Ketone Supplements for High Blood Pressure

(KEAS Trial)

Overseen By Braxton A Linder, MS

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Auburn University

Must not be taking: Pradaxa, Eliquis

Disqualifiers: Hypertension, Cancer, Diabetes, Obesity, others

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

Compensation: Varies

Number of Visits: 2

Duration: 10 days

35 Participants Needed

Trial Summary

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 it safe to use ketone supplements for high blood pressure?

Research on ketone supplements, like β-Hydroxybutyric acid, shows they can increase heart function and relax blood vessels without significantly affecting blood pressure. However, some people may experience unpleasant taste or mild stomach discomfort, but no serious safety concerns have been reported in healthy individuals. ^{1 2 3 4 5}

How does the treatment β-OHB for high blood pressure differ from other treatments?

The treatment β-OHB (a ketone body) is unique because it may lower blood pressure by reducing vascular resistance and improving heart function without the side effects often associated with traditional blood pressure medications. This approach is novel as it uses a natural metabolite to potentially improve vascular health and manage hypertension. ^{1 2 6 7 8}

What is the purpose of this trial?

Most Americans consume excess dietary salt based on the recommendations set by the American Heart Association and Dietary Guidelines for Americans. High dietary salt impairs the ability of systemic blood vessels and the kidneys to control blood pressure, which contributes to excess salt consumption being associated with increased risk for chronic kidney disease and cardiovascular disease, the leading cause of death in America. There is a critical need for strategies to counteract the effects of high dietary salt as consumption is likely not going to decrease. One promising option is ketones, metabolites that are produced in the liver during prolonged exercise and very low-calorie diets. While exercise and low-calorie diets are beneficial, not many people engage in these activities. However, limited evidence indicates that ketone supplements improve cardiovascular health in humans. Additionally published rodent data indicates that ketone supplements prevent high salt-induced increases in blood pressure, blood vessel dysfunction, and kidney injury. Our human pilot data also indicates that high dietary salt reduces intrinsic ketone production, but it is unclear whether ketone supplementation confers humans protection against high salt similar to rodents. Therefore, the investigators seek to conduct a short-term high dietary salt study to determine whether ketone supplementation prevents high dietary salt from eliciting increased blood pressure, blood vessel dysfunction, and kidney injury/impaired blood flow. The investigators will also measure inflammatory markers in blood samples and isolate immune cells that control inflammation. Lastly, the investigators will also measure blood ketone concentration and other circulating metabolites that may be altered by high salt, which could allow us to determine novel therapeutic targets to combat high salt.

Research Team

Austin T Robinson, PhD

Principal Investigator

Auburn University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: High Salt, High β-OHB Experimental Treatment 1 Intervention

Participants will consume the supplemental intervention for 10 days. On day 10 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. Starting on day 9, participants will undergo ambulatory blood pressure monitoring and 24-hour urine collection.

Group II: High Salt, No β-OHB Active Control 1 Intervention

Participants will consume the supplemental intervention for 10 days. On day 10 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. Starting on day 9, participants will undergo ambulatory blood pressure monitoring and 24-hour urine collection.

Group III: No Salt, No β-OHB Placebo Group 1 Intervention

Participants will consume the supplemental intervention for 10 days. On day 10 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. Starting on day 9, participants will undergo ambulatory blood pressure monitoring and 24-hour urine collection.

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?

Auburn University

Lead Sponsor

Trials

81

Recruited

14,600+

University of Utah

Collaborator

Trials

1,169

Recruited

1,623,000+

Indiana University

Collaborator

Trials

1,063

Recruited

1,182,000+

University of Missouri-Columbia

Collaborator

Trials

387

Recruited

629,000+

Findings from Research

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]

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]

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]

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]

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 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]

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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Ketone body 3-hydroxybutyrate elevates cardiac output through peripheral vasorelaxation and enhanced cardiac contractility. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Oral D/L-3-Hydroxybutyrate Stimulates Cholecystokinin and Insulin Secretion and Slows Gastric Emptying in Healthy Males. [2021]

3. United States 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. [2021]

4. England pubmed.ncbi.nlm.nih.gov

The Effect of Novel Exogenous Ketone Supplements on Blood Beta-Hydroxybutyrate and Glucose. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Differential Effects of Beta-Hydroxybutyrate Enantiomers on Induced Pluripotent Stem Derived Cardiac Myocyte Electrophysiology. [2022]

6. United States 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. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Hemodynamic Effects of Ketone Bodies in Patients With Pulmonary Hypertension. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

The janus face of ketone bodies in hypertension. [2023]