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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how a drink containing ketone esters can assist individuals with heart failure. Researchers aim to determine if this drink improves heart function compared to a regular drink without ketones. Participants will consume either the ketone drink or a placebo (a drink without active ingredients) to compare results. Individuals with heart failure who have had stable symptoms for at least three months and can perform treadmill tests may be suitable for this study. As an unphased trial, this study provides a unique opportunity to contribute to groundbreaking research that could lead to new heart failure treatments.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ketone supplements, like the ketone ester tested in this trial, are generally safe and easy for most people to handle. A previous study found that a type of ketone called free D-BHB safely increased ketone levels in the blood, a state known as ketosis.

However, it's important to remember that while these supplements appear safe in the short term, information about their long-term effects remains insufficient. Some studies have demonstrated short-term benefits for heart health, such as improved heart function and reduced heart stress.

Overall, current research suggests that trying ketone supplements is safe, but awareness of the unknowns regarding long-term use is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Most treatments for heart failure focus on managing symptoms with medications like beta-blockers, ACE inhibitors, or diuretics. But ketone ester offers a different approach by providing an alternative energy source for the heart. This treatment is exciting because it could potentially enhance heart function by fueling the heart with ketones, which are more efficient than glucose. Additionally, the ketone ester is administered as a beverage, making it a non-invasive option. Researchers are hopeful that this novel mechanism may improve energy metabolism and overall heart performance in patients with heart failure.

What evidence suggests that ketone ester supplements could be effective for heart failure?

Research shows that ketone esters might help people with heart failure. Studies have found that ketone esters provide the heart with an alternative energy source, potentially reducing inflammation and stress. In animal studies, regular use of ketone esters helped prevent and treat heart failure. In humans, one study showed that just 14 days of ketone ester treatment improved heart function in patients with stable heart failure. This trial will test the effects of ketone ester supplements, with some participants receiving a Keto Ester Beverage and others a placebo. These findings suggest that ketone esters could support heart health in those with heart failure. ^{2 3 5 6 7}

Who Is on the Research Team?

Yuchi Han, MD, MMSc

Principal Investigator

Ohio State University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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 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]

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]

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 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]

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]

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]

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]

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. 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, ...

3. 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 ...

4. 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 ...

5. 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 ...

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

Evaluation of the safety and tolerability of exogenous ketosis ... Free D-BHB was a safe and well-tolerated intervention for inducing sustained exogenous ketosis. Being bioidentical, salt-free and lacking intermediate ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04370600

NCT04370600 | Nutritional Ketosis in Heart Failure Chronic, ambulatory heart failure patients will be given ketone ester dietary supplementation to determine therapeutic efficacy, metabolic adaptation ...