Ketone Ester for Heart Failure

(HFrEF Trial)

Overseen By Stephanie Milosovic, BS, DPT

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Duke University

Disqualifiers: Cirrhosis, Atrial fibrillation, Diabetes, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 1 day

25 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to understand the effects of a ketone drink on exercise capacity and other cardiovascular parameters in patients with heart failure. In heart failure, patients are limited in their ability to do all the things they want to do, and exercise as much as they would like, due to becoming tired and short of breath early. There may be several reasons why these symptoms occur. This study is assessing whether the ketone drink can improve these symptoms. This drink has been given status by Food and Drug Administration as "generally regarded as safe". The use of DeltaG in this study is experimental. DeltaG has not been approved by the Food and Drug Administration (FDA) for the use being evaluated in this study.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must have stable cardiovascular medical therapy for at least 2 weeks before joining. It's best to discuss your specific medications with the study team.

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 ketone ester safe for human consumption?

Research shows that ketone esters are generally safe for humans. Studies in healthy adults found no significant safety concerns when consuming ketone esters for up to 28 days, with only mild nausea reported in a few cases. ^{2 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 oxidation, 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. ^{2 3 4 5 9}

Research Team

Senthil Selvaraj, MD

Principal Investigator

Duke University

Eligibility Criteria

This trial is for people with heart failure who have a reduced ability of the heart to pump blood (ejection fraction of 45% or less) and experience moderate symptoms like getting tired or short of breath easily. They should be on stable heart medication for at least two weeks.

Inclusion Criteria

My heart doesn’t pump well (EF 45% or less) and I have moderate heart symptoms.

My heart medication has not changed in the last 2 weeks.

Exclusion Criteria

I have a serious lung condition.

History of heart transplant, left ventricular assist device, or use of inotropic medication

Intentional ketogenic diet in the last week

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either the ketone ester or placebo and undergo various cardiovascular assessments

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the intervention

4 weeks

Treatment Details

Interventions

• Ketone Ester

Trial Overview The study is testing if a ketone drink, considered safe by the FDA but not yet approved for this use, can help improve exercise capacity and other heart-related functions in patients with heart failure.

Participant Groups

Group I: ketone ester Experimental Treatment 1 Intervention

(R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone ester

Group II: placebo Placebo Group 1 Intervention

KE-free solution

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

American Heart Association

Collaborator

Trials

352

Recruited

6,196,000+

Findings from Research

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]

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]

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]

A ketone ester supplement can induce acute nutritional ketosis, which changes how the body uses energy during exercise, particularly in elite cyclists.

This shift in energy utilization leads to reduced lactate production and improved performance in time-trial events, suggesting potential benefits for athletes during prolonged or intense exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fueling Performance: Ketones Enter the Mix. Egan, B., D'Agostino, DP.[2018]

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]

References

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

Ketones regulate endothelial homeostasis. [2022]

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

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

3. Netherlands pubmed.ncbi.nlm.nih.gov

Ketone metabolism in the failing heart. [2021]

4. 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]

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

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

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

Fueling Performance: Ketones Enter the Mix. [2018]

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

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