Evidence Trace, complete trial record
In plain terms
In plain terms: Exogenous Ketones (Ketone Esters and Salts) shows early signals in human research but the evidence is limited -- small trials, surrogate endpoints, or not yet independently replicated. It is an emerging area, not yet a proven one.
Exogenous Ketones (Ketone Esters and Salts)
C
Limited: small, mixed or unreplicated trials
The endpoint this grade is based on: Surrogate biomarker endpoint, Drinks of beta-hydroxybutyrate, as a ketone ester or as ketone salts, that raise blood ketones without fasting or a ketogenic diet. Single doses lower blood glucose after a meal or glucose drink, and two-week trials in heart failure raised cardiac output (both C, measured markers). Endurance performance, migraine prevention and blood pressure were tested without benefit (D Route 2).
The evidence as the record states it
Falkenhain et al. (Adv Nutr, 2022; PMID 35380602): systematic review and meta-analysis of 43 trials, 586 participants; a single dose of exogenous ketones lowered blood glucose by 0.47 mmol/L against a comparator (95% CI 0.36 to 0.57), more with ketone monoesters than with salts; limited evidence on longer use. Monteyne et al. (Diabetologia, 2024; PMID 38483543): randomized double-blind crossover, 10 adults with type 2 diabetes, 0.5 g/kg ketone monoester before a mixed meal; 2-hour glucose about 18 percent lower than placebo, with no change in insulin; funded by Canadian and UK research councils. Walsh et al. (J Clin Endocrinol Metab, 2021; PMID 33367782): randomized crossover, 14 adults with obesity, 12 g of beta-hydroxybutyrate as a monoester before each meal for 14 days; postprandial glucose 8.0 percent and 24-hour average glucose 7.8 percent lower than placebo on continuous glucose monitoring. Berg-Hansen et al. (Circulation, 2024; PMID 38533643): randomized double-blind crossover, 24 adults with heart failure with reduced ejection fraction, ketone ester four times daily for 14 days against an isocaloric comparator; resting cardiac output 0.3 L/min higher and wedge pressure 2 mm Hg lower. Gopalasingam et al. (Circulation, 2024; PMID 39162035): randomized double-blind crossover, 24 adults with type 2 diabetes and heart failure with preserved ejection fraction, 25 g four times daily for 2 weeks; cardiac output 0.2 L/min higher and filling pressure lower than placebo. Liao et al. (Heart, 2026; PMID 40957670): meta-analysis of six randomized trials of ketone supplementation in heart failure; left ventricular ejection fraction 3.1 percentage points higher, with low to high certainty. Selvaraj et al. (JACC Heart Fail, 2025; PMID 40243975): randomized placebo-controlled crossover, 20 adults with heart failure with preserved ejection fraction, acute ketone ester; peak oxygen uptake and constant-load endurance unchanged; NIH and foundation funded. Brooks et al. (Int J Sport Nutr Exerc Metab, 2022; PMID 35042186): meta-analysis of 8 randomized trials, 80 participants; acute ketone monoesters and precursors did not improve endurance performance (Hedges g 0.14, 95% CI -0.20 to 0.47). Putananickal et al. (Cephalalgia, 2022; PMID 34541914): randomized double-blind crossover, 41 adults with episodic migraine, DL-beta-hydroxybutyrate for 12 weeks per period; migraine days and intensity no different from placebo (mean difference -1.1 days, 95% CI -5.07 to 2.85). One author later founded a company selling a beta-hydroxybutyrate product for migraine. Marcotte-Chenard et al. (J Diet Suppl, 2024; PMID 38145410): meta-analysis of 10 acute and chronic studies, 187 participants; no change in systolic or diastolic blood pressure, with a tendency toward higher resting heart rate at higher doses. Mohib et al. (Nutrients, 2025; PMID 41097203): systematic review of 51 studies in adults with disease; benefits mostly on surrogate endpoints, with insufficient data on clinical outcomes. Grade C on two uses with measured markers that are not established stand-ins for a clinical outcome; endurance performance, migraine prevention and blood pressure are D on Route 2.
PMID 35380602 PMID 38483543 PMID 33367782 PMID 38533643 PMID 39162035 PMID 40957670 PMID 40243975 PMID 35042186 PMID 34541914 PMID 38145410 PMID 41097203
Evidence by specific use
Blood glucose after a meal or glucose drink
Grade C
Falkenhain et al. (Adv Nutr, 2022; PMID 35380602): systematic review and meta-analysis of 43 trials, 586 participants; a single dose of exogenous ketones lowered blood glucose by 0.47 mmol/L against a comparator (95% CI 0.36 to 0.57), more with ketone monoesters than with salts; limited evidence on longer use. Monteyne et al. (Diabetologia, 2024; PMID 38483543): randomized double-blind crossover, 10 adults with type 2 diabetes, 0.5 g/kg ketone monoester before a mixed meal; 2-hour glucose about 18 percent lower than placebo, with no change in insulin; funded by Canadian and UK research councils. Walsh et al. (J Clin Endocrinol Metab, 2021; PMID 33367782): randomized crossover, 14 adults with obesity, 12 g of beta-hydroxybutyrate as a monoester before each meal for 14 days; postprandial glucose 8.0 percent and 24-hour average glucose 7.8 percent lower than placebo on continuous glucose monitoring. Glucose after a meal is a measured marker; the B definition admits a glycemic marker as an established stand-in in the form of HbA1c, and no trial has measured HbA1c, so the use stays at C.
PMID 35380602 PMID 38483543 PMID 33367782
Cardiac output and filling pressures in heart failure
Grade C
Berg-Hansen et al. (Circulation, 2024; PMID 38533643): randomized double-blind crossover, 24 adults with heart failure with reduced ejection fraction, ketone ester four times daily for 14 days against an isocaloric comparator; resting cardiac output 0.3 L/min higher and wedge pressure 2 mm Hg lower. Gopalasingam et al. (Circulation, 2024; PMID 39162035): randomized double-blind crossover, 24 adults with type 2 diabetes and heart failure with preserved ejection fraction, 25 g four times daily for 2 weeks; cardiac output 0.2 L/min higher and filling pressure lower than placebo. Liao et al. (Heart, 2026; PMID 40957670): meta-analysis of six randomized trials of ketone supplementation in heart failure; left ventricular ejection fraction 3.1 percentage points higher, with low to high certainty. Both trials come from one center, run two weeks, and measure hemodynamics rather than hospitalization or death; cardiac output is not an established stand-in for a clinical outcome. C.
PMID 38533643 PMID 39162035 PMID 40957670
Exercise capacity in heart failure with preserved ejection fraction
Grade D
Selvaraj et al. (JACC Heart Fail, 2025; PMID 40243975): randomized placebo-controlled crossover, 20 adults with heart failure with preserved ejection fraction, acute ketone ester; peak oxygen uptake and constant-load endurance unchanged; NIH and foundation funded. Tested on the functional outcome and no benefit: D on Route 2.
PMID 40243975
Endurance exercise performance
Grade D
Brooks et al. (Int J Sport Nutr Exerc Metab, 2022; PMID 35042186): meta-analysis of 8 randomized trials, 80 participants; acute ketone monoesters and precursors did not improve endurance performance (Hedges g 0.14, 95% CI -0.20 to 0.47). D on Route 2.
PMID 35042186
Migraine prevention
Grade D
Putananickal et al. (Cephalalgia, 2022; PMID 34541914): randomized double-blind crossover, 41 adults with episodic migraine, DL-beta-hydroxybutyrate for 12 weeks per period; migraine days and intensity no different from placebo (mean difference -1.1 days, 95% CI -5.07 to 2.85). One author later founded a company selling a beta-hydroxybutyrate product for migraine. Tested on the outcome it is sold for and no benefit: D on Route 2.
PMID 34541914
Marcotte-Chenard et al. (J Diet Suppl, 2024; PMID 38145410): meta-analysis of 10 acute and chronic studies, 187 participants; no change in systolic or diastolic blood pressure, with a tendency toward higher resting heart rate at higher doses. Blood pressure is an established stand-in, and it did not move: D on Route 2.
PMID 38145410
Why Grade C and not Grade B
Grade C reflects early or limited human evidence -- small trials, surrogate endpoints, or preliminary findings not yet independently replicated. The evidence points in a promising direction but does not yet meet the standard for Grade B. A single well-powered, independently replicated trial with a meaningful endpoint would move this to Grade B or higher.
What this grade covers and what it does not
Grade C, the record's best uses: blood glucose after a meal or glucose drink, lower in a meta-analysis of 43 trials (Falkenhain et al., Adv Nutr, 2022; PMID 35380602) and in randomized trials in type 2 diabetes and obesity (PMID 38483543, PMID 33367782); and cardiac output in heart failure, higher in two two-week crossover trials from one center (PMID 38533643, PMID 39162035). WHY NOT B: both are measured markers that are not established stand-ins for a clinical outcome; for glucose the established stand-in is HbA1c, which no trial has measured, and no heart failure trial has measured hospitalization or death. WHAT THIS GRADE DOES NOT COVER: endurance performance (PMID 35042186), migraine prevention (PMID 34541914), blood pressure (PMID 38145410) and exercise capacity in heart failure (PMID 40243975) were tested without benefit, D on Route 2.
What would move this grade
A well-powered randomized trial with an objective, clinically meaningful primary endpoint and at least one independent replication would support Grade B or higher.
How to track whether this is working
Blood beta-hydroxybutyrate by fingerstick meter confirms the product raised ketones; the glucose trials measured glucose after a standard meal or by continuous glucose monitor. Cardiac output was measured by right heart catheterization in the heart failure trials and is not a home measure.