Oral Ketones for Heart Failure

Overseen By Carolina Solis-Herrera, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: The University of Texas Health Science Center at San Antonio

Must be taking: Heart failure medications

Must not be taking: SGLT2 inhibitors

Disqualifiers: Pregnancy, Cancer, Cardiovascular event, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether oral Ketone Esters (a type of supplement) can improve heart function in individuals with both Type 2 Diabetes and heart failure. The focus is on heart failure where the heart doesn't pump effectively. Participants will take the supplement to determine if it enhances heart muscle function. This trial may suit those with both Type 2 Diabetes and heart failure, who have a stable treatment plan and are not on certain diabetes medications. As an Early Phase 1 trial, this research aims to understand how the treatment works in people, offering participants a chance to be among the first to try this new approach.

Will I have to stop taking my current medications?

The trial requires that you stay on a stable dose of your current heart failure medications. However, if you are taking SGLT2 inhibitors or medications that might impair heart function or worsen blood sugar control, you cannot participate.

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

Research has shown that oral ketone esters (KE) have been studied for their effects on the heart, particularly in individuals with heart failure. One study found that taking KE can lead to prolonged ketosis, a state where the body uses fat for energy instead of carbohydrates. This may benefit the heart and metabolism in those with heart failure. Another study suggested that KE might improve heart function in animals with type 2 diabetes, indicating possible positive effects in humans as well.

Regarding safety, most reports indicate that KE is generally well-tolerated. Serious side effects are rarely mentioned, though some mild digestive issues might occur. As this is an early phase study, the main focus is on understanding the safety of KE and how the body processes it. The treatment is still under careful review to ensure its safety for humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for heart failure, which typically involve medications like ACE inhibitors, beta-blockers, and diuretics, the oral Ketone Monoester (KE) offers a novel approach by providing an alternative energy source for the heart. Researchers are excited about this treatment because it leverages ketones' ability to efficiently fuel heart cells, potentially improving heart function and energy efficiency. This unique mechanism could offer significant benefits, particularly for patients whose hearts struggle to produce or use energy effectively.

What evidence suggests that oral Ketone Esters could be effective for heart failure?

Research has shown that ketone esters (KE) can improve heart function. Studies have found benefits for heart and metabolism in people with heart failure who take oral ketones. In this trial, participants will receive monitored administration of oral ketone monoester. In animal studies, ketone esters helped prevent and treat heart failure. Additionally, slightly higher blood ketone levels improved heart function in animals with type 2 diabetes. Early results suggest that oral ketones can increase the amount of blood the heart pumps and reduce heart stiffness in people with related conditions. These findings indicate that ketone esters might aid in managing heart failure and type 2 diabetes. ^{1 2 3 6 7}

Who Is on the Research Team?

Carolina Solis-Herrera, MD

Principal Investigator

University of Texas Health Science Center San Antonio

Are You a Good Fit for This Trial?

Adults aged 18-80 with Type 2 Diabetes and Heart Failure (HFrEF), having a BMI of 23-38, stable heart medications, and functioning kidneys. Women must agree to use contraception. Excluded are those with recent cardiovascular events, certain drug treatments for diabetes or heart issues, pregnancy, substance abuse problems, major diseases that limit study participation or a history of cancer (except certain skin cancers in remission).

Inclusion Criteria

I am on a stable dose of medication for heart failure as per guidelines.

Your blood pressure should not be higher than 145/85 mmHg.

Your HbA1c levels are between 6.0% and 10.0%.

Exclusion Criteria

I am not allergic to the drugs or their ingredients used in the study.

I do not have major organ diseases or physical limitations that would prevent me from completing the study.

I am not taking any medications that could worsen heart function or blood sugar control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Acute Treatment

Participants receive two doses of oral ketones and undergo cardiac MRI and blood draws

1 day

1 visit (in-person)

Chronic Treatment

Participants self-administer oral ketones daily and undergo additional MRIs and blood draws

6 days

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

What Are the Treatments Tested in This Trial?

Interventions

• Ketone Monoester (KE)

Trial Overview The trial is testing the effects of an oral supplement called Ketone Monoester on heart function in patients with both Type 2 Diabetes and HFrEF. It aims to understand if this supplement can change how the heart works by providing it with ketones that don't rely on insulin.

How Is the Trial Designed?

Group I: Ketone Ester administration Experimental Treatment 1 Intervention

1. Monitored administration of oral Ketone monoester at 400mg/kg dosed twice on visit 2 (cardiac MRI day) 2. Self administered oral β-hydroxybutyrate (BOHB) at 400mg/kg/day for a period of 6 days

Ketone Monoester (KE) is already approved in United States, European Union for the following indications:

Approved in United States as Ketone Esters for:

• General wellness
• Athletic performance enhancement
• Research use

Approved in European Union as Ketone Esters for:

• General wellness
• Athletic performance enhancement
• Research use

Who Is Running the Clinical Trial?

The University of Texas Health Science Center at San Antonio

Lead Sponsor

Trials

486

Recruited

92,500+

National Center for Advancing Translational Sciences (NCATS)

Collaborator

Trials

394

Recruited

404,000+

Published Research Related to This Trial

An oral supplement of D-beta-hydroxybutyrate (D-BHB) is quickly absorbed and raises blood ketone levels significantly, making it a potent alternative to traditional ketogenic diets.

D-BHB is more effective at increasing ketone levels with fewer calories compared to other sources like racemic BHB or medium chain triglycerides, and it shows potential for therapeutic use in heart and kidney diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolism of Exogenous D-Beta-Hydroxybutyrate, an Energy Substrate Avidly Consumed by the Heart and Kidney. Cuenoud, B., Hartweg, M., Godin, JP., et al.[2020]

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]

The natural ketone body d-β-hydroxybutyrate (βHB) can potentially improve metabolic function and help manage chronic diseases like diabetes and Alzheimer's, and a new ingestible βHB monoester allows for rapid elevation of blood ketone levels without the downsides of traditional high-fat diets.

The βHB monoester has been shown to be safe for human consumption in studies involving athletes and healthy volunteers, and it may have specific applications in treating various conditions, including neurodegenerative diseases and heart failure, although further research is needed to fully understand its limitations and potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Why a d-β-hydroxybutyrate monoester? Soto-Mota, A., Norwitz, NG., Clarke, K.[2020]

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]

Chronic supplementation of ketone bodies, specifically using a ketone ester, significantly improved heart function in mice with established heart failure, preventing further decline in cardiac performance over two weeks.

The treatment not only elevated blood levels of β-hydroxybutyrate without causing ketoacidosis but also reduced heart muscle hypertrophy and fibrosis, suggesting that ketone therapy could be a promising approach for managing heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic exogenous ketone supplementation blunts the decline of cardiac function in the failing heart. Takahara, S., Soni, S., Phaterpekar, K., et al.[2022]

A 28-day toxicity study in rats showed that (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester, is safe, as it did not cause any significant toxic effects or abnormalities in blood parameters, despite some differences observed.

In a developmental toxicity study, pregnant rats given the ketone monoester showed no adverse effects on pregnancy outcomes or fetal development, further supporting its safety for potential use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. Clarke, K., Tchabanenko, K., Pawlosky, R., et al.[2022]

In a study involving 18 adults with prediabetes, ingestion of the ketone monoester β-hydroxybutyrate (KEβHB) significantly elevated blood ketone levels and resulted in lower levels of remnant cholesterol and triglycerides, indicating potential cardiovascular benefits.

The positive effects on lipid profile were more pronounced in individuals with higher habitual saturated fat intake, suggesting that KEβHB may be particularly beneficial for those at risk of cardiovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of acute ketosis on lipid profile in prediabetes: findings from a cross-over randomized controlled trial. Liu, Y., Bharmal, SH., Kimita, W., et al.[2022]

The ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate effectively elevates blood ketone levels in healthy volunteers, reaching maximum plasma concentrations of 3.30 mM for β-hydroxybutyrate within 1-2 hours after ingestion.

This ketone monoester was generally well-tolerated over a 5-day period, although some gastrointestinal side effects were noted at higher doses, indicating it is a safe alternative to traditional ketogenic diets for enhancing physical and cognitive performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Clarke, K., Tchabanenko, K., Pawlosky, R., et al.[2022]

The novel ketone ester bis hexanoyl (R)-1,3-butanediol (BH-BD) effectively increases blood levels of beta-hydroxybutyrate (BHB) in a dose-dependent manner, as demonstrated in studies with Sprague Dawley rats and C57/BL6 mice.

BH-BD is well tolerated at all tested doses, and its metabolism involves hydrolysis into hexanoate and (R)-1,3-butanediol, which are then converted into BHB, indicating its potential as a safe energy substrate and signaling metabolite.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol. Stubbs, BJ., Blade, T., Mills, S., et al.[2021]

Citations

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

Cardiovascular and Metabolic Effects of Modulating ... Oral dosing of BD led to prolonged ketosis and cardiovascular and metabolic benefits in patients with heart failure with reduced ejection fraction.

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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8649133/

Ketone Ester D‐β‐Hydroxybutyrate‐(R)‐1,3 Butanediol ... The aim of this study was to determine whether moderate elevation in D‐β‐hydroxybutyrate improves cardiac function in animals with type 2 diabetes mellitus.

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

Therapeutic Ketosis for Heart Failure: A State-of-the-Art ... Therapeutic ketosis, which is a metabolic state in which blood ketone levels are mildly elevated, could have great potential to ameliorate heart failure.

5. ahajournals.org ahajournals.org/doi/10.1161/CIRCULATIONAHA.124.069732

Randomized Crossover Trial of 2-Week Ketone Ester ... In patients with T2D and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness.

6. tandfonline.com tandfonline.com/doi/full/10.1080/21551197.2025.2466163

1,3-Butanediol, and Its Acute Effect on ß-Hydroxybutyrate ... Cardiovascular effects of oral ketone ester treatment in patients with heart failure with reduced ejection fraction: a randomized ...

7. jacc.org jacc.org/doi/10.1016/j.jacc.2020.12.065

Therapeutic Potential of Ketone Bodies for Patients With ... In a study in high salt-sensitive hypertensive rats, mild ketosis induced by 1,3-butanediol reduced blood pressure, possibly mediated by reduced ...