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

Trial Summary

What is the purpose of this trial?

This study will provide insight into whether cardiac function changes with oral Ketone Esters (KE) administered to patients with Type 2 Diabetes Mellitus (T2DM) and Heart failure with reduced ejection fraction (HFrEF). Plasma ketones are avidly extracted by cardiac muscle and their uptake is not dependent upon insulin or influenced by insulin resistance.

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.

What data supports the effectiveness of the treatment Ketone Monoester (KE) for heart failure?

Research suggests that d-β-hydroxybutyrate (βHB), a component of Ketone Monoester, may help improve metabolism in chronic diseases like heart disease by acting as an efficient fuel and signaling molecule. Additionally, studies show that ketone esters can safely elevate blood ketone levels, which might offer therapeutic benefits for conditions related to impaired metabolism. ^{1 2 3 4 5}

Is oral ketone monoester safe for human consumption?

Research shows that ketone monoester is generally safe and well-tolerated in healthy adults, with mild nausea being the most common side effect. Studies in both humans and animals have not shown significant adverse effects, supporting its safety for consumption. ^{1 3 4 5 6}

How does the drug Ketone Monoester differ from other heart failure treatments?

Ketone Monoester is unique because it provides an alternative energy source for the heart by increasing blood ketone levels without the need for a high-fat diet, potentially improving heart function in heart failure patients. ^{1 3 7 8 9}

Research Team

Carolina Solis-Herrera, MD

Principal Investigator

University of Texas Health Science Center San Antonio

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Why a d-β-hydroxybutyrate monoester? [2020]

2. England pubmed.ncbi.nlm.nih.gov

In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol. [2021]

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

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

4. Netherlands pubmed.ncbi.nlm.nih.gov

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Effect of acute ketosis on lipid profile in prediabetes: findings from a cross-over randomized controlled trial. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Metabolism of Exogenous D-Beta-Hydroxybutyrate, an Energy Substrate Avidly Consumed by the Heart and Kidney. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Chronic exogenous ketone supplementation blunts the decline of cardiac function in the failing heart. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Ketone metabolism in the failing heart. [2021]