Ketone Supplements for High Blood Pressure

(KEAS Trial)

Overseen By Braxton A Linder, MS

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Indiana University

Must not be taking: Pradaxa, Eliquis

Disqualifiers: Hypertension, Cancer, Diabetes, Obesity, 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: 2

Duration: 10 days

35 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether ketone supplements, specifically β-OHB, can help manage high blood pressure caused by excessive salt intake. The research investigates how these supplements might protect the heart and kidneys from salt damage. Participants will be divided into groups that either take ketone supplements or do not, while consuming different levels of salt. The trial seeks individuals with a resting blood pressure below 150/90, no history of heart or kidney diseases, and the ability to comfortably cycle on an exercise bike for up to an hour. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could lead to new methods for protecting heart and kidney health.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on medications like Pradaxa or Eliquis that prevent you from giving blood, you may not be eligible to participate.

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

Research has shown that beta-hydroxybutyrate (β-OHB) is generally safe for use. One study found that β-OHB can be safely added to food in various forms, indicating safety for most adults. However, another study found a potential link between high levels of β-OHB and serious heart problems. While not everyone will experience these issues, awareness of the possibility is important.

Overall, evidence suggests that β-OHB is safe for many people. Prospective trial participants should consult their doctor to understand how β-OHB might affect their health. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Unlike the standard treatments for high blood pressure, which usually include medications like ACE inhibitors or beta-blockers, β-OHB is a ketone supplement that may offer a new way to manage this condition. β-OHB is unique because it acts as an energy source for the body, potentially improving arterial function and reducing inflammation, which are not typical targets of current treatments. Researchers are excited about β-OHB as it represents a novel approach by targeting metabolic pathways, offering the possibility of not just managing blood pressure but also improving overall cardiovascular health in a different way.

What evidence suggests that ketone supplements might be an effective treatment for high blood pressure?

Research has shown that ketone supplements, such as β-OHB, might help lower blood pressure. In this trial, participants will be divided into groups to assess the effects of β-OHB. One group will follow a high salt diet without β-OHB, while another will follow a high salt diet with β-OHB. Studies have found that these supplements can improve heart health and reduce blood pressure, especially in individuals with high salt consumption. In animal studies, ketone supplements prevented high blood pressure and kidney issues caused by excessive salt. Human studies suggest that these supplements can raise ketone levels in the blood and improve kidney function. This evidence indicates that ketone supplements could offer a new way to manage high blood pressure, particularly for those with high salt intake. ^{3 5 6 7 8}

Who Is on the Research Team?

Austin T Robinson, PhD

Principal Investigator

Indiana University

Are You a Good Fit for This Trial?

This trial is for healthy young adults aged 18-39 without major health issues like heart disease, cancer, diabetes, or obesity. Participants must be able to cycle on an exercise bike and have a resting blood pressure no higher than 150/90 mmHg and BMI below 35 kg/m2.

Inclusion Criteria

I don't have diabetes, kidney issues, lung problems, heart diseases, autoimmune conditions, or a history of cancer.

I can give blood without any health or medication issues.

My BMI is under 35, or I am healthy despite my BMI.

Exclusion Criteria

Communication barriers

Your blood pressure is higher than 150/90 mmHg.

Your blood pressure is very low, less than 90/50 mmHg.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-intervention

Participants complete baseline assessments including mental health, dietary intake, physical activity, cardiorespiratory fitness, and sleep quality

14 days

1 visit (in-person)

Treatment

Participants consume the supplemental intervention for 10 days, with assessments of blood pressure, arterial stiffness, endothelial function, renal blood flow, and blood collection for inflammatory and immune responses

10 days

1 visit (in-person) on day 10

Follow-up

Participants are monitored for safety and effectiveness after treatment, including changes in blood pressure and cardiovascular function

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• β-OHB

Trial Overview The KEAS study tests if ketone supplements can protect against the negative effects of high salt intake on blood pressure and kidney function in young adults. It compares the impact of different combinations of dietary salt and β-OHB (a type of ketone) levels.

How Is the Trial Designed?

Group I: Placebo/Placebo, then Salt/Placebo, then Salt/Ketone Active Control 3 Interventions

Participants will consume each of the supplement combinations for 10 days (in this assigned order). On Day 10 of each interventional condition, participants will arrive at the laboratory where the investigators will assess resting blood pressure, arterial stiffness, endothelial function, renal blood flow, and submaximal exercise blood pressure reactivity. Blood will be collected to investigate inflammatory and immune responses to the dietary conditions. A washout period will be required prior to starting each of the next two supplement combination assignments.

Group II: Salt/Placebo, then Salt/Ketone, then Placebo/Placebo Active Control 3 Interventions

Participants will consume each of the supplement combinations for 10 days (in this assigned order). On Day 10 of each interventional condition, participants will arrive at the laboratory where the investigators will assess resting blood pressure, arterial stiffness, endothelial function, renal blood flow, and submaximal exercise blood pressure reactivity. Blood will be collected to investigate inflammatory and immune responses to the dietary conditions. A washout period will be required prior to starting each of the next two supplement combination assignments.

Group III: Salt/Ketone, then Placebo/Placebo, then Salt/Placebo Active Control 3 Interventions

Participants will consume each of the supplement combinations for 10 days (in this assigned order). On Day 10 of each interventional condition, participants will arrive at the laboratory where the investigators will assess resting blood pressure, arterial stiffness, endothelial function, renal blood flow, and submaximal exercise blood pressure reactivity. Blood will be collected to investigate inflammatory and immune responses to the dietary conditions. A washout period will be required prior to starting each of the next two supplement combination assignments.

β-OHB is already approved in United States, European Union for the following indications:

Approved in United States as β-Hydroxybutyric acid for:

• No specific FDA-approved indications for β-OHB as a standalone treatment; however, it is used in various dietary supplements and research contexts.

Approved in European Union as β-Hydroxybutyric acid for:

• No specific EMA-approved indications for β-OHB as a standalone treatment; however, it is used in various dietary supplements and research contexts.

Who Is Running the Clinical Trial?

Indiana University

Lead Sponsor

Trials

1,063

Recruited

1,182,000+

Auburn University

Lead Sponsor

Trials

81

Recruited

14,600+

University of Utah

Collaborator

Trials

1,169

Recruited

1,623,000+

University of Missouri-Columbia

Collaborator

Trials

387

Recruited

629,000+

Published Research Related to This Trial

Lifestyle changes are recommended to lower blood pressure before considering medications, with caloric restriction showing clear benefits for hypertensive patients, despite its challenges.

While ketogenic diets have mixed results on hypertension, ketone bodies like β-hydroxybutyrate may improve vascular health, suggesting that ketone supplements could be a promising low-dose treatment option with fewer side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The janus face of ketone bodies in hypertension. Costa, TJ., Linder, BA., Hester, S., et al.[2023]

In a study involving 20 patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH), infusion of the ketone body 3-hydroxybutyrate (3-OHB) significantly improved cardiac output by 27% and reduced pulmonary vascular resistance by 18%.

Experimental studies in rats showed that 3-OHB administration relaxed pulmonary arteries without increasing right ventricular pressures, suggesting a potential mechanism for its beneficial effects in PAH and CTEPH patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemodynamic Effects of Ketone Bodies in Patients With Pulmonary Hypertension. Nielsen, R., Christensen, KH., Gopalasingam, N., et al.[2023]

Ingesting a pre-workout supplement containing beta-hydroxybutyrate (BHB) salts, caffeine, and amino acids significantly improved high-intensity exercise performance, increasing time to exhaustion by about 8.3% in Keto-Naïve and 9.8% in Keto-Adapted individuals.

The supplement led to a rapid increase in circulating BHB levels, which remained elevated during recovery, indicating effective metabolism of the supplement in both dietary groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pre-Workout Supplement of Ketone Salts, Caffeine, and Amino Acids Improves High-Intensity Exercise Performance in Keto-Naïve and Keto-Adapted Individuals. Kackley, ML., Short, JA., Hyde, PN., et al.[2021]

In a study comparing two formulations of beta-hydroxybutyrate (βOHB) on cardiac myocytes, R βOHB was found to prolong action potential duration, while the racemic mixture ±βOHB shortened it, indicating that the effects of βOHB on heart cells are stereoselective.

Both formulations of βOHB influenced calcium transients differently, with ±βOHB increasing peak calcium levels and R βOHB reducing them, suggesting that βOHB has roles beyond being just an energy source, potentially impacting heart cell function in significant ways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential Effects of Beta-Hydroxybutyrate Enantiomers on Induced Pluripotent Stem Derived Cardiac Myocyte Electrophysiology. Klos, ML., Hou, W., Nsengimana, B., et al.[2022]

3-hydroxybutyrate (3-OHB) significantly increases cardiac output and stroke volume in rats without affecting heart rate or blood pressure, suggesting it enhances heart function directly.

3-OHB also relaxes various blood vessels, lowering systemic vascular resistance, which contributes to its potential therapeutic benefits in managing heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketone body 3-hydroxybutyrate elevates cardiac output through peripheral vasorelaxation and enhanced cardiac contractility. Homilius, C., Seefeldt, JM., Axelsen, JS., et al.[2023]

The engineered E. coli strain (E. coli DF) demonstrated a highly efficient biocatalytic process, converting 73.4 mM of 2-oxo-4-phenylbutyric acid (OPBA) to 71.8 mM of (R)-HPBA in just 90 minutes, achieving a productivity of 47.9 mM per hour.

This biocatalytic method produced (R)-HPBA with an enantiomeric excess greater than 99%, indicating its potential as a superior alternative for synthesizing this important precursor for angiotensin-converting enzyme inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficient production of (R)-2-hydroxy-4-phenylbutyric acid by using a coupled reconstructed D-lactate dehydrogenase and formate dehydrogenase system. Sheng, B., Zheng, Z., Lv, M., et al.[2021]

In a study involving 12 healthy individuals, all tested ketone supplements raised blood β-OHB levels, with the highest increase observed after consuming the ketone monoester, indicating its superior efficacy in elevating ketone levels.

All supplements effectively lowered blood glucose levels without significant differences between them, but the D-β-hydroxybutyric acid with R-1,3-butanediol was the most acceptable to participants, showing promise for better adherence due to reduced gastrointestinal discomfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Novel Exogenous Ketone Supplements on Blood Beta-Hydroxybutyrate and Glucose. Falkenhain, K., Daraei, A., Little, JP.[2023]

Oral consumption of D/L-3-hydroxybutyrate (D/L-3-OHB) significantly stimulates the release of cholecystokinin and increases insulin and C-peptide levels, indicating its role in gut signaling and metabolic regulation.

The study found that D/L-3-OHB slows gastric emptying compared to intravenous administration, highlighting the distinct effects of oral ketone supplements versus physiological ketosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral D/L-3-Hydroxybutyrate Stimulates Cholecystokinin and Insulin Secretion and Slows Gastric Emptying in Healthy Males. Rittig, N., Svart, M., Thomsen, HH., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6542293/

Salt-Responsive Metabolite, β-Hydroxybutyrate, Attenuates ... High salt diet reduces the ketone body beta-hydroxybutyrate (βOHB). Reduced βOHB results in increased renal Nlrp3 inflammasome activity in hypertension.

2. sciencedirect.com sciencedirect.com/science/article/pii/S2452302X25002803

Ketone Bodies in Cardiovascular Disease Cardiac effects of KBs include improving cardiac energetics, ameliorating pathological remodeling, and enhancing cardiac function. Systemic metabolic effects of ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9733433/

The janus face of ketone bodies in hypertension - PMC We propose that ketone supplements warrant investigation as low-dose antihypertensive therapy that decreases total peripheral resistance with minimal adverse ...

4. nature.com nature.com/articles/s44161-023-00259-1

Ketones and the cardiovascular system ... βOHB concentrations in the circulation, resulted in improved kidney function and lowered blood pressure following high salt intake.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05477368?term=NCT05477368&rank=1

Examining the Feasibility of Prolonged Ketone Supplement ... These supplements can raise blood ketones without having to fast or eat a "keto" diet. Previous studies have shown that these supplement drinks can lower blood ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8932950/

Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts - PMC A recent study demonstrated that elevated plasma β-OHB level might serve as a potential predictor of major adverse cardiovascular events (MACEs) in probands and ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05273411

The Effect of Different Ketone Supplements on β-OHB and ... The main objective of this study is to determine the effect of three different ketone supplements on blood ketones and blood glucose. The results of this pilot ...

8. efsa.onlinelibrary.wiley.com efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2022.7449

Safety of β‐hydroxybutyrate salts as a novel food pursuant to ... The NF consists of sodium, magnesium and calcium BHB salts, and is proposed to be used by adults as a food ingredient in a number of food categories and as ...