Acute Ketone Monoester Supplementation Impairs 20-min Time-Trial Performance in Trained Cyclists: A Randomized, Crossover Trial

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Devin G. McCarthy Department of Kinesiology, McMaster University, Hamilton, ON, Canada

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Jack Bone Department of Kinesiology, McMaster University, Hamilton, ON, Canada

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Matthew Fong Department of Kinesiology, McMaster University, Hamilton, ON, Canada

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Phillippe J.M. Pinckaers Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands

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William Bostad Department of Kinesiology, McMaster University, Hamilton, ON, Canada

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Douglas L. Richards Department of Medicine, McMaster University, Hamilton, ON, Canada

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Luc J.C. van Loon Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands

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Martin J. Gibala Department of Kinesiology, McMaster University, Hamilton, ON, Canada

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Acute ketone monoester (KE) supplementation can alter exercise responses, but the performance effect is unclear. The limited and equivocal data to date are likely related to factors including the KE dose, test conditions, and caliber of athletes studied. We tested the hypothesis that mean power output during a 20-min cycling time trial (TT) would be different after KE ingestion compared to a placebo (PL). A sample size of 22 was estimated to provide 80% power to detect an effect size dz of 0.63 at an alpha level of .05 with a two-tailed paired t test. This determination considered 2.0% as the minimal important difference in performance. Twenty-three trained cyclists (N = 23; peak oxygen uptake: 65 ± 12 ml·kg−1 min−1; M ± SD), who were regularly cycling >5 hr/week, completed a familiarization trial followed by two experimental trials. Participants self-selected and replicated their diet and exercise for ∼24 hr before each trial. Participants ingested either 0.35 g/kg body mass of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate KE or a flavor-matched PL 30 min before exercise in a randomized, triple-blind, crossover manner. Exercise involved a 15-min warm-up followed by the 20-min TT on a cycle ergometer. The only feedback provided was time elapsed. Preexercise venous [β-hydroxybutyrate] was higher after KE versus PL (2.0 ± 0.6 vs. 0.2 ± 0.1 mM, p < .0001). Mean TT power output was 2.4% (0.6% to 4.1%; mean [95% confidence interval]) lower after KE versus PL (255 ± 54 vs. 261 ± 54 W, p < .01; dz = 0.60). The mechanistic basis for the impaired TT performance after KE ingestion under the present study conditions remains to be determined.

Nutritional ketosis induced through the ingestion of ketogenic supplements can alter physiological responses to exercise (Evans et al., 2017). This practice has also been purported to enhance performance, at least under selected conditions, although the precise mechanistic basis is unclear (Evans et al., 2022; Pinckaers et al., 2017). As noted by Dearlove et al. (2019), context is key in assessing the potential performance effects of ketone body supplements. Important considerations include supplement type, increase in blood ketone body concentrations, relative exercise intensity, and the training state of participants studied. The ketone monoester (KE) supplement has emerged as the preferred ketone body supplement because, for a given dose, it elicits a greater increase in blood ketone body concentrations and is generally well tolerated (Stubbs et al., 2017, 2019). With regard to exercise intensity, a key consideration is whether acute KE supplementation potentially impairs performance under conditions that necessitate a high rate of carbohydrate oxidation as occurs during some types of athletic competition (Coyle et al., 1986; Hawley & Leckey, 2015). Regarding study participants, the effect of KE on performance in a sample of well-trained athletes compared to recreationally active individuals may increase the ecological validity of the study.

Studies assessing the effect of acute KE ingestion on endurance cycling performance in trained individuals have yielded equivocal data, which may be explained in part by between-study differences in any nutritional controls implemented, KE dosing strategy, and the specific performance test used (Cox et al., 2016; Evans et al., 2019; Margolis & Fallon, 2020; McCarthy et al., 2021; Poffé et al., 2021, 2020, 2021). A seminal study in the field reported that KE ingestion before and during 60 min of cycling at 75% peak power raised blood β-hydroxybutyrate concentration to ∼2–3 mM and improved 30-min time-trial performance in eight trained individuals who were studied in the overnight fasted state (Cox et al., 2016). Other studies that have generally found no effect of KE ingestion on performance used test protocols that involved a period of constant-work exercise prior to the performance test (Evans et al., 2019; McCarthy et al., 2021). A recent study by Poffe et al. (2021) reported that ingestion of ∼50 g of KE (∼0.7 g/kg body mass) during a warm-up increased venous blood β-hydroxybutyrate concentration to ∼3.5 mM and impaired subsequent 30-min cycling time-trial performance in 12 well-trained cyclists who were studied 2 hr after breakfast ingestion. It has been suggested that eliciting a blood β-hydroxybutyrate concentration in the range of 1–3 mM during an exercise may elicit the most favorable conditions for potential performance enhancement, perhaps by limiting the potential gastrointestinal distress, blood acidosis, and increased cardiorespiratory stress associated with relatively larger doses of KE supplements (Evans et al., 2017, 2022). Additional work is warranted to clarify the effect of acute KE supplementation—including strategies that elicit an increase in blood β-hydroxybutyrate concentration to ∼1–3 mM—on time-trial performance following a standardized warm-up in trained individuals in the postprandial state, which is the manner in which many athletes typically compete.

The purpose of this study was to determine whether acute KE supplementation affects endurance exercise performance in trained individuals. Using a randomized, crossover, and triple-blinded design, trained cyclists ingested a (R)-3-hydroxybutyl (R)-3-hydroxybutyrate KE supplement or a taste- and volume-matched ketone-free placebo (PL), and then performed a laboratory-based 20-min cycling time trial. Performance using this approach is highly reproducible in trained cyclists, with a reported day-to-day coefficient of variation of 1.4% using the same equipment and procedures as employed in the present study (Macinnis et al., 2019). The test is also strongly correlated with functional threshold power (Macinnis et al., 2019), another performance metric that in turn is strongly correlated with 40-km road race performance (Coyle et al., 1991). Given the equivocal nature of the limited performance studies to date, we tested the nondirectional hypothesis that mean 20-min time-trial power output would be different after ingestion of KE and PL.

Methods

Study Design

This randomized, crossover, triple-blinded trial involved four visits to the laboratory for each participant: an initial peak oxygen uptake (V˙O2peak) test, a familiarization trial, and two experimental trials. The experimental trials differed only by the supplement ingested before exercise, that is, KE or ketone-free PL. Each participant was randomized into one of two treatment orders by coin flip (block size of 1 and heads = PL trial first) by a researcher who was not involved in data collection. The participants, researchers who interacted with the participants, and researchers involved in data analysis were blinded to the experimental conditions. This project was approved by the Hamilton Integrated Research Ethics Board (#13837) and registered prior to the start of data collection on ClinicalTrials.gov (NCT05226962). The manuscript was prepared in accordance with the Proper Reporting of Evidence in Sport and Exercise Nutrition Trials guidelines (Betts et al., 2020).

Participants

The inclusion criteria for this study were the following: (a) healthy adults aged between 18 and 60 years, (b) consuming >50 g/day of carbohydrate, that is, not following a ketogenic diet (Aragon et al., 2017), (c) experience with competitive cycling or time trials or racing, (d) habitually engaging in ≥5 hr/week of cycling training over ≥3 days/week, and (e) having an estimated V˙O2peak of ≥55 ml·kg−1·min−1 for males and ≥48 ml·kg−1·min−1 for females based on the online calculator available at: https://www.worldfitnesslevel.org. Weekly cycling volume and frequency and the V˙O2peak criteria were based on the characteristics of “trained athletes” described by (Decroix et al., 2016; De Pauw et al., 2013). Interested individuals were first informed of the study requirements, including the inclusion criteria described above and provided with an electronic copy of the informed consent form. They were also asked to complete a Get Active Questionnaire (Canadian Society for Exercise Physiology) to assess general readiness to engage in physical activity and a custom questionnaire to assess habitual nutrition, physical activity, and menstrual cycle. Those who satisfied all the inclusion criteria were asked to provide written informed consent and were then recruited into the study.

Study sample size was estimated based on the presumption that 2.0% was the minimal important difference. This difference is similar in magnitude to that reported in the limited number of studies that have reported a significant effect of acute KE supplementation on time-trial performance (Cox et al., 2016; Peacock et al., 2022; Poffé et al., 2021). It is also comparable to the improvement observed with other nutritional interventions shown to elicit an ergogenic effect including carbohydrate mouth rinsing and ingestion of carbohydrate, caffeine, and sodium bicarbonate (Brietzke et al., 2019; Carr et al., 2011; Conger et al., 2011). Estimated means (343 W), SDs (35 W), and correlation among repeated measures (.95) were based on data from Macinnis et al. (2019) for a 20-min time trial in trained cyclists. A computation using G*Power version 3.1 (Faul et al., 2007) for a paired t test with two tails revealed that an estimated total sample size of 22 participants provided 80% power to detect a change at an alpha level of .05 with effect size Cohen’s dz of 0.63. To preserve power, a total of 25 participants were recruited. Recruitment and data collection occurred from February 2022 through August 2022. Posters advertising the study were shared on McMaster University campus, social media platforms, and with local cycling clubs. Thirty-four participants were initially assessed for eligibility, and 23 of the 25 individuals who were recruited and randomized completed the entire study (Supplementary Figure S1 [available online]). One participant dropped out due to a knee injury that occurred during a nonstudy-related activity and the other dropped out due to scheduling conflicts. The characteristics of the 23 participants who completed the study are reported in Table 1.

Table 1

Participant Characteristics

All (n = 23)
Age (years)31 ± 9
Weight (kg)76 ± 11
Height (m)1.77 ± 0.07
V˙O2peak
 (L/min)4.9 ± 1.0
 (ml·kg−1·min−1)65 ± 12
Peak power output (W)390 ± 60
HRpeak (beats·min−1)185 ± 13
VT1 (%V˙O2peak)64 ± 8
RCP (%V˙O2peak)85 ± 7

Note. Data are presented as mean ± SD for n = 23 participants except n = 21 for HRpeak and n = 22 for VT1. V˙O2peak = peak oxygen uptake; HRpeak = peak heart rate; VT1 = ventilatory threshold 1; RCP = respiratory compensation point.

Interventions

The experimental interventions were acute ingestion of either 0.35 g/kg body mass of a KE or ketone-free PL 30 min before exercise. The commercial (R)-3-hydroxybutyl (R)-3-hydroxybutyrate KE beverage (deltaG ketone performance, TDeltaS) contained 120 kcal per 59-ml bottle (4 g carbohydrate, 25 g of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate) and was all purchased in the same order. The PL beverage was matched to the KE for flavor, volume, and carbohydrate content (16 kcal per 59 ml). It contained the same ingredients as the KE except the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate was replaced by 0.05% denatonium benzoate (Bitrex).

Pre-Experimental Procedures

V˙O2peak was determined as we have previously described (McCarthy et al., 2021). Briefly, the ramp test began with a 3-min warm-up at 50 W and workload was increased 1 W every 2 s until the participant reached volitional exhaustion and ceased pedaling or decreased the cadence to <60 rpm. Expired gases (Quark CPET, COSMED Inc.) and heart rate (HR; model A300, Polar Electro) were recorded continuously throughout. The familiarization trial mimicked the experimental trials except that no supplements were provided before exercise and no blood samples were collected. After the trial, participants ingested ∼10 ml of the ketone-free PL supplement to become accustomed to the bitter flavor but were not informed whether they received the KE or PL.

Experimental Procedures

The two experimental trials were separated by 7 days and performed at the same time of day (±1 hr) for a given participant. Owing to scheduling conflicts, the two trials for five participants were separated by 8 to 14 days. For female participants, the two experimental trials were performed in the same phase of their hormonal cycle. One participant was taking oral contraceptives and completed both trials in the active phase of their cycle; the other completed both trials in the early follicular phase of their hormonal cycle. Participants were instructed to maintain their usual dietary and exercise habits throughout the study. Nutritional strategies outside of the laboratory were self-selected by each participant in accordance with their habitual dietary practices, approved by a researcher, and repeated for all trials, similar to Burke et al. (2017, 2020). The day before and morning of the trials, participants were instructed to eat and drink how they would normally prepare for a race. The intent was for the pattern of nutrition intake to be matched as precisely as possible between trials. Participants were also instructed to avoid alcohol and intense training on the day before and of the trials. A continuous glucose monitoring device (Abbott Libre Sense Glucose Sport Biosensor, Supersapiens) was inserted into the back of the participant’s arm, per manufacturer instructions, before the first experimental trial and remained in the participants arm until the second experimental trial was completed.

An overview of the experimental trial is shown in Figure 1. Upon arrival at the laboratory, participants sat upright and ingested 0.35 g/kg body mass of the KE or a flavor- and volume-matched ketone-free PL beverage from an opaque container. After ingesting the drink, they rested for 30 min, during which they completed a dietary recall questionnaire with the researcher. About 25 min into the rest period, a venous blood sample was drawn from an antecubital vein into a lithium-heparinized syringe and analyzed within 15 min by a researcher who did not interact with the participants and was not otherwise involved with data analysis to preserve blinding. Point-of-care analyzers determined [β-hydroxybutyrate] (β-ketone test strips, Freestyle Precision Neo, Abbott Laboratories) and [glucose], [lactate], total CO2, and pH (EPOC, Siemens Healthcare; Nawrocki et al., 2021) in whole venous blood samples. After the rest period, participants completed a 15-min self-determined warm-up followed by the 20-min time trial on the electronically braked cycle ergometer (Velotron, Racer Mate Inc.) based on the methods described by Macinnis et al. (2019). The ergometer used in the study allows riders to change power output either by increasing/decreasing cadence or by changing the simulated gear. The time-trial was performed in the presence of two researchers in an otherwise closed laboratory. No food or drink except for water ad libitum was provided during the time trial. The only feedback provided to the participant was time elapsed. Bike handlebar and seat configuration as well as fan speed and location were the same for both trials. HR was recorded continuously throughout exercise (Polar A300). Mean power output was recorded after completion of the time trial. Peak and overall perceived exertion scores were obtained using the Borg 20-point scale (Borg, 1982) within 1 min of completion of the time trial. Participants then completed a validated gastrointestinal symptom questionnaire for sports nutrition exercise trials to assess perceptions experienced during the time trial (Gaskell et al., 2019). Briefly, participants circled an integer from 1 to 10 that corresponded to a severity for 19 different gastrointestinal symptoms, 0 was no symptom present, 1–4 mild symptoms, 5–9 severe symptoms, and 10 extremely severe symptoms. Finally, a questionnaire was completed to assess supplement blinding effectiveness as we have previously described (McCarthy et al., 2021). Participants were provided with no feedback regarding any time-trial data until completion of the study.

Figure 1
Figure 1

—Overview of the experimental protocol. Trained cyclists (n = 23) ingested 0.35 g/kg body mass of a KE supplement (deltaG ketone performance) or a ketone-free PL in a randomized, crossover, triple-blinded manner (bottle image). Glucose was measured via continuous glucose monitoring. Blood drop = venous blood sampling; RPE = rating of perceived exertion; numbers = time in minutes; KE = ketone monoester; PL = placebo.

Citation: International Journal of Sport Nutrition and Exercise Metabolism 33, 4; 10.1123/ijsnem.2022-0255

Statistical Analysis

Data represent means ± SDs for n = 23 participants based on both experimental trials unless otherwise stated. Blood gas analysis was not performed on n = 1 blood sample due to technical difficulties with the analyzer. Continuous glucose monitoring data represent n = 19 as data were not obtained for one or both trials for n = 4 participants because either the sensor fell off within 24 hr of the trial or there were technical errors related to data transmission from the sensor. Rating of perceived exertion data were not obtained for n = 1 participant. Normality was tested using a Shapiro–Wilk test. Paired two-tailed t tests assessed differences between conditions (KE vs. PL) for mean 20-min time-trial power output, mean and peak heart rate, blood [β-hydroxybutyrate], [glucose], [lactate], total CO2, [bicarbonate], and pH before exercise, and mean [glucose] during exercise. Mean and peak rating of perceived exertion and total gastrointestinal symptom severity and incidence were tested for differences between conditions using a Wilcoxon test. A time period effect was assessed for mean time-trial power output by a two-tailed paired t test (Trials 1 vs. 2). Exploratory two-way repeated-measures analysis of variance (Condition × Time) tests were performed on power output, HR, and glucose via continuous glucose monitoring during the time trial. Statistical significance was accepted as p ≤ .05. All statistical analyses were performed using commercial software (Prism version 9, GraphPad Software). Normally distributed data are presented as mean ± SD, nonparametric data as median (interquartile range), change data as mean (95% confidence intervals), and effect sizes as Cohen’s dz.

Results

Time-Trial Data

Mean 20-min time-trial power output was 6.2 (1.7 to 10.2) W or 2.4% (0.6% to 4.1%) lower after KE versus PL ingestion (255 ± 54 vs. 261 ± 54, p = .01, dz = 0.60; Figure 2). Mean power output was not different when compared for order effect (Trial 1: 260 ± 53, Trial 2: 257 ± 56 W, p = .44, dz = 0.03). Mean heart rate during the time trial was lower after KE versus PL ingestion; however, peak heart rate, mean interstitial glucose (n = 19), and mean and peak rating perceived exertions were not different between conditions (Table 2). Eleven of the 22 participants reported a numerically higher rating of perceived exertion after KE versus PL ingestion, seven reported the same rating of perceived exertion in both conditions, and four reported a lower rating of perceived exertion after KE versus PL ingestion.

Figure 2
Figure 2

—Mean power output during the 20-min cycling time trial after ingestion of 0.35 g/kg KE or a ketone-free PL. Left: Bars are mean ± SD (n = 23). Middle: Lines connect individual participant data points. Right: Long line represents the mean change, error bars are the 95% confidence interval of the change, and dots are individual participants (open = male and closed = female). *p < .05 KE versus PL (paired two-tailed t test). KE = ketone monoester; PL = placebo.

Citation: International Journal of Sport Nutrition and Exercise Metabolism 33, 4; 10.1123/ijsnem.2022-0255

Table 2

Physiological and Perceptual Measurements During the 20-min Time Trial Performed 30 min After Ingestion of 0.35 g/kg KE or a Ketone-Free PL

PLKEΔpdz
Mean glucose (mg/dl)88 ± 1781 ± 12−7 (2 to −16).120.38
Heart rate (beats/min)
 Mean167 ± 15165 ± 14−2 (0 to −4).030.48
 Peak181 ± 13178 ± 13−2 (1 to −5).110.34
RPE (/20)
 Mean17 (16–18)17 (16–18)0.5 (0 to  1).11
 Peak19 (19–20)19 (19–20)0 (0 to 1).75

Note. Data are presented as mean ± SD for n = 23 participants for heart rate and n = 19 for mean glucose. Data are presented as median (interquartile range) for n = 22 for RPE as this was not normally distributed. Change scores of KE–PL (Δ) are presented as mean (95% confidence interval) for glucose and heart rate and median (95% confidence intervals) for RPE. Analyses are based on a two-tailed paired t test or Wilcoxon’s test as appropriate for KE versus PL. dz = Cohen’s effect size; RPE = rating of perceived exertion; KE = ketone monoester; PL = placebo.

*p < .05 versus PL.

Blood Data

The ketone body β-hydroxybutyrate was higher in whole venous blood samples after KE versus PL ingestion (2.0 ± 0.6 vs. 0.2 ± 0.1, p < .0001, dz = 3.1; Figure 3). Other blood measurements sampled before exercise are summarized in Table 3. Venous blood glucose, bicarbonate, and total CO2 content were lower after KE versus PL ingestion. Condition did not affect venous blood pH or lactate. Pre-exercise glucose determined by continuous glucose monitoring was 8 (0–15) mg/dl lower in after KE versus PL ingestion (75 ± 12 vs. 82 ± 17 mg/dl, p = .048, dz = 0.48).

Figure 3
Figure 3

—Preexercise whole venous blood β-hydroxybutyrate concentration after ingestion of 0.35 g/kg KE or a ketone-free PL. Bars are mean ± SD (n = 23), and lines connect individual participant data points. *p < .05 KE versus PL (paired two-tailed t test). KE = ketone monoester; PL = placebo.

Citation: International Journal of Sport Nutrition and Exercise Metabolism 33, 4; 10.1123/ijsnem.2022-0255

Table 3

Resting Venous Blood Metabolites and Acid–Base Status 30-min After Ingestion of 0.35 g/kg Body Mass of KE or a Ketone-Free PL

PLKEΔpdz
Glucose (mM)5.2 ± 0.64.7 ± 0.9*0.5 (0.1 to 1.0).020.57
Lactate (mM)2.0 ± 1.11.8 ± 0.90.2 (−0.4 to 0.7).560.13
pH7.32 ± 0.047.31 ± 0.030.01 (−0.02 to 0.03).650.10
Bicarbonate (mM)29.9 ± 1.928.2 ± 1.8*1.7 (0.8 to 2.6).00070.87
Total CO2 (mmHg)30.5 ± 2.028.9 ± 2.0*1.7 (0.7 to 2.6).0010.85

Note. Data are presented as mean ± SD for n = 23 participants β-hydroxybutyrate and n = 22 for other measures. Change scores (Δ) for KE–PL are mean (95% confidence interval). Analyses are based on a two-tailed paired t test for KE versus PL. dz = Cohen’s effect size; RPE = rating of perceived exertion; KE = ketone monoester; PL = placebo.

*p < .05 versus PL.

Questionnaire Data

Total gastrointestinal symptom incidence (1 [0 to 3] vs. 0 [0 to 0] of 19, p = .0005) and severity (0[0 to 1] vs 0[0 to 0] of 10, p = .0004) were statistically higher after KE versus PL ingestion. Upper gastrointestinal symptom incidence (1 [0 to 2] vs. 0 [0 to 0] of 7, p = .0001) and severity (0.4 [0 to 1] vs. 0 [0 to 0.1] of 10, p < .0001) were higher after KE versus PL ingestion, but incidence and severity of lower, other, and defecation gastrointestinal symptoms were not different between conditions (p < .28 for all). Within upper gastrointestinal symptoms, severity of belching (p = .03), heartburn (p = .004), bloating (p = .03), and stomach pain (p = .03) were higher after KE versus PL ingestion but urge to regurgitate (p = .12) was not different and there were no incidences of regurgitation or projectile vomiting. The median severity of any symptom assessed did not exceed a score of 1.

In response to “Could you tell whether you received the ketone monoester or PL?” n = 9 indicated “no” after both trials, n = 10 indicated “yes” after one trial, and n = 4 indicated “yes” after both trials. Of the 18 questionnaires that “yes” was selected, n = 11 follow-up responses to “Did you receive ketone monoester or PL?” matched the solution received (i.e., correct guess) and n = 7 did not match (i.e., incorrect guess). N = 3 participants correctly guessed the solution received in both trials.

Exploratory Time-Based Analyses

Mean power output in every quarter of the time trial was lower after KE versus PL ingestion (condition p = .01 and interaction p = .92; Figure 4a). HR at 5, 10, 15, and 20 min of the time trial was lower after KE versus PL ingestion (condition p = .04 and interaction p = .69; Figure 4b). Neither condition (p = .09) nor Condition × Time (p = .17) affected glucose via continuous glucose monitoring throughout the time trial (Figure 4c).

Figure 4
Figure 4

—(a) Power output, (b) heart rate, and (c) glucose determined from continuous glucose monitoring during the 20-min time trial after ingestion of 0.35 g/kg KE (gray circles) or a ketone-free PL (open circles). Data are presented as mean ± SD (n = 23 for power output and heart rate and n = 19 for glucose). *p < .05 main effect condition (KE vs. PL) from exploratory two-way repeated-measures analysis of variance. KE = ketone monoester; PL = placebo.

Citation: International Journal of Sport Nutrition and Exercise Metabolism 33, 4; 10.1123/ijsnem.2022-0255

Discussion

The primary finding of this study was that mean power output during a 20-min cycling time trial was lower after acute ingestion of a 0.35 g/kg body mass of a KE supplement ingested 30 min before exercise as compared with a ketone-free PL drink in trained cyclists who were studied in the postprandial state. The difference in time-trial power output was ∼2.4% lower after KE versus PL ingestion, which exceeded the minimal important difference that was established prior to data collection and for the purposes of estimating sample size.

Our findings agree with recent work by Poffe et al. (2021) who studied trained cyclists 2 hr after ingestion of a carbohydrate-rich breakfast. These authors reported that acute ingestion of 50 g (∼0.7 g/kg body mass) of KE with co-ingestion of carbohydrates elevated blood β-hydroxybutyrate to ∼3.5 mM and impaired 30-min cycling time-trial performance by ∼1.4% compared with carbohydrates alone. In that study, participants manually adjusted workload at 5-min intervals throughout the time trial, whereas in the present study participants adjusted workload at any time by altering the simulated “gear” and/or cadence. Both of these studies are also in agreement with the work of Leckey et al. (2017), who reported that acetoacetate diester ingestion impaired 31-km time-trial (∼50 min) performance in professional cyclists who were studied under conditions that simulated sport nutrition guidelines. The reported increase in blood β-hydroxybutyrate concentration in that study was <1 mM (Leckey et al., 2017), and all participants reported gastrointestinal distress potentially owing to the nature of the supplement. Overall, while the available body of work remains limited, it appears that ketogenic supplement ingestion impairs relatively short-duration, high-intensity cycling performance.

It has been proposed that ketogenic supplement ingestion may be ergogenic if the exercise test is performed under conditions that result in a circulating β-hydroxybutyrate concentration of 1–3 mM (Evans et al., 2017). Venous β-hydroxybutyrate concentration after KE supplement ingestion in the current study was ∼2 mM, but this was associated with impaired time-trial performance. These data, therefore, do not support the notion that increasing blood β-hydroxybutyrate concentration to a range of 1–3 mM is ergogenic, at least under the present study conditions. The potential effect of KE dose and the corresponding rise of blood β-hydroxybutyrate concentration on endurance performance in various tests requiring 1–2 hr of moderate- to high-intensity efforts are less clear (Cox et al., 2016; Evans & Egan, 2018; Evans et al., 2019; Peacock et al., 2022).

The lower HR during the time trial after KE ingestion may relate to effects of KE ingestion on peak HR and/or perceived exertion or reflect the lower time-trial power output. Interpreting these HR data are challenging because ingestion of 0.6 g/kg KE increased HR during submaximal cycling at a constant workload that was equivalent to ventilatory threshold intensity (McCarthy et al., 2021, 2023). It is unknown whether the comparatively lower dose of KE used in the current study would similarly affect exercise HR or whether HR responses to KE ingestion differ depending on relative exercise intensity. This is further complicated by the fact that mean power output was different during the 2 time trials in the present study. Despite the lower power output and HR achieved during the time trial after KE ingestion, ratings of perceived exertion were not statistically different between conditions. We previously reported that ingestion of 0.6 g/kg body mass KE increased perceived exertion during exercise at a fixed workload, and this response was related to subsequent performance in a approximately 15-min time trial (McCarthy et al., 2021). Thus, these data suggest that perceived exertion and HR remained affected by a relatively smaller dose of KE, but more work is needed to fully understand these effects.

Ingestion of 0.35 g/kg body mass of KE (∼25 g) did not affect preexercise blood pH but affected other metabolites involved in blood acid–base balance. In contrast, blood pH was lowered in fasted participants after ingestion of ∼0.3 g/kg body mass of KE (Dearlove et al., 2019; Stubbs et al., 2017) as well as in fed participants after ingestion of 45–50 g of KE (∼0.7 g/kg body mass; Poffé et al., 2021, 2020, 2021; Poffe et al., 2021). A stress to blood acid–base balance by KE ingestion in the current study is suggested by a lowering of blood [bicarbonate] and total CO2. These changes could indicate that excess hydrogen ions, presumably from the KE drink, required buffering by bicarbonate, which would then result in less free blood [bicarbonate] and more CO2 in the blood, trigger a rise in ventilation to compensate, and then the hyperventilation would reduce blood CO2. Thus, blood acid–base status was presumably still challenged in the current study before exercise, and it is possible that the hydrogen ions produced during exercise would have had a bigger effect on blood pH after KE compared to PL ingestion.

As seen in some studies (Evans & Egan, 2018; McCarthy et al., 2021; Poffé et al., 2020, 2021), KE ingestion slightly elevated the incidence and severity of gastrointestinal distress; however, the magnitude of change is unlikely to be practically relevant. Notably, a study primarily examining gastrointestinal symptoms during exercise after KE ingestion determined the incidence and severity of such to be no different than carbohydrate intake (Stubbs et al., 2019). The marginally higher gastrointestinal distress observed after KE versus PL ingestion in the current study was specific to the upper gastrointestinal tract and corresponded to an overall mean score of 1 versus 0 on a 10-point scale. The KE supplement is proposed to be largely absorbed in the upper gastrointestinal tract when provided in a low dose (Shivva et al., 2016), and, therefore, the lack of reported symptoms beyond the upper gastrointestinal tract may be because they were never exposed to the KE. Nonetheless, the gastrointestinal symptoms in response to KE ingestion were minimal.

A reduction in blood glucose at rest and during exercise is observed in many studies after KE ingestion (Falkenhain et al., 2022). A previously study from our laboratory reported that ingestion of 0.6 g/kg body mass KE reduced blood glucose when measured at rest but not immediately postexercise (McCarthy et al., 2021). In the present study, blood glucose before exercise was lowered by KE ingestion as determined by both venous sampling and continuous glucose monitoring, but exercise glucose determined by continuous glucose monitoring was not different between conditions. The mechanisms underlying the effect of KE on blood glucose during exercise are unclear, and studies involving stable isotope tracers are needed to comprehensively examine glucose kinetics during exercise.

A strength of the present work was that, in designing and conducting the study, we sought to meet best practice guidelines including those related to minimizing the risk of bias in reporting (Betts et al., 2020). The study protocol was registered prior to data collection and included information related to our hypotheses, sample size, and key outcomes. The final sample size (n = 23) exceeded our a priori estimate in this regard, which in turn was based on the difference observed from nutritional interventions generally considered to be ergogenic and day-to-day repeatability of the performance test used. A limitation of the present study is that the real-world extrapolation of the outcome is specific to the nature of the 20-min time trial, that is, high-intensity continuous type exercises. In addition, the 15-min self-determined warm-up does not necessarily mimic the longer, variable-intensity strategies that are often used by elite cyclists prior to competition. While 20-min time-trial performance is correlated with functional threshold power and both tests involve similar metabolic and physiologic demands, more work is required to determine the effects of KE ingestion on longer-duration endurance events. In addition, this study focused on performance and provides little insight into potential mechanisms that may explain the observed differences in performance. A comprehensive recent review by Evans et al. (2022) considers some of the potential mechanisms, and additional research is needed to advance the field in this regard.

In conclusion, we show that acute ingestion of 0.35 g/kg body mass KE impaired 20-min time-trial performance in trained cyclists when compared with a PL. Our data suggest that this effect may relate to the effect of KE ingestion on blood acid–base status, HR, and/or perceived exertion. This KE-associated impairment of performance occurred despite meaningful gastrointestinal distress during the time trial and [β-hydroxybutyrate] being elevated to a previously hypothesized ergogenic range. More work is required to elucidate the underlying physiological responses to acute KE ingestion and how these in turn may be linked to changes in exercise capacity.

Acknowledgments

We thank Fiona Powley and Sydney Baumgarten for assistance using the continuous glucose monitors, and our participants for their time and effort. Continuous glucose monitors were a kind gift from Supersapiens. Authorship: Conceptualization: McCarthy, Fong, Pinckaers, van Loon, and Gibala. Methodology: McCarthy, Fong, and Gibala. Validation: McCarthy and Fong. Investigation: McCarthy, Fong, Bone, Bostad, and Pinckaers. Resources: Gibala. Data curation: McCarthy, Fong, and Bone. Writing—original draft: McCarthy. Writing—review and editing: All authors. Visualization: McCarthy. Supervision: van Loon and Gibala. Project administration: McCarthy. Funding acquisition: Gibala. All authors approved the final version of this paper. Funding Sources: This work was supported by a Discovery Operating Grant from the Natural Sciences and Engineering Research Council (NSERC) to Gibala. McCarthy held an NSERC Canada Graduate Scholarship—Doctoral and Bostad held an NSERC Postgraduate Scholarship—Doctoral. Pinckaers was supported by receiving the Naomi Cermak Memorial Graduate Travel Scholarship. Protocol: This trial was registered as a clinical trial before data collection was initiated (NCT05226962).

References

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Supplementary Materials

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  • Figure 1

    —Overview of the experimental protocol. Trained cyclists (n = 23) ingested 0.35 g/kg body mass of a KE supplement (deltaG ketone performance) or a ketone-free PL in a randomized, crossover, triple-blinded manner (bottle image). Glucose was measured via continuous glucose monitoring. Blood drop = venous blood sampling; RPE = rating of perceived exertion; numbers = time in minutes; KE = ketone monoester; PL = placebo.

  • Figure 2

    —Mean power output during the 20-min cycling time trial after ingestion of 0.35 g/kg KE or a ketone-free PL. Left: Bars are mean ± SD (n = 23). Middle: Lines connect individual participant data points. Right: Long line represents the mean change, error bars are the 95% confidence interval of the change, and dots are individual participants (open = male and closed = female). *p < .05 KE versus PL (paired two-tailed t test). KE = ketone monoester; PL = placebo.

  • Figure 3

    —Preexercise whole venous blood β-hydroxybutyrate concentration after ingestion of 0.35 g/kg KE or a ketone-free PL. Bars are mean ± SD (n = 23), and lines connect individual participant data points. *p < .05 KE versus PL (paired two-tailed t test). KE = ketone monoester; PL = placebo.

  • Figure 4

    —(a) Power output, (b) heart rate, and (c) glucose determined from continuous glucose monitoring during the 20-min time trial after ingestion of 0.35 g/kg KE (gray circles) or a ketone-free PL (open circles). Data are presented as mean ± SD (n = 23 for power output and heart rate and n = 19 for glucose). *p < .05 main effect condition (KE vs. PL) from exploratory two-way repeated-measures analysis of variance. KE = ketone monoester; PL = placebo.

  • Aragon, A.A., Schoenfeld, B.J., Wildman, R., Kleiner, S., VanDusseldorp, T., Taylor, L., Earnest, C.P., Arciero, P.J., Wilborn, C., Kalman, D.S., Stout, J.R., Willoughby, D.S., Campbell, B., Arent, S.M., Bannock, L., Smith-Ryan, A.E., & Antonio, J. (2017). International society of sports nutrition position stand: Diets and body composition. Journal of the International Society of Sports Nutrition, 14(1), Article 16. https://doi.org/10.1186/s12970-017-0174-y

    • Search Google Scholar
    • Export Citation
  • Betts, J.A., Gonzalez, J.T., Burke, L.M., Close, G.L., Garthe, I., James, L.J., Jeukendrup, A.E., Morton, J.P., Nieman, D.C., Peeling, P., Phillips, S.M., Stellingwerff, T., van Loon, L.J.C., Williams, C., Woolf, K., Maughan, R., & Atkinson, G. (2020). Present 2020: Text expanding on the checklist for proper reporting of evidence in sport and exercise nutrition trials. International Journal of Sport Nutrition and Exercise Metabolism, 30, 213. https://doi.org/10.1123/ijsnem.2019-0326

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Borg, G.A. (1982). Psychophysical bases of perceived exertion. Medicine & Science in Sports & Exercise, 14(5), 337381. https://doi.org/10.1249/00005768-198205000-00012

    • Search Google Scholar
    • Export Citation
  • Brietzke, C., Franco-Alvarenga, P.E., Coelho-Júnior, H.J., Silveira, R., Asano, R.Y., & Pires, F.O. (2019). Effects of carbohydrate mouth rinse on cycling time trial performance: A systematic review and meta-analysis. Sports Medicine, 49(1), 5766. https://doi.org/10.1007/s40279-018-1029-7

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Burke, L.M., Ross, M.L., Garvican-Lewis, L.A., Welvaert, M., Heikura, I.A., Forbes, S.G., Mirtschin, J.G., Cato, L.E., Strobel, N., Sharma, A.P., & Hawley, J.A. (2017). Low carbohydrate, high fat diet impairs exercise economy and negates the performance benefit from intensified training in elite race walkers. The Journal of Physiology, 595(9), 27852807. https://doi.org/10.1113/JP273230

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Burke, L.M., Sharma, A.P., Heikura, I.A., Forbes, S.F., Holloway, M., McKay, A.K.A., Bone, J.L., Leckey, J.J., Welvaert, M., & Ross, M.L. (2020). Crisis of confidence averted: Impairment of exercise economy and performance in elite race walkers by ketogenic low carbohydrate, high fat (LCHF) diet is reproducible. PLoS One, 15(6), Article 4027. https://doi.org/10.1371/journal.pone.0234027

    • Search Google Scholar
    • Export Citation
  • Carr, A.J., Hopkins, W.G., & Gore, C.J. (2011). Effects of acute alkalosis and acidosis on performance: A meta-analysis. Sports Medicine, 41(10), 801814. https://doi.org/10.2165/11591440-000000000-00000

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Conger, S.A., Warren, G.L., Hardy, M.A., & Millard-stafford, M.L. (2011). Does caffeine added to carbohydrate provide additional ergogenic benefit for endurance? International Journal of Sport Nutrition & Exercise Metabolism, 21(1), 7184. https://doi.org/10.1123/ijsnem.21.1.71

    • Search Google Scholar
    • Export Citation
  • Cox, P.J., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., Murray, A.J., Stubbs, B., West, J., McLure, S.W., King, M.T., Dodd, M.S., Holloway, C., Neubauer, S., Drawer, S., Veech, R.L., Griffin, J.L., & Clarke, K. (2016). Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metabolism, 24, 256268. https://doi.org/10.1016/j.cmet.2016.07.010

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Coyle, E.F., Coggan, A.R., Hemmert, M.K., & Ivy, J.L. (1986). Muscle glycogen utilization during prolonged strenuous exercise when fed carbohydrate. Journal of Applied Physiology, 61(1), 165172. https://doi.org/10.1152/jappl.1986.61.1.165

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Coyle, E.F., Feltner, M.E., Kautz, S.A., Hamilton, M.T., Montain, S.J., Baylor, A.M., Abraham, L.D., & Petrek, G.W. (1991). Physiological and biomechanical factors associated with elite endurance cycling performance. Medicine & Science in Sports & Exercise, 23(1), 93107. https://papers3://publication/uuid/1159D463-C2B8-40B4-9232-357C1B4B6733

    • Search Google Scholar
    • Export Citation
  • Dearlove, D.J., Faull, O.K., Rolls, E., Clarke, K., & Cox, P.J. (2019). Nutritional ketoacidosis during incremental exercise in healthy athletes. Frontiers in Physiology, 10, Article 290. https://doi.org/10.3389/fphys.2019.00290

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Decroix, L., De Pauw, K., Foster, C., & Meeusen, R. (2016). Guidelines to classify female subject groups in sport-science research. International Journal of Sports Physiology and Performance, 11, 204213. https://doi.org/10.1123/ijspp.2015-0153

    • PubMed
    • Search Google Scholar
    • Export Citation
  • De Pauw, K., Roelands, B., Cheung, S.S., de Geus, B., Rietjens, G., & Meeusen, R. (2013). Guidelines to classify subject groups in sport-science research. International Journal of Sports Physiology and Performance, 8, 111122. https://doi.org/10.1123/ijspp.8.2.111

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Evans, M., Cogan, K.E., & Egan, B. (2017). Metabolism of ketone bodies during exercise and training: Physiological basis for exogenous supplementation. The Journal of Physiology, 595(9), 28572871. https://doi.org/10.1113/JP273185

    • PubMed
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