Ketone Supplement for Heart Failure

Overseen By Jeff Volek, Ph.D.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Ohio State University

Must not be taking: SGLT2 inhibitors

Disqualifiers: Type I diabetes, Severe kidney disease, Recent myocardial infarction, others

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is being done to evaluate how a ketone ester (KE) beverage affects heart function and health in people with heart failure compared to a placebo beverage (a beverage made with standard food ingredients that do not contain ketone esters).

Will I have to stop taking my current medications?

The trial requires that your current heart and diabetes medications have been stable for at least 3 months before joining, and the dosage should not change for 1 month before starting. However, you can reduce or stop these medications during the study if needed. Changes in oral diuretics are allowed but must be stable for 1 week before starting the trial.

What data supports the effectiveness of the treatment Ketone Ester for heart failure?

Research suggests that ketone esters can improve heart function in heart failure by providing an additional energy source for the heart, which is often energy-starved in this condition. Studies in animals and some human trials have shown that increasing ketone levels can help the heart work better, especially in heart failure with reduced ejection fraction (a measure of how well the heart pumps blood). ^{1 2 3 4 5}

Is the ketone supplement safe for humans?

Research shows that ketone supplements, like ketone esters, are generally safe and well-tolerated in healthy adults, with no significant changes in vital signs or lab tests, although mild nausea was occasionally reported. ^{1 6 7 8 9}

How is the ketone ester treatment different from other heart failure treatments?

Ketone ester treatment is unique because it provides an additional energy source for the heart by increasing ketone body levels, which can improve heart function in heart failure. Unlike traditional treatments that focus on neurohormonal and hemodynamic factors, this approach targets the heart's metabolism directly, potentially offering benefits in cases where other treatments may not be as effective. ^{1 2 3 4 10}

Research Team

Yuchi Han, MD, MMSc

Principal Investigator

Ohio State University

Eligibility Criteria

Adults aged 18-80 with heart failure, BMI of 25-50 or Type II Diabetes/prediabetes, stable heart and diabetes medications for at least 3 months, and able to do treadmill tests. Excludes those with recent major surgeries, certain heart conditions like transplants or severe arrhythmias, pregnant women, drug/alcohol abuse history, severe kidney disease, uncontrolled blood pressure or life expectancy less than a year.

Inclusion Criteria

I have had heart condition symptoms that are not the most severe for at least 3 months.

I have a BMI between 25 and 50, or I have Type II Diabetes, prediabetes, or metabolic syndrome.

Your heart function and blood pressure in your lungs are not within normal range.

Exclusion Criteria

Criterion: You are allergic to Gadolinium-based contrast agents.

You have metal implants or aneurysm clips that are not safe for MRI scans.

Your heart's pumping ability is less than 50%.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Participants consume the Ketone Ester or Placebo beverage twice daily for 6 weeks

6 weeks

Daily monitoring of blood markers, blood pressure, heart rate, and overall health

Washout

Participants undergo a 4-week washout period before crossing over to the other group

4 weeks

Treatment Phase 2

Participants crossover to the other group and consume the Ketone Ester or Placebo beverage twice daily for another 6 weeks

6 weeks

Daily monitoring of blood markers, blood pressure, heart rate, and overall health

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ketone Ester

Trial Overview The trial is testing the effects of a ketone ester beverage on exercise tolerance and cardiac function in people with heart failure. Participants will be randomly assigned to receive either the ketone ester drink or a placebo (a non-ketone standard beverage) to compare outcomes.

Participant Groups

Group I: Ketone Ester Experimental Treatment 1 Intervention

This arm will provide a Keto Ester Beverage for consumption.

Group II: Keto Ester Acute Experimental Treatment 1 Intervention

This arm will provide a Keto Ester Beverage for consumption.

Group III: Placebo Placebo Group 1 Intervention

This arm will provide a Placebo Beverage for consumption.

Group IV: Placebo Acute Placebo Group 1 Intervention

This arm will provide a Placebo Beverage for consumption.

Who Is Running the Clinical Trial?

Ohio State University

Lead Sponsor

Trials

891

Recruited

2,659,000+

Findings from Research

Chronic oral supplementation with ketone esters (KE) significantly improved heart function in rodent models of heart failure, with the KE-1 diet preventing left ventricular dysfunction and the KE-2 diet enhancing recovery post-myocardial infarction (MI).

The KE-2 diet not only improved heart function but also normalized myocardial ATP levels and altered gene expression related to ketone metabolism, suggesting that ketone bodies can serve as an effective alternative fuel for the failing heart.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure. Yurista, SR., Matsuura, TR., Silljé, HHW., et al.[2021]

In heart failure, the heart struggles to produce enough energy due to decreased mitochondrial metabolism, but ketone bodies can serve as an alternative energy source, potentially improving heart function.

While ketogenic diets alone have shown limited benefits for heart function, intravenous ketone infusions and ketone ester cocktails may enhance cardiac performance, suggesting that boosting ketone oxidation could be a promising treatment strategy for heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketone metabolism in the failing heart. Lopaschuk, GD., Karwi, QG., Ho, KL., et al.[2021]

In patients with acute decompensated heart failure (HF), ketone body concentrations, particularly acetone, were significantly higher at the onset compared to after stabilization, indicating that acute HF may increase ketogenesis.

The study found that treatment with empagliflozin did not influence ketone body levels, and while higher baseline acetone levels were associated with worse outcomes, it did not remain a significant predictor after adjusting for age and sex.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longitudinal Changes in Circulating Ketone Body Levels in Patients With Acute Heart Failure: A Post Hoc Analysis of the EMPA-Response-AHF Trial. Voorrips, SN., Boorsma, EM., Beusekamp, JC., et al.[2023]

Ketone metabolic modulation shows promise as a novel treatment for heart failure (HF), particularly in patients with reduced ejection fraction, as it may enhance myocardial energy use during the disease's progression.

Current evidence suggests that exogenous ketone therapy could provide beneficial effects in both animal models and humans with HF, indicating a potential new therapeutic approach alongside traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure. Selvaraj, S., Kelly, DP., Margulies, KB.[2021]

Cardiac endothelial cells can oxidize ketone bodies, which promotes their proliferation, migration, and the formation of new blood vessels, indicating a potential mechanism for improving heart function.

A ketogenic diet, which raises ketone body levels, was shown to enhance endothelial cell proliferation and prevent blood vessel loss in hypertrophied mouse hearts, suggesting a promising approach for treating heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketones regulate endothelial homeostasis. Lopaschuk, GD., Hess, DA., Verma, S.[2022]

In a 28-day study involving 59 healthy adults, the novel exogenous ketone diester bis-hexanoyl-(R)-1,3-butanediol (BH-BD) was found to be well-tolerated and safe, with no significant differences in tolerability scores compared to a placebo.

BH-BD effectively increased blood ketone levels one hour after consumption, indicating its potential for promoting nutritional ketosis without adverse effects on vital signs or laboratory measures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. Chen, O., Blonquist, TM., Mah, E., et al.[2021]

A study involving 24 healthy adults showed that consuming a ketone monoester three times a day for 28 days safely elevated blood ketone levels without affecting body weight, blood glucose, cholesterol, or kidney function.

The only reported side effect was mild nausea in a small number of instances, indicating that the ketone monoester is well-tolerated for sustained use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. Soto-Mota, A., Vansant, H., Evans, RD., et al.[2020]

The study demonstrated that the ketone body acetoacetate can be used as a radiotracer to assess heart failure in a rat model induced by doxorubicin, showing increased blood levels and mitochondrial uptake in the heart, indicating its potential as an alternate nutrient for cardiac function.

Kinetic analysis using [(11)C]-acetoacetate revealed decreased uptake rates in heart failure rats, correlating with a significant reduction in left ventricular ejection fraction, suggesting that this radiotracer can effectively evaluate cardiac function without the need for stress testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[(11)C]-Acetoacetate PET imaging: a potential early marker for cardiac heart failure. Croteau, E., Tremblay, S., Gascon, S., et al.[2016]

In a study involving 10 recreational endurance runners, ingestion of a commercially available oral ketone supplement (β-hydroxybutyrate-salt + MCT) did elevate plasma ketone levels but did not significantly improve 5-km running performance compared to a placebo.

No notable differences were found in other physiological or perceptual measures during the exercise, suggesting that while the supplement increased ketone levels, it did not enhance exercise performance or related responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of an Exogenous Ketone Supplement on Five-Kilometer Running Performance. Prins, PJ., Koutnik, AP., D'Agostino, DP., et al.[2020]

Ketone bodies, particularly β-hydroxybutyric acid and acetone, increase during oxidative stress conditions like exercise and fasting, and their levels are notably elevated in patients with heart failure, indicating a potential role in energy metabolism for heart cells.

The mild ketosis induced by sodium glucose cotransporter 2 inhibitors may contribute to the cardiovascular and renal benefits seen in type 2 diabetes patients, suggesting a therapeutic mechanism linked to ketone body metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketone bodies and the heart. Papazafiropoulou, AK., Georgopoulos, MM., Katsilambros, NL.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Ketone metabolism in the failing heart. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Longitudinal Changes in Circulating Ketone Body Levels in Patients With Acute Heart Failure: A Post Hoc Analysis of the EMPA-Response-AHF Trial. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Ketones regulate endothelial homeostasis. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

[(11)C]-Acetoacetate PET imaging: a potential early marker for cardiac heart failure. [2016]

9. Poland pubmed.ncbi.nlm.nih.gov

Effects of an Exogenous Ketone Supplement on Five-Kilometer Running Performance. [2020]

10. Poland pubmed.ncbi.nlm.nih.gov

Ketone bodies and the heart. [2022]