Ketone Ester for Metabolic Syndrome
Recruiting in Palo Alto (17 mi)
Overseen byDimitrios I Kapogiannis, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
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
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.
12345Is 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.
24567How 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.
12489Eligibility 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
+3 more
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.
+16 more
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)
Participant Groups
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.
2Treatment groups
Active Control
Placebo Group
Group I: Ketone Ester drink/ Arm 1Active Control1 Intervention
25 participants
Group II: Placebo/ Arm 2Placebo Group1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institute of Aging, Clinical Research UnitBaltimore, MD
Loading ...
Who Is Running the Clinical Trial?
National Institute on Aging (NIA)Lead Sponsor
References
Why a d-β-hydroxybutyrate monoester? [2020]Much of the world's prominent and burdensome chronic diseases, such as diabetes, Alzheimer's, and heart disease, are caused by impaired metabolism. By acting as both an efficient fuel and a powerful signalling molecule, the natural ketone body, d-β-hydroxybutyrate (βHB), may help circumvent the metabolic malfunctions that aggravate some diseases. Historically, dietary interventions that elevate βHB production by the liver, such as high-fat diets and partial starvation, have been used to treat chronic disease with varying degrees of success, owing to the potential downsides of such diets. The recent development of an ingestible βHB monoester provides a new tool to quickly and accurately raise blood ketone concentration, opening a myriad of potential health applications. The βHB monoester is a salt-free βHB precursor that yields only the biologically active d-isoform of the metabolite, the pharmacokinetics of which have been studied, as has safety for human consumption in athletes and healthy volunteers. This review describes fundamental concepts of endogenous and exogenous ketone body metabolism, the differences between the βHB monoester and other exogenous ketones and summarises the disease-specific biochemical and physiological rationales behind its clinical use in diabetes, neurodegenerative diseases, heart failure, sepsis related muscle atrophy, migraine, and epilepsy. We also address the limitations of using the βHB monoester as an adjunctive nutritional therapy and areas of uncertainty that could guide future research.
Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. [2022]Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of β-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714 mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1-2h, reaching 3.30 mM and 1.19 mM for β-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8-3.1h for β-hydroxybutyrate and 8-14 h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714 mg/kg body weight, three times daily, over 5 days (equivalent to 0.42, 1.07, and 2.14 g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet.
The Effect of Novel Exogenous Ketone Supplements on Blood Beta-Hydroxybutyrate and Glucose. [2023]Exogenous ketone monoesters can raise blood β-OHB and lower glucose without other nutritional modifications or invasive procedures. However, unpleasant taste and potential gastrointestinal discomfort may make adherence to supplementation challenging. Two novel ketone supplements promise an improved consumer experience but differ in their chemical properties; it is currently unknown how these affect blood β-OHB and blood glucose compared to the ketone monoester. In a double-blind randomized cross-over pilot study, N=12 healthy individuals (29 ± 5 years, BMI = 25 ± 4 kg/m2, 42% female) participated in three experimental trials with a different ketone supplement providing 10 grams of active ingredient in each; (i) the monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, (ii) D-β-hydroxybutyric acid with R-1,3-butanediol, and (iii) R-1,3-butanediol. Blood β-OHB and glucose were measured via finger prick capillary blood samples at baseline and across 240 minutes post-supplementation. Supplement acceptability, hunger, and gastrointestinal distress were assessed via questionnaires. β-OHB was elevated compared to baseline in all conditions. Total and incremental area under the curve (p < 0.05) and peak β-OHB (p  < 0.001) differed between conditions with highest values seen in the ketone monoester condition. Blood glucose was reduced after consumption of each supplement, with no differences in total and incremental area under the curve across supplements. Supplement acceptability was greatest for D-β-hydroxybutyric acid with R-1,3-butanediol, with no effect on hunger or evidence of gastrointestinal distress across all supplements. All ketone supplements tested raised β-OHB with highest values seen after ketone monoester ingestion. Blood glucose was lowered similarly across the assessed time frame with all three supplements.
14-Day Ketone Supplementation Lowers Glucose and Improves Vascular Function in Obesity: A Randomized Crossover Trial. [2021]Postprandial hyperglycemia increases systemic inflammation and is a risk factor for cardiovascular disease. A ketone monoester (KME) drink containing β-hydroxybutyrate (β-OHB) rapidly lowers plasma glucose, which may be a strategy protecting against postprandial hyperglycemia.
Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. [2020]Throughout history, the only way humans could raise their blood ketone levels was by several days of fasting or by following a strict low-carb, high-fat diet. A recently developed, dietary source of ketones, a ketone monoester, elevates d-β-hydroxybutyrate (βHB) to similar concentrations within minutes, with βHB remaining raised for several hours. To date, the longest human safety study of the exogenous ketone ester was for 5 days, but longer consumption times may be desired. Here we report results for 24 healthy adults, aged 18-70 years, who drank 25 ml (26.8 g) of the ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, three times a day for 28 days (a total of 2.1 L). Anthropomorphic measurements, plus fasting blood and urine analyses were made weekly. It was found that elevating blood βHB concentrations from 0.1 to 4.1 (±1.1) mM three times a day for 28 days had no effect on body weights or composition, fasting blood glucose, cholesterol, triglyceride or electrolyte concentrations, nor blood gases or kidney function, which were invariably normal. Mild nausea was reported following 6 of the 2,016 drinks consumed. We conclude that sustained exogenous ketosis using a ketone monoester is safe and well-tolerated by healthy adults.
Gastrointestinal Effects of Exogenous Ketone Drinks are Infrequent, Mild, and Vary According to Ketone Compound and Dose. [2021]Exogenous ketone drinks may improve athletic performance and recovery, but information on their gastrointestinal tolerability is limited. Studies to date have used a simplistic reporting methodology that inadequately represents symptom type, frequency, and severity. Herein, gastrointestinal symptoms were recorded during three studies of exogenous ketone monoester (KME) and salt (KS) drinks. Study 1 compared low- and high-dose KME and KS drinks consumed at rest. Study 2 compared KME with isocaloric carbohydrate (CHO) consumed at rest either when fasted or after a standard meal. Study 3 compared KME+CHO with isocaloric CHO consumed before and during 3.25 hr of bicycle exercise. Participants reported symptom type and rated severity between 0 and 8 using a Likert scale at regular intervals. The number of visits with no symptoms reported after ketone drinks was n = 32/60 in Study 1, n = 9/32 in Study 2, and n = 20/42 in Study 3. Following KME and KS drinks, symptoms were acute but mild and were fully resolved by the end of the study. High-dose KS drinks caused greater total-visit symptom load than low-dose KS drinks (13.8 ± 4.3 vs. 2.0 ± 1.0; p
Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults. [2021]Nutritional ketosis is a state of mildly elevated blood ketone concentrations resulting from dietary changes (e.g., fasting or reduced carbohydrate intake) or exogenous ketone consumption. In this study, we determined the tolerability and safety of a novel exogenous ketone diester, bis-hexanoyl-(R)-1,3-butanediol (BH-BD), in a 28-day, randomized, double-blind, placebo-controlled, parallel trial (NCT04707989). Healthy adults (n = 59, mean (SD), age: 42.8 (13.4) y, body mass index: 27.8 (3.9) kg/m2) were randomized to consume a beverage containing 12.5 g (Days 0-7) and 25 g (Days 7-28) of BH-BD or a taste-matched placebo daily with breakfast. Tolerability, stimulation, and sedation were assessed daily by standardized questionnaires, and blood and urine samples were collected at Days 0, 7, 14, and 28 for safety assessment. There were no differences in at-home composite systemic and gastrointestinal tolerability scores between BH-BD and placebo at any time in the study, or in acute tolerability measured 1-h post-consumption in-clinic. Weekly at-home composite tolerability scores did not change when BH-BD servings were doubled. At-home scores for stimulation and sedation did not differ between groups. BH-BD significantly increased blood ketone concentrations 1-h post-consumption. No clinically meaningful changes in safety measures including vital signs and clinical laboratory measurements were detected within or between groups. These results support the overall tolerability and safety of consumption of up to 25 g/day BH-BD.
Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans. [2023]Exogenous ketone ester and ketone ester mixed with ketone free acid formulations are rapidly entering the commercial marketspace. Short-term animal and human studies using these products suggest significant potential for primary or secondary prevention of a number of chronic disease conditions. However, a number of questions need to be addressed by the field for optimal use in humans, including variable responses among available exogenous ketones at different dosages; frequency of dosing; and their tolerability, acceptability, and efficacy in long-term clinical trials. The purpose of the current investigation was to examine the tolerability, acceptability, and circulating R-beta-hydroxybutyrate (R-βHB) and glucose responses to a ketone monoester (KME) and ketone monoester/salt (KMES) combination at 5 g and 10 g total R-βHB compared with placebo control (PC). Fourteen healthy young adults (age: 21 ± 2 years, weight: 69.7 ± 14.2 kg, percent fat: 28.1 ± 9.3%) completed each of the five study conditions: placebo control (PC), 5 g KME (KME5), 10 g KME (KME10), 5 g (KMES5), and 10 g KMES (KMES10) in a randomized crossover fashion. Circulating concentrations of R-βHB were measured at baseline (time 0) following an 8-12 h overnight fast and again at 15, 30, 60, and 120 min following drink ingestion. Participants also reported acceptability and tolerability during each condition. Concentrations of R-βHB rose to 2.4 ± 0.1 mM for KME10 after 15 min, whereas KMES10 similarly peaked (2.1 ± 0.1 mM) but at 30 min. KME5 and KMES5 achieved similar peak R-βHB concentrations (1.2 ± 0.7 vs. 1.1 ± 0.5 mM) at 15 min. Circulating R-βHB concentrations were similar to baseline for each condition by 120 min. Negative correlations were observed between R-βHB and glucose at the 30 min time point for each condition except KME10 and PC. Tolerability was similar among KME and KMES, although decreases in appetite were more frequently reported for KMES. Acceptability was slightly higher for KMES due to the more frequently reported aftertaste for KME. The results of this pilot investigation illustrate that the KME and KMES products used increase circulating R-βHB concentrations to a similar extent and time course in a dose-dependent fashion with slight differences in tolerability and acceptability. Future studies are needed to examine variable doses, frequency, and timing of exogenous ketone administration for individuals seeking to consume ketone products for health- or sport performance-related purposes.
On the Metabolism of Exogenous Ketones in Humans. [2022]Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate "ketogenic" diet, but adherence to such diets can be difficult. An alternative way to increase blood D-β-hydroxybutyrate (D-βHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium βHB. Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of βHB. Both drinks elevated blood D-βHB concentrations (D-βHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3-4 h. KS drinks were found to contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-βHB and L-βHB was <1.5% of the total βHB ingested and was in proportion to the blood AUC. D-βHB, but not L-βHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-βHB concentrations was determined in 16 participants. Food lowered blood D-βHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-βHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-βHB AUC of 1.3-1.4 moles.min. Conclusion: We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis.