Ketone Supplement for Heart Failure
Recruiting in Palo Alto (17 mi)
Overseen byYuchi Han, MD, MMSc
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Ohio State University
Must not be taking: SGLT2 inhibitors
Disqualifiers: Type I diabetes, Severe kidney disease, Recent myocardial infarction, others
Trial Summary
What is the purpose of this trial?This study is being done to evaluate how a ketone ester (KE) beverage affects heart function and health in people with heart failure compared to a placebo beverage (a beverage made with standard food ingredients that do not contain ketone esters).
Will I have to stop taking my current medications?
The trial requires that your current heart and diabetes medications have been stable for at least 3 months before joining, and the dosage should not change for 1 month before starting. However, you can reduce or stop these medications during the study if needed. Changes in oral diuretics are allowed but must be stable for 1 week before starting the trial.
What data supports the effectiveness of the treatment Ketone Ester for heart failure?
Research suggests that ketone esters can improve heart function in heart failure by providing an additional energy source for the heart, which is often energy-starved in this condition. Studies in animals and some human trials have shown that increasing ketone levels can help the heart work better, especially in heart failure with reduced ejection fraction (a measure of how well the heart pumps blood).
12345Is the ketone supplement safe for humans?
Research shows that ketone supplements, like ketone esters, are generally safe and well-tolerated in healthy adults, with no significant changes in vital signs or lab tests, although mild nausea was occasionally reported.
16789How is the ketone ester treatment different from other heart failure treatments?
Ketone ester treatment is unique because it provides an additional energy source for the heart by increasing ketone body levels, which can improve heart function in heart failure. Unlike traditional treatments that focus on neurohormonal and hemodynamic factors, this approach targets the heart's metabolism directly, potentially offering benefits in cases where other treatments may not be as effective.
123410Eligibility Criteria
Adults aged 18-80 with heart failure, BMI of 25-50 or Type II Diabetes/prediabetes, stable heart and diabetes medications for at least 3 months, and able to do treadmill tests. Excludes those with recent major surgeries, certain heart conditions like transplants or severe arrhythmias, pregnant women, drug/alcohol abuse history, severe kidney disease, uncontrolled blood pressure or life expectancy less than a year.Inclusion Criteria
I have had heart condition symptoms that are not the most severe for at least 3 months.
I have a BMI between 25 and 50, or I have Type II Diabetes, prediabetes, or metabolic syndrome.
Your heart function and blood pressure in your lungs are not within normal range.
+6 more
Exclusion Criteria
Criterion: You are allergic to Gadolinium-based contrast agents.
You have metal implants or aneurysm clips that are not safe for MRI scans.
Your heart's pumping ability is less than 50%.
+35 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment Phase 1
Participants consume the Ketone Ester or Placebo beverage twice daily for 6 weeks
6 weeks
Daily monitoring of blood markers, blood pressure, heart rate, and overall health
Washout
Participants undergo a 4-week washout period before crossing over to the other group
4 weeks
Treatment Phase 2
Participants crossover to the other group and consume the Ketone Ester or Placebo beverage twice daily for another 6 weeks
6 weeks
Daily monitoring of blood markers, blood pressure, heart rate, and overall health
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing the effects of a ketone ester beverage on exercise tolerance and cardiac function in people with heart failure. Participants will be randomly assigned to receive either the ketone ester drink or a placebo (a non-ketone standard beverage) to compare outcomes.
4Treatment groups
Experimental Treatment
Placebo Group
Group I: Ketone EsterExperimental Treatment1 Intervention
This arm will provide a Keto Ester Beverage for consumption.
Group II: Keto Ester AcuteExperimental Treatment1 Intervention
This arm will provide a Keto Ester Beverage for consumption.
Group III: PlaceboPlacebo Group1 Intervention
This arm will provide a Placebo Beverage for consumption.
Group IV: Placebo AcutePlacebo Group1 Intervention
This arm will provide a Placebo Beverage for consumption.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
The Ross Heart HospitalColumbus, OH
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Who Is Running the Clinical Trial?
Ohio State UniversityLead Sponsor
References
Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure. [2021]Accumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and that increasing cardiac ketone delivery ameliorates cardiac dysfunction. As an initial step toward development of ketone therapies, we investigated the effect of chronic oral ketone ester (KE) supplementation as a prevention or treatment strategy in rodent heart failure models.
Ketone metabolism in the failing heart. [2021]The high energy demands of the heart are met primarily by the mitochondrial oxidation of fatty acids and glucose. However, in heart failure there is a decrease in cardiac mitochondrial oxidative metabolism and glucose oxidation that can lead to an energy starved heart. Ketone bodies are readily oxidized by the heart, and can provide an additional source of energy for the failing heart. Ketone oxidation is increased in the failing heart, which may be an adaptive response to lessen the severity of heart failure. While ketone have been widely touted as a "thrifty fuel", increasing ketone oxidation in the heart does not increase cardiac efficiency (cardiac work/oxygen consumed), but rather does provide an additional fuel source for the failing heart. Increasing ketone supply to the heart and increasing mitochondrial ketone oxidation increases mitochondrial tricarboxylic acid cycle activity. In support of this, increasing circulating ketone by iv infusion of ketone bodies acutely improves heart function in heart failure patients. Chronically, treatment with sodium glucose co-transporter 2 inhibitors, which decreases the severity of heart failure, also increases ketone body supply to the heart. While ketogenic diets increase circulating ketone levels, minimal benefit on cardiac function in heart failure has been observed, possibly due to the fact that these dietary regimens also markedly increase circulating fatty acids. Recent studies, however, have suggested that administration of ketone ester cocktails may improve cardiac function in heart failure. Combined, emerging data suggests that increasing cardiac ketone oxidation may be a therapeutic strategy to treat heart failure.
Longitudinal Changes in Circulating Ketone Body Levels in Patients With Acute Heart Failure: A Post Hoc Analysis of the EMPA-Response-AHF Trial. [2023]Ketone bodies are endogenous fuels produced by the liver under conditions of metabolic or neurohormonal stress. Circulating ketone bodies are increased in patients with chronic heart failure (HF), yet little is known about the effect of acute HF on ketosis. We tested the hypothesis that ketogenesis is increased in patients with acute decompensated HF.
Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure. [2021]Despite existing therapy, patients with heart failure (HF) experience substantial morbidity and mortality, highlighting the urgent need to identify novel pathophysiological mechanisms and therapies, as well. Traditional models for pharmacological intervention have targeted neurohormonal axes and hemodynamic disturbances in HF. However, several studies have now highlighted the potential for ketone metabolic modulation as a promising treatment paradigm. During the pathophysiological progression of HF, the failing heart reduces fatty acid and glucose oxidation, with associated increases in ketone metabolism. Recent studies indicate that enhanced myocardial ketone use is adaptive in HF, and limited data demonstrate beneficial effects of exogenous ketone therapy in studies of animal models and humans with HF. This review will summarize current evidence supporting a salutary role for ketones in HF including (1) normal myocardial ketone use, (2) alterations in ketone metabolism in the failing heart, (3) effects of therapeutic ketosis in animals and humans with HF, and (4) the potential significance of ketosis associated with sodium-glucose cotransporter 2 inhibitors. Although a number of important questions remain regarding the use of therapeutic ketosis and mechanism of action in HF, current evidence suggests potential benefit, in particular, in HF with reduced ejection fraction, with theoretical rationale for its use in HF with preserved ejection fraction. Although it is early in its study and development, therapeutic ketosis across the spectrum of HF holds significant promise.
Ketones regulate endothelial homeostasis. [2022]In a recent paper in EMBO Molecular Medicine, Weis et al. reveal that cardiac endothelial cells can oxidize ketone bodies, which enhances cell proliferation, migration, and vessel sprouting. Furthermore, increasing ketone body levels with a ketogenic diet can increase endothelial cell proliferation and prevent blood vessel rarefication in hypertrophied mouse hearts. This suggests that increasing endothelial cell ketone oxidation has potential in treating heart failure.
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.
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.
[(11)C]-Acetoacetate PET imaging: a potential early marker for cardiac heart failure. [2016]The ketone body acetoacetate could be used as an alternate nutrient for the heart, and it also has the potential to improve cardiac function in an ischemic-reperfusion model or reduce the mitochondrial production of oxidative stress involved in cardiotoxicity. In this study, [(11)C]-acetoacetate was investigated as an early marker of intracellular damage in heart failure.
Effects of an Exogenous Ketone Supplement on Five-Kilometer Running Performance. [2020]Numerous oral ketone supplements are marketed with the claim that they will rapidly induce ketosis and improve exercise performance. The purpose of this study was to assess exercise performance time and related physiological, metabolic and perceptual responses of recreational endurance runners after ingestion of a commercially available oral ketone supplement. Recreational endurance runners (n = 10; age: 20.8 ± 1.0 years; body mass: 68.9 ± 5.6 kg; height: 175.6 ± 4.9 cm) participated in a double-blind, crossover, repeated-measures study where they were randomized to 300 mg.kg-1 body weight of an oral β-hydroxybutyrate-salt + Medium Chain Triglyceride (βHB-salt+MCT) ketone supplement or a flavor matched placebo (PLA) 60 min prior to performing a 5-km running time trial (5KTT) on a treadmill. Time, HR, RPE, affect, RER, VO2, VCO2, and VE were measured during the 5-km run. The Session RPE and affect (Feeling Scale) were obtained post-5KTT. Plasma glucose, lactate and ketones were measured at baseline, 60-min post-supplement, and immediately post-5KTT. Plasma R-βHB (endogenous isomer) was elevated from baseline and throughout the entire protocol under the βHB-salt+MCT condition (p < 0.05). No significant difference (58.3 ± 100.40 s; 95% CI: -130.12 - 13.52; p = 0.100) was observed between the βHB-salt+MCT supplement (1430.0 ± 187.7 s) and the PLA (1488.3 ± 243.8 s) in time to complete the 5KTT. No other differences (p > 0.05) were noted in any of the other physiological, metabolic or perceptual measures.
Ketone bodies and the heart. [2022]Ketone bodies are low chain organic substances with four carbon atoms, with β-hydroxybutyric acid and acetone being the main ketone bodies in blood circulation. Under physiological conditions their levels are low while during conditions of oxidative stress, such as exercise, fasting state and acute illness, ketone body levels are increased. Recent findings have shown that in patients with heart failure their plasma concentration is increased. There is a positive correlation between increased energy metabolism of myocardial cells and the levels of β-hydroxybutyric acid and acetone. Furthermore, it has been hypothesized that the mild ketosis caused by sodium glucose cotransporter 2 inhibitors is one of the possible pathogenetic mechanisms explaining the significant cardiovascular and renal benefits observed in patients with type 2 diabetes treated with these agents. The aim of the present review is to summarize the role of ketone bodies in both normal and pathological conditions, such as heart failure.