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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a special drink containing ketones, known as Ketone Ester, can enhance exercise ability and overall heart function in people with heart failure. Heart failure often causes fatigue and shortness of breath, limiting daily activities. The study will compare the effects of the ketone drink to a placebo (a drink with no active ingredient) to determine if it can reduce these symptoms. Individuals who have managed heart failure with medication for at least two weeks and experience symptoms like shortness of breath or fatigue might be suitable for this trial. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in heart failure treatment.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that ketone esters might be safe for people with heart failure. Studies found that taking ketone esters for 14 days improved heart function in patients with stable heart failure, suggesting the treatment is well-tolerated.

The Food and Drug Administration (FDA) considers this ketone drink "generally regarded as safe," but it hasn't been approved specifically for heart failure. This means it's generally safe to consume, but its effects on heart failure remain under investigation.

It's important to note that ketone esters may not be suitable for everyone. People with heart failure who need to limit salt intake should be cautious, as some ketone products can contain salts. Always consult a healthcare provider before trying new treatments. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for heart failure?

Unlike the standard treatments for heart failure, which often focus on improving heart function with medications like ACE inhibitors, beta-blockers, and diuretics, the ketone ester treatment works by providing an alternative energy source for the heart. Researchers are excited about this treatment because it uses (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone ester, that could potentially boost heart energy metabolism, something traditional treatments don't address directly. This novel approach might improve heart function and patient outcomes by enhancing the heart's efficiency in using energy.

What evidence suggests that this treatment might be an effective treatment for heart failure?

Research suggests that ketone esters, which participants in this trial may receive, could help people with heart failure. Studies have shown that ketone bodies can provide an alternative energy source for the heart and may also help reduce inflammation and cell damage. In one study, a 14-day treatment with ketone esters improved heart health in patients with stable heart failure. Another study found that ketone esters improved heart function in animals with heart failure. These findings indicate that ketone esters might enhance heart health and exercise ability in people with heart failure. ^{2 3 4 6 7}

Who Is on the Research Team?

Senthil Selvaraj, MD

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

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.

Intentional ketogenic diet in the last week

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S1071916425001010

Therapeutic Ketosis for Heart Failure: A State-of-the-Art ... In heart failure specifically, ketone bodies may provide an alternative energy source for the failing heart as well as reduce inflammation and oxidative stress.

2. ahajournals.org ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.067971

Cardiovascular Effects of Oral Ketone Ester Treatment in ... The results of this study demonstrate favorable cardiovascular effects of 14-day ketone ester treatment in patients with stable heart failure ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12394354/

Salutary Effects of Nutritional Ketosis for the Diseased Human ... Ketone ester administration in 20 healthy adults achieved an average [BHB] of 3.2 during TTE imaging; HR (+ 15%), SV (+ 8%), LVEF (+ 5%), and ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06398964

Effects of 2-week Ketosis on the Heart's Ketone Body ... Recent research suggests that 3-OHB might have benefits for HF patients beyond just providing energy. It seems to reduce inflammation and oxidative stress in ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7819534/

Ketone Ester Treatment Improves Cardiac Function and ... Conclusions: Chronic oral supplementation with KE was effective in both prevention and treatment of heart failure in 2 preclinical animal models. In addition, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11009516/

Evaluation of the safety and tolerability of exogenous ketosis ... For example, ketone salts may not be suitable for patients who should restrict their salt intake, such as those with heart failure or kidney disease. On the ...

7. ahajournals.org ahajournals.org/doi/10.1161/JAHA.124.038461

Cardiovascular and Metabolic Effects of Modulating ... Persistent treatment with a ketone ester for 14 days is associated with improved cardiovascular effects in patients with HFrEF or heart failure ...