Ketone Ester for Metabolic Syndrome

Overseen By Dimitrios I Kapogiannis, M.D.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: National Institute on Aging (NIA)

Must be taking: Triglycerides, HDL, Blood pressure, Glucose

Must not be taking: Metformin

Disqualifiers: Cognitive impairment, Brain disorders, Psychiatric conditions, HIV, Pregnancy, others

Compensation: Varies

Number of Visits: 6

Duration: 28 days

150 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: In Alzheimer s disease (AD) the brain cannot use glucose as a fuel. The brain can use ketones as a fuel instead of glucose. Researchers want to test a supplement, Ketone Ester (KE). It may improve brain metabolic function and cognition in normal people and, perhaps, down the road, in patients with AD. Objective: To study the change in brain ketone levels in people after 28 days of taking KE compared with baseline and placebo. Also, to study changes in cognitive performance. Eligibility: People 55 years old or older with metabolic syndrome and no cognitive impairment Design: Participants will have 4 visits. Participants will be screened at Visit 1 with: Medical history Physical exam Blood and urine tests Cognitive testing Participants will be randomly assigned to receive either the study supplement or a placebo with same amount of calories. Neither they nor the researchers will know which they receive. Visit 2 will include repeats of some screening tests. It will also include: Stool sample (brought from home) MRI/MRS: Participants will lie on a table that slides in and out of a scanner. A coil will be placed over their head. They may be asked to perform leg exercises. First dose of study supplement or placebo About 2 weeks after Visit 2, Visit 3 will include blood and urine tests and a questionnaire. About 2 weeks after Visit 3, Visit 4 will include repeats of the Visit 2 tests. Participants will drink the study supplement or placebo 3 times per day during the study. They will keep a daily log of each dose. They will bring the log to Visits 3 and 4. Participants will by contacted by phone once per week during the study to see how they are doing.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are taking metformin or following a ketogenic diet or taking other ketogenic supplements.

What data supports the effectiveness of the treatment HVMN Ketone Esther drink for metabolic syndrome?

Research suggests that ketone monoesters, like those in the HVMN Ketone Esther drink, can quickly raise blood ketone levels, which may help improve metabolism and lower blood sugar levels. This could potentially benefit conditions related to metabolic syndrome, such as obesity and cardiovascular issues, by reducing inflammation and improving vascular function. ^{1 2 3 4 5}

Is the ketone ester treatment safe for humans?

Research shows that ketone ester drinks are generally safe and well-tolerated in healthy adults, with only mild gastrointestinal effects reported in some cases. Studies have found no significant changes in vital signs or lab measurements, even with prolonged use. ^{2 4 5 6 7}

How does the ketone ester drink treatment differ from other treatments for metabolic syndrome?

The ketone ester drink is unique because it quickly raises blood ketone levels without the need for a high-fat diet, potentially improving metabolism and lowering blood sugar, which can help manage metabolic syndrome. ^{1 2 4 8 9}

Research Team

Dimitrios I Kapogiannis, M.D.

Principal Investigator

National Institute on Aging (NIA)

Eligibility Criteria

Adults aged 55 or older with metabolic syndrome but no cognitive impairment can join this study. They must be able to consent, take oral meds, and follow the study plan including MRI/MRS scans. Excluded are those with significant psychiatric conditions, certain infections, on metformin or non-English speakers.

Inclusion Criteria

I am 55 years old or older.

I can take pills by mouth.

Ability to provide informed consent and willingness to sign a written informed consent document

Exclusion Criteria

Participant has any concurrent medical condition, so that participation in the clinical study would not be in her/his best interest, in the PI s judgement

I have diabetes (type 1 or 2).

I am on a ketogenic or very low calorie diet, or taking ketogenic supplements, and unwilling to stop while on the trial.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Treatment

Participants receive the study supplement or placebo for 28 days, with assessments at Visits 2, 3, and 4

28 days

4 visits (in-person), weekly phone calls

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a follow-up visit to obtain DNA

1 visit

1 visit (in-person)

Treatment Details

Interventions

• HVMN Ketone Esther drink
• Ketone Ester drink
• Placebo: isocaloric dextrose drink

Trial Overview The trial is testing if a Ketone Ester (KE) drink improves brain metabolism and cognition compared to a placebo in healthy adults. Participants will not know which they're getting and will have multiple visits for tests like MRIs and cognitive assessments over 28 days.

Participant Groups

Group I: Ketone Ester drink/ Arm 1 Active Control 1 Intervention

25 participants

Group II: Placebo/ Arm 2 Placebo Group 1 Intervention

25 participants

HVMN Ketone Esther drink is already approved in United States for the following indications:

Approved in United States as Ketone Ester for:

• Research use for cognitive enhancement and Alzheimer's disease prevention

Who Is Running the Clinical Trial?

National Institute on Aging (NIA)

Lead Sponsor

Trials

1,841

Recruited

28,150,000+

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 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 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 involving 14 adults with obesity, a ketone monoester (KME) drink significantly reduced postprandial glucose levels by 8.0% compared to a placebo, indicating its potential to improve glucose control.

KME supplementation also enhanced vascular function, as shown by an increase in brachial artery flow-mediated dilation, and was well tolerated by participants, suggesting it could be a safe, nonpharmacological strategy for improving cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

14-Day Ketone Supplementation Lowers Glucose and Improves Vascular Function in Obesity: A Randomized Crossover Trial. Walsh, JJ., Neudorf, H., Little, JP.[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]

Exogenous ketone drinks, both monoester and salt forms, can cause mild gastrointestinal symptoms, with symptom severity influenced by the dose and type of drink consumed, as well as whether the individual is at rest or exercising.

High-dose ketone salt drinks resulted in more gastrointestinal symptoms compared to low-dose versions, but overall, symptoms were acute and resolved by the end of the study, indicating that while they may cause discomfort, they are generally tolerable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal Effects of Exogenous Ketone Drinks are Infrequent, Mild, and Vary According to Ketone Compound and Dose. Stubbs, BJ., Cox, PJ., Kirk, T., 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]

In a study involving 14 healthy young adults, both ketone monoester (KME) and ketone monoester/salt (KMES) formulations significantly increased circulating R-beta-hydroxybutyrate (R-βHB) levels in a dose-dependent manner, with KME10 reaching a peak concentration of 2.4 mM after 15 minutes.

Both formulations were well-tolerated, but KMES was slightly more acceptable due to a better taste, while KME was associated with a more frequent decrease in appetite, indicating that user experience may vary between different ketone products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans. Bolyard, ML., Graziano, CM., Fontaine, KR., et al.[2023]

Exogenous ketone drinks, such as ketone esters and ketone salts, effectively raise blood D-β-hydroxybutyrate (D-βHB) levels, with significant increases observed in a study of 15 participants, indicating a practical alternative to traditional ketogenic diets.

Both types of ketone drinks lowered blood glucose and triglyceride levels without causing adverse effects on blood electrolytes, suggesting they are safe and beneficial for metabolic health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

On the Metabolism of Exogenous Ketones in Humans. Stubbs, BJ., Cox, PJ., Evans, RD., et al.[2022]

References

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

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

2. Netherlands pubmed.ncbi.nlm.nih.gov

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

3. England pubmed.ncbi.nlm.nih.gov

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

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

14-Day Ketone Supplementation Lowers Glucose and Improves Vascular Function in Obesity: A Randomized Crossover Trial. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Gastrointestinal Effects of Exogenous Ketone Drinks are Infrequent, Mild, and Vary According to Ketone Compound and Dose. [2021]

7. Switzerland 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. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

On the Metabolism of Exogenous Ketones in Humans. [2022]