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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a supplement called Ketone Ester (KE) to determine its potential to boost brain function and improve thinking skills. The focus is on individuals with metabolic syndrome, a condition that includes high blood pressure or high blood sugar, who have no memory or thinking problems. Participants will take either the KE supplement or a placebo (a harmless substance resembling the supplement) for 28 days to compare changes in brain energy use and thinking skills. Those with metabolic syndrome and no cognitive issues may find this trial suitable. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research on brain health and metabolic syndrome.

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.

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

Research has shown that ketone esters are generally safe for most people. In studies comparing different ketone supplements, participants typically did not report major side effects. Instead, they experienced benefits such as increased energy and improved focus. However, some individuals might experience mild stomach discomfort, a common reaction to new dietary supplements.

One study found that ketone esters can induce a state called ketosis, where the body uses ketones for energy instead of sugar, without causing harmful changes in blood fat levels. Research supports the safety of ketone esters.

Evidence also indicates that ketone esters can enhance athletic performance and mental clarity. Overall, existing research suggests that ketone esters are safe when taken as directed, though individual reactions may vary. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Unlike standard treatments for metabolic syndrome, which often include lifestyle changes and medications like statins and antihypertensives, the Ketone Ester drink offers a unique approach by utilizing ketone esters as an active ingredient. Ketone esters provide an alternative energy source that can improve metabolic efficiency and potentially aid in weight management, a critical aspect of addressing metabolic syndrome. Researchers are excited about this treatment because it targets the metabolic pathways directly, potentially offering benefits in energy utilization and reduction of risk factors associated with metabolic syndrome.

What evidence suggests that Ketone Ester might be an effective treatment for metabolic syndrome?

Research has shown that ketone esters can provide the brain with an alternative energy source, especially when it cannot use glucose effectively. In this trial, one group of participants will receive the Ketone Ester drink, which studies have found might boost brain function by supplying a steady energy source. This is particularly important for conditions like Alzheimer's, where the brain struggles to use glucose. Early findings also suggest that ketone esters can help control blood sugar levels, benefiting those with metabolic issues. Although specific data on brain improvements in Alzheimer's is limited, the positive results in brain function and blood sugar management suggest potential benefits. ^{1 2 3 6 7}

Who Is on the Research Team?

Dimitrios I Kapogiannis, M.D.

Principal Investigator

National Institute on Aging (NIA)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9734240/

Exogenous Ketone Supplements in Athletic Contexts Some studies have suggested beneficial effects of EKS to endurance performance, recovery, and overreaching, although many studies have failed to observe ...

2. amazon.com amazon.com/KetoneAid-Worlds-Strongest-Exogenous-Caffeine/dp/B07S7F9X9Z

KetoneAid Ke4 Ketone Ester Concentrate Provides clean energy for athletic performance, mental clarity, metabolic health, and deep sleep; 12 servings per bottle, 2.5 grams of Ketone Ester (d-bhb ...

3. trialx.com trialx.com/clinical-trials/listings/251708/the-metabolic-effects-of-hydroxybutyrate-on-working-skeletal-muscle/

The Metabolic Effects of β-hydroxybutyrate on Working Skeletal ... OBJECTIVE The study aims to investigate the effects of beta-hydroxybutyrate ingested as a monoester on skeletal muscle function and metabolism during muscle ...

4. digitalcommons.library.uab.edu digitalcommons.library.uab.edu/cgi/viewcontent.cgi?article=1457&context=etd-collection

Acceptability and Tolerability of Ketone Supplements and ... The study compared two ketone supplements, KME and KME+S, at two doses. KME+S was more acceptable, but KME had more aftertaste. KME+S may be more cost- ...

5. researchgate.net researchgate.net/publication/325996321_Intermittent_Running_and_Cognitive_Performance_after_Ketone_Ester_Ingestion

Intermittent Running and Cognitive Performance after ... The results obtained show that consuming a ketone monoester supplement 30 min prior to an OGTT reduced the glycaemic response and markers of ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4173993/

Ketone ester effects on metabolism and transcription - PMC Feeding ketone body esters leads to pure ketosis, unaccompanied by elevation of free fatty acids, producing a physiological state not previously seen in nature.

7. ketone.com ketone.com/blogs/blog/exogenous-ketones-ketoneaid-vs-hvmn-ketone-ester?srsltid=AfmBOop3x5sBcC-FDrr46Uem6dwfatgG7E624zX-_VduxR35NVU27FLG

KetoneAid vs. H.V.M.N. Ketone Ester KetoneAid vs. H.V.M.N: Compare two top ketone esters for energy, focus, and endurance. Which exogenous ketone supplement delivers the best performance?