Ketone bodies

NutraPedia - Evidence-Based Supplement Research

Back to Table of Contents
Health Goals: energy weight focus

Research Overview

Current research positions ketone body metabolism (primarily D-β-hydroxybutyrate and acetoacetate) as both an energy-distribution system and a signaling network that influences inflammation, redox biology, gene regulation, and inter-organ crosstalk. The most studied areas include (i) brain energetics in low-glucose states and neurodegenerative disease (especially Alzheimer’s disease) using ketogenic diets, medium-chain triglycerides, or exogenous ketones; (ii) cardiovascular metabolism, particularly heart failure, where ketones are increasingly viewed as an adaptive fuel and potential modulator of remodeling, fibrosis, endothelial function, and oxidative stress; and (iii) drug-induced alterations in ketone biology, notably the effects of SGLT2 inhibitors on circulating ketones and the associated risk of diabetic ketoacidosis (DKA). Across these domains, reviews emphasize that ketones are not solely “starvation fuels” but can exert physiologic roles even when carbohydrate availability is relatively high.

The strongest evidence supports ketones as clinically relevant alternative fuels under conditions of impaired glucose utilization and as contributors to cardiometabolic phenotypes. In neurodegeneration, clinical and imaging studies in Alzheimer’s disease most consistently show that raising circulating ketones can increase brain ketone uptake and may yield modest cognitive or functional benefits in some cohorts, aligning with the concept of an “energy rescue” when cerebral glucose metabolism is compromised. In cardiovascular disease, converging experimental and early clinical evidence supports increased cardiac ketone utilization in heart failure as potentially adaptive, and mechanistic work suggests pleiotropic effects beyond energetics (e.g., inflammation and oxidative stress modulation). In parallel, the association between SGLT2 inhibitors and increased ketone levels is supported by plausible mechanisms—reduced insulin dose/insulin signaling, increased glucagon, and altered renal handling of ketones—consistent with observed DKA risk signals, while also intersecting with hypotheses that mild ketosis may contribute to some heart-failure benefits.

Key gaps remain in defining causality, dose–response relationships, and context specificity. For neurodegenerative disease, larger and longer randomized trials are needed to determine which patients benefit, whether benefits extend beyond symptomatic/energetic effects, and how intervention type (dietary vs exogenous ketones) and achieved ketone levels relate to outcomes. For cardiovascular disease, the field needs clearer mechanistic separation of ketone “fuel” effects from signaling effects, rigorous testing of therapeutic ketosis strategies (including safety and feasibility), and translation from preclinical models (e.g., ischemia–reperfusion studies) to clinical endpoints. More broadly, organ- and cell-type-specific actions of β-hydroxybutyrate versus acetoacetate, interactions with immune and fibrotic pathways, and safety considerations (especially DKA risk in susceptible populations and with SGLT2 inhibitors) require systematic study to guide therapeutic application.

Research Overview

Research on exogenous ketones has most heavily focused on acute physiological effects—particularly the ability of ketone salts and ketone monoesters to raise circulating β-hydroxybutyrate (BHB) and influence metabolic markers such as blood glucose—and on acute exercise performance outcomes. Multiple randomized trials synthesized in systematic reviews/meta-analyses consistently show that ingestion of exogenous ketones reliably elevates blood BHB, with monoesters producing larger increases than salts, and is associated with a modest acute reduction in blood glucose. Exercise-focused meta-analyses spanning sprint to ~50-minute endurance-type efforts generally report no clear ergogenic benefit, with no consistent changes in metabolic (e.g., lactate, glucose), cardiorespiratory (e.g., oxygen uptake, heart rate), or perceptual (e.g., rating of perceived exertion) responses despite elevated ketone levels.

The strongest evidence therefore supports two conclusions: (1) exogenous ketones acutely increase circulating ketone concentrations (dose/form dependent, with monoesters typically more potent), and (2) they modestly lower blood glucose acutely relative to baseline and placebo comparators. Emerging evidence also suggests potential cardiovascular effects: a recent meta-analysis of human studies reports improvements in systolic function and hemodynamics (e.g., increased left ventricular ejection fraction, cardiac output, and stroke volume; reduced systemic vascular resistance) in heart failure populations, with subgroup analyses suggesting similar directional effects in individuals without heart failure. In addition, at least one randomized, placebo-controlled trial indicates that short-term D-BHB supplementation may improve subjective sleep quality domains in healthy adults, though this evidence base is comparatively small.

Key gaps include limited data on longer-term supplementation (beyond acute dosing), clinically meaningful endpoints (e.g., glycemic control over weeks/months, cardiometabolic outcomes, functional capacity), and comparative effectiveness across ketone formulations, doses, and co-interventions (diet composition, exercise modality, timing relative to meals/training). Exercise research needs expansion to other performance contexts where benefits are hypothesized (e.g., ultraendurance, repeated-day events, recovery, cognition under fatigue), with better characterization of responders/non-responders and potential trade-offs (e.g., gastrointestinal tolerability, electrolyte load with salts). For cardiovascular and sleep outcomes, larger, well-controlled trials with objective measures (e.g., echocardiography protocols, polysomnography/actigraphy) and standardized reporting are needed to confirm efficacy, define mechanisms, and establish safety across diverse populations.

1. What conditions has Exogenous Ketones been studied for?

  • Sleep quality in healthy adults: A randomized, placebo-controlled, double-blind, parallel-group trial in healthy Japanese adults tested oral D-β-hydroxybutyric acid (D-BHB) for 14 days.

  • Exercise performance (acute use): Multiple randomized controlled trials (RCTs) summarized in systematic reviews/meta-analyses evaluated acute ketone supplements (ketone esters, ketone salts, ketone precursors/monoesters) for sprint-to-~50 minute performance and endurance outcomes (time trial, time to exhaustion).

  • Heart failure and cardiac function/hemodynamics: A meta-analysis of human studies evaluated ketone therapy (ketone ester and β-hydroxybutyrate interventions) on cardiac systolic function and hemodynamic measures in patients with heart failure (HF), with subgroup analyses also including individuals without HF.

  • Blood glucose regulation (acute effects): A systematic review/meta-analysis of randomized and nonrandomized trials assessed acute exogenous ketone ingestion effects on blood β-hydroxybutyrate (BHB) and blood glucose.

2. Does it work in treating those conditions? Summarize the evidence.

  • Sleep quality (healthy adults): Evidence from one 14-day RCT suggests improvements in subjective sleep quality domains with D-BHB vs placebo. After 14 days, compared with placebo, both low (1.5 g) and high (2.9 g) D-BHB groups had significantly higher OSA-MA scores for “Sleepiness on rising” and “Frequent dreaming.” The low-dose group improved “Initiation and maintenance of sleep,” and the high-dose group improved “Refreshing on rising.” Limitations: single study, specific population (healthy Japanese adults), short duration, and subjective measures.

  • Exercise performance (acute): Two meta-analyses found no clear ergogenic effect for acute exogenous ketones across studied exercise types.

    • Meta-analysis of 13 RCTs: no significant effect on overall performance (Hedges g = -0.05; 95% CI, -0.30 to 0.20), including endurance time-trials (g = -0.04) and no difference for ketone esters or salts.

    • Meta-analysis of 8 RCTs (80 participants): no significant effect on endurance performance overall (Hedges g = 0.136; 95% CI, -0.195 to 0.467), with no benefit for time to exhaustion (g ≈ 0) or time trial (g = 0.057).

    Across studies, blood ketones rose after supplementation, but performance and common physiological/perceptual exercise responses did not consistently improve.

  • Heart failure/cardiac function: A meta-analysis of seven human studies reported that ketone therapy improved cardiac systolic function and some hemodynamics in HF:

    • Left ventricular ejection fraction improved (SMD 0.52; 95% CI, 0.25–0.80; I2=0%).

    • Cardiac output improved (SMD 0.84; 95% CI, 0.36–1.32; I2=68%).

    • Stroke volume improved (SMD 0.47; 95% CI, 0.10–0.84; I2=39%).

    • Systemic vascular resistance decreased (SMD -0.92; 95% CI, -1.52 to -0.33; I2=74%).

    • Mean arterial pressure was not significantly changed (SMD -0.09; 95% CI, -0.40 to 0.22; I2=0%).

    Important limitations: heterogeneity for several outcomes (notably cardiac output and systemic vascular resistance), and the study does not specify study sizes, duration, ketone formulations/doses, or clinical endpoints (e.g., symptoms, hospitalization, mortality). These findings are promising but not definitive “treatment” evidence.

  • Blood glucose (acute): A systematic review/meta-analysis of 43 trials (586 participants) found acute exogenous ketones raise blood BHB and lower blood glucose:

    • After ingestion vs before: BHB increased by MD 1.73 mM (95% CI: 1.26, 2.21) and glucose decreased by MD -0.54 mM (95% CI: -0.68, -0.40).

    • Ketones vs placebo: BHB increased by MD 1.98 mM (95% CI: 1.52, 2.45) and glucose decreased by MD -0.47 mM (95% CI: -0.57, -0.36).

    • Monoesters produced significantly greater effects than salts (P < 0.001).

    This supports an acute glucose-lowering effect, but the study notes limited evidence on prolonged supplementation, so implications for chronic glycemic control or diabetes outcomes remain uncertain.

3. What health benefits does it have?

  • Improved subjective sleep quality (short-term, healthy adults): In a 14-day RCT, D-BHB improved several OSA-MA sleep domains vs placebo (including initiation/maintenance of sleep at low dose and refreshing on rising at high dose).

  • Acute reduction in blood glucose with increased circulating ketones: Across 43 trials, acute ingestion increased BHB by ~1.7–2.0 mM and lowered glucose by ~0.47–0.54 mM on average; monoesters had larger effects than salts.

  • Potential improvements in cardiac systolic function and hemodynamics: In a meta-analysis of seven human studies, ketone therapy improved LVEF, cardiac output, and stroke volume and reduced systemic vascular resistance, without changing mean arterial pressure. Clinical significance and long-term outcomes were not established in the study.

  • Not supported as a performance enhancer for typical endurance/sprint events (acute): While not a “benefit,” the evidence suggests expectations should be tempered for performance gains in events up to ~50 minutes.

4. Does it have any downsides or side effects?

The studies reviewed here contain limited direct reporting of adverse events. Based on what is stated:

  • Exercise studies: Meta-analyses reported no consistent changes in metabolic (lactate/glucose), respiratory, cardiovascular (heart rate), or perceptual responses (rating of perceived exertion) during exercise with acute ketone supplementation. These are not side effects per se, but suggest no consistent acute physiological “cost” in those measured domains.

  • Hemodynamics: In the HF meta-analysis, mean arterial pressure was not significantly affected, while systemic vascular resistance decreased. The studies do not describe adverse symptoms (e.g., hypotension-related events), so safety interpretation is limited.

  • Glucose lowering: Acute glucose reductions were observed. In principle, glucose lowering could be a concern for people prone to hypoglycemia (e.g., those using insulin or insulin secretagogues), but the studies do not report hypoglycemia rates or adverse events.

  • General limitation: Because adverse events are not summarized in these studies, conclusions about tolerability (e.g., gastrointestinal effects often discussed with ketone salts/esters in broader literature) cannot be made from the provided evidence.

5. Is it beneficial or harmful for any genetic variations (pharmacogenomics)?

None of the studies reviewed here report analyses by genotype or specific genetic variants, and no pharmacogenomic conclusions can be drawn from them.

  • No evidence in these studies linking response or risk from exogenous ketones to genetic variants (e.g., ketone metabolism, transport, or cardiac energetics genes).

  • Practical implication: At present, based on these studies, there is no evidence-based basis to recommend exogenous ketones differently according to genetic testing results.

References

  1. Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics.
    Patrycja Puchalska, Peter A Crawford (2017) - Cell metabolism
  2. Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases.
    Nicole Jacqueline Jensen, Helena Zander Wodschow, Malin Nilsson, Jørgen Rungby (2020) - International journal of molecular sciences
  3. Ketones and the Heart: Metabolic Principles and Therapeutic Implications.
    Timothy R Matsuura, Patrycja Puchalska, Peter A Crawford, Daniel P Kelly (2023) - Circulation research
  4. SGLT2 Inhibitors May Predispose to Ketoacidosis.
    Simeon I Taylor, Jenny E Blau, Kristina I Rother (2015) - The Journal of clinical endocrinology and metabolism
  5. Metabolic and Signaling Roles of Ketone Bodies in Health and Disease.
    Patrycja Puchalska, Peter A Crawford (2021) - Annual review of nutrition
  6. Therapeutic Potential of Ketone Bodies for Patients With Cardiovascular Disease: JACC State-of-the-Art Review.
    Salva R Yurista, Cher-Rin Chong, Juan J Badimon, Daniel P Kelly, Rudolf A de Boer, B Daan Westenbrink (2021) - Journal of the American College of Cardiology
  7. Cardioprotective Effect of Empagliflozin and Circulating Ketone Bodies During Acute Myocardial Infarction.
    Carlos G Santos-Gallego, Juan Antonio Requena-Ibáñez, Belen Picatoste, Brian Fardman, Kiyotake Ishikawa, Renata Mazurek, Michael Pieper, Samantha Sartori, Jorge Rodriguez-Capitán, Valentin Fuster, Juan J Badimon (2023) - Circulation. Cardiovascular imaging
  8. Ketogenic Diet in Alzheimer's Disease.
    Marta Rusek, Ryszard Pluta, Marzena Ułamek-Kozioł, Stanisław J Czuczwar (2019) - International journal of molecular sciences
  9. Metabolic Messengers: ketone bodies.
    Alisa B Nelson, Eric D Queathem, Patrycja Puchalska, Peter A Crawford (2023) - Nature metabolism
  10. Common and divergent molecular mechanisms of fasting and ketogenic diets.
    Antonio Paoli, Grant M Tinsley, Mark P Mattson, Immaculata De Vivo, Ravi Dhawan, Tatiana Moro (2024) - Trends in endocrinology and metabolism: TEM
  11. Ketone Bodies in Neurological Diseases: Focus on Neuroprotection and Underlying Mechanisms.
    Huajun Yang, Wei Shan, Fei Zhu, Jianping Wu, Qun Wang (2019) - Frontiers in neurology
  12. β-hydroxybutyrate and its metabolic effects on age-associated pathology.
    Young-Min Han, Tharmarajan Ramprasath, Ming-Hui Zou (2020) - Experimental & molecular medicine
  13. Effect of Ketogenic Diet on Obesity and Other Metabolic Disorders: Narrative Review.
    Temesgen Baylie, Tiget Ayelgn, Markeshaw Tiruneh, Kibur Hunie Tesfa (2024) - Diabetes, metabolic syndrome and obesity : targets and therapy
  14. Neuroketotherapeutics: A modern review of a century-old therapy.
    Scott J Koppel, Russell H Swerdlow (2018) - Neurochemistry international
  15. Ketogenic Diet and Ketone Bodies against Ischemic Injury: Targets, Mechanisms, and Therapeutic Potential.
    Ciara I Makievskaya, Vasily A Popkov, Nadezda V Andrianova, Xinyu Liao, Dmitry B Zorov, Egor Y Plotnikov (2023) - International journal of molecular sciences
  16. Metabolomics in cardiometabolic diseases: Key biomarkers and therapeutic implications for insulin resistance and diabetes.
    David Rizo-Roca, John D Henderson, Juleen R Zierath (2025) - Journal of internal medicine
  17. The Evolution of Ketosis: Potential Impact on Clinical Conditions.
    Latha Nagamani Dilliraj, Giovanna Schiuma, Djidjell Lara, Giovanni Strazzabosco, James Clement, PierPaolo Giovannini, Claudio Trapella, Marco Narducci, Roberta Rizzo (2022) - Nutrients
  18. Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low-grade inflammation the neglected component?
    Francesco Prattichizzo, Valeria De Nigris, Stefano Micheloni, Lucia La Sala, Antonio Ceriello (2018) - Diabetes, obesity & metabolism
  19. The Effect of Ketogenic Diet on Inflammatory Arthritis and Cardiovascular Health in Rheumatic Conditions: A Mini Review.
    Jacopo Ciaffi, Dmitri Mitselman, Luana Mancarella, Veronica Brusi, Lucia Lisi, Piero Ruscitti, Paola Cipriani, Riccardo Meliconi, Roberto Giacomelli, Claudio Borghi, Francesco Ursini (2021) - Frontiers in medicine
  20. Intermittent fasting and neurodegenerative diseases: Molecular mechanisms and therapeutic potential.
    Renjun Lv, Bin Liu, Ziying Jiang, Runfa Zhou, Xiaoxing Liu, Tangsheng Lu, Yanping Bao, Chunxia Huang, Guichang Zou, Zongyong Zhang, Lin Lu, Qingqing Yin (2025) - Metabolism: clinical and experimental
  21. Effect of d-β-hydroxybutyrate on sleep quality in healthy participants: a randomized, double-blind, placebo-controlled study
    Shohei Katsuya, Yoshikazu Kawata, Yosuke Kawamura, Jun Kawamura, Jun Tsubota (2025)
  22. Acute Ketone Supplementation and Exercise Performance: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
    Pedro L Valenzuela, Javier S Morales, Adrián Castillo-García, Alejandro Lucia (2020)
  23. Acute Ingestion of Ketone Monoesters and Precursors Do Not Enhance Endurance Exercise Performance: A Systematic Review and Meta-Analysis
    Emma Brooks, Gilles Lamothe, Taniya S Nagpal, Pascal Imbeault, Kristi Adamo (2022)
  24. Targeting Ketone Body Metabolism Improves Cardiac Function and Hemodynamics in Patients With Heart Failure: A Systematic Review and Meta-Analysis
    Tingting Lv, Chunyan Liu, Shitian Guo, Menglu Wu, Xiang Wang (2025)
  25. Effects of Exogenous Ketone Supplementation on Blood Glucose: A Systematic Review and Meta-analysis
    Kaja Falkenhain, Ali Daraei, Scott C Forbes, Jonathan P Little (2022)


This article summarizes published research for educational purposes. It is not medical advice. Talk to your doctor before starting, stopping, or changing any supplement or medication.

Want personalized supplement recommendations based on your genetics?
Upload Whole Genome Sequencing (WGS) raw DNA data today!
Or upload raw DNA data to get started with your free analysis!