform targeted quantitative metabolomics to assess changes in substrate metabolism
Skeletal Muscle Oxidative Capacity	Week 6	MRI assessment of skeletal muscle oxidative phosphorylation capacity
Arteriovenous O2 content difference	Week 6	quotient of VO2 to cardiac output

Trial Locations

Locations (1)

University of Pennsylvania Health System; 🇺🇸 Philadelphia, Pennsylvania, United States