Ketone Diester Ingestion Impairs Time-Trial Performance in Professional Cyclists

May combine two claims.

There was no difference in ratings of perceived exertion between KET and PLAC trials despite lower heart rate and power output in the KET condition.

“There was no difference in RPE between trials despite the lower HR and PO in the KET condition.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Ratings of perceived exertion increased in both KET and PLAC trials from mid- to post-time trial.

“RPE increased in both the KET (16 ± 2 to 19 ± 2) and the PLAC (15 ± 2 to 19 ± 1) trials from mid- to post-TT (P < 0.001).”

May combine two claims.

Serum β-hydroxybutyrate, serum acetoacetate, and urine ketone concentrations increased from rest following ketone ingestion and were higher than placebo throughout the trial.

“Serum β-hydroxybutyrate, serum acetoacetate, and urine ketone concentrations increased from rest following ketone ingestion and were higher than placebo throughout the trial.”

May combine two claims.

One participant experienced severe side effects from KET ingestion during and after the warm-up, including prolonged vomiting and dizziness, and was unable to complete the time trial.

“Eleven cyclists commenced this study, but one participant experienced severe side effects from KET ingestion during and after the warm-up, including prolonged vomiting and dizziness and was unable to complete the TT.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Six participants identified an 'unusual' centrally-derived feeling during the time trial in the KET trial that they thought might be associated with better performance.

“Although each of the riders nominated their gut symptoms as a distraction or interference to performance, six participants identified an “unusual” centrally-derived feeling during the TT in the KET trial that they thought might be associated with better performance.”

May combine two claims.

Blood βHB concentrations increased from pre-TT to post-TT in the KET trial (P < 0.001) and this increase was maintained until t = TT + 60 min (P = 0.03).

“Blood βHB concentrations increased from pre-TT to post-TT in the KET trial (P < 0.001) and this increase was maintained until t = TT + 60 min (P = 0.03; Figure 5B).”

May combine two claims.

Serum βHB concentrations increased in the KET trial following dose one of KET ingestion (t = 90 min) and remained significantly higher than the PLAC trial until t = TT + 60 min.

“There was an increase in βHB concentrations in the KET trial following dose one of KET ingestion (t = 90 min) and βHB remained significantly higher than PLAC trial until t = TT + 60 min.”

May combine two claims.

Serum βHB concentrations increased from t = 0 in the PLAC trial at the onset of the warm up (t = 100 min) but remained lower than in the KET trial.

“An increase in βHB concentrations from t = 0 was measured in the PLAC trial at the onset of the warm up (t = 100 min; Figure 4B) however βHB remained lower than in the KET trial.”

May combine two claims.

Serum FFA concentrations showed an effect of time (P < 0.001) and treatment (P = 0.021).

“There was an effect of time (P < 0.001) and treatment (P = 0.021) for serum FFA concentrations (Figure 4A).”

Probably not a substantial claim: may not pass S3 (load-bearing).

There was an effect of time for power output and cadence during the time trial.

“There was an effect of time (P < 0.001) for power output and cadence during the TT, as displayed in Figure 3.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The participant who experienced severe side effects from KET ingestion withdrew from further participation in the study.

“This participant withdrew from further participation in the study.”

May combine two claims.

There was a significant condition × time interaction for blood glucose (P = 0.036) and lactate concentrations (P < 0.001).

“There was a significant condition × time interaction for blood glucose (P = 0.036) and lactate concentrations (P < 0.001; Figures 6A,B).”

May combine two claims.

Serum AcAc concentration significantly increased from t = 0 min following dose one of KET ingestion (P = 0.001) and remained higher until t = TT + 60 min.

“Serum AcAc concentration significantly increased from t = 0 min following dose one of KET ingestion (P = 0.001) and remained higher until t = TT + 60 min (Figure 4C).”

May combine two claims.

Serum βHB concentrations peaked immediately following the TT (>0.4 mmol/L) rather than at ~1 h following ingestion as aimed.

“We measured a modest increase in serum βHB concentrations in the ketone trial, reaching >0.3 mmol/L following the warm-up, but to our surprise serum βHB concentrations peaked immediately following the TT (>0.4 mmol/L; Figure 4B).”

May combine two claims.

Blood lactate concentrations increased from pre-warm up at the end of stage 3 (t = 110 min) in both the KET and PLAC trials but had returned to resting values pre-TT for both trials.

“Blood lactate concentrations increased from pre-warm up at the end of stage 3 (t = 110 min) in both the KET and PLAC trials but had returned to resting values pre- TT for both trials.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

There was a main effect of time in the KET and PLAC trials for VO2, VCO2, and RER (P < 0.001), with an increase throughout the incremental warm up from stage 1 to stage 3.

“There was a main effect of time in the KET and PLAC trials for VO2, VCO2, and RER (P < 0.001), where an increase was observed throughout the incremental warm up from stage 1 to stage 3 (Table 1).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

There was a main effect of time for BM (P < 0.001) with a similar loss in the KET (1.6 ± 0.7 kg) and PLAC (1.4 ± 0.4 kg) trials.

“There was a main effect of time for BM (P < 0.001) where a similar loss was measured in the KET (1.6 ± 0.7 kg) and PLAC (1.4 ± 0.4 kg) trials.”

May combine two claims.

Urine ketone concentration did not differ at t = 0 between KET and PLAC, but following KET ingestion, urine ketones were higher at pre-TT, post-TT, and at t = TT + 60 min for KET.

“No differences were observed at t = 0 between KET and PLAC for urine ketone concentration, but following KET ingestion, urine ketones were higher at pre-TT, post-TT, and at t = TT + 60 min for KET.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study conformed to the Declaration of Helsinki and was approved by the Ethics Committee of the Australian Institute of Sport.

“This study conformed to the standards set by the Declaration of Helsinki and was approved (#20161005) by the Ethics Committee of the Australian Institute of Sport (AIS).”

Probably not a substantial claim: may not pass S3 (load-bearing).

There was no order effect on performance due to the crossover allocation of treatments.

“All cyclists completed the TT in a faster time in PLAC compared with KET, with the crossover allocation of treatments meaning that there was no order effect on performance.”

Classified as probably not a substantial claim. May combine two claims.

High circulating concentrations of ketone bodies could inhibit the flux of other muscle substrates, either by impairing muscle carbohydrate oxidation and/or inhibiting adipose tissue lipolysis.

“Nevertheless, there is some concern that the presence of high circulating concentrations of ketone bodies could inhibit the flux of other muscle substrates, either by impairing (rather than “sparing”) muscle CHO oxidation and/or inhibiting adipose tissue lipolysis (Evans et al., 2017).”

• cites Evans et al., 2017 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

None of the participants had previously ingested a ketone ester supplement and were therefore unable to recognize its characteristics.

“In any case, none of the participants had previously ingested a ketone ester supplement and were therefore unable to recognize its characteristics.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

As exercise intensity increases, there is a greater reliance on carbohydrate-based fuels and a reduction in the utilization of fat substrates.

“As exercise intensity increases, there is a greater reliance on carbohydrate (CHO) based fuels (i.e., muscle and liver glycogen, blood glucose, lactate) and a reduction in the utilization of fat substrates (Brooks and Mercier, 1994).”

• cites Brooks and Mercier, 1994 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

All participants provided written informed consent.

“After comprehensive details of the study protocol were explained to the participants verbally and in writing, all participants provided written informed consent.”

Classified as probably not a substantial claim. May combine two claims.

The study was a randomized crossover, double-blind, placebo-controlled design using elite professional cyclists.

“The study was a randomized crossover, double-blind, placebo-controlled design using elite (professional) cyclists attending a pre-season camp at the AIS, Canberra.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Expired gases were collected into a calibrated Douglas bag gas analysis system.

“During the maximal test, expired gases were collected into a calibrated and customized Douglas bag gas analysis system, as previously described (Russell et al., 2002).”

• cites Russell et al., 2002Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Participants were familiarized with the cycling ergometer and the experimental exercise protocol before the experimental phase.

“Before commencing the experimental phase, participants visited the laboratory to complete an incremental exercise test and a familiarization with the cycling ergometer (Velotron, Racermate Inc., Seattle, WA, USA) and the experimental exercise protocol (simulated 2017 World Championships time trial course, Bergen Norway).”

Probably not a substantial claim: may not pass S3 (load-bearing).

All participants correctly nominated the trial in which they received KET, identifying it via gastrointestinal side-effects.

“All participants correctly nominated the trial in which they received KET, identifying it via the gastrointestinal side-effects.”

Classified as probably not a substantial claim.

Carbohydrate and caffeine intake were standardized the evening before and morning of a trial day.

“CHO and caffeine intake were standardized the evening before and morning of a trial day and participants were also instructed to abstain from alcohol during the 24 h period prior to a trial day.”

Classified as probably not a substantial claim.

The SRM cycling power meter was calibrated.

“The set-up of the bike was performed by team mechanics to replicate each rider's unique bicycle position and was fitted with a calibrated (Gardner et al., 2004) SRM cycling power meter (scientific version, 8 strain gauge, Schoberer Rad Meβtechnik; Jülich, Germany), set to sample at 1-s intervals.”

• cites Gardner et al., 2004Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Only four of the cyclists correctly identified the trial in which they completed the time trial in the fastest time, with one cyclist equivocal.

“However, only four of the cyclists correctly identified the trial in which they completed the TT in the fastest time, with one cyclist equivocal.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Pilot testing revealed that the intake of a small volume of diet cola immediately after the KET and PLAC drinks was able to quickly mask the taste and texture of the previous drink.

“Pilot testing revealed that the intake of a small volume of diet cola immediately after the KET and PLAC was able to quickly mask the taste and texture of the previous drink.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The KET and PLAC drinks were not completely taste-matched, but a comparably novel and bitter-tasting placebo was prepared from flavor essences.

“It was not possible to completely replicate the taste of the KET drink, but a comparably novel and bitter-tasting PLAC was prepared from a mixture of flavor essences (rum, almond, and bitters Angostura).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Chronic exposure to a ketogenic diet raises plasma ketone bodies to 1-2 mmol/L after several days.

“Meanwhile, chronic exposure to a ketogenic diet [low CHO (<50 g/d), low-moderate protein (~15% of energy), high fat (75–80% of energy)] raises plasma ketone bodies to 1–2 mmol/L after several days, with concentrations reaching the apparent plateau achieved by prolonged fasting, according to the level of CHO restriction and duration of “keto-adaptation” (Pinckaers et al., 2017).”

• cites Pinckaers et al., 2017Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Ingestion of ketone salts appears to be less effective in increasing circulating ketone body concentrations and carries a significant salt load.

“Ingestion of the former appears to be less effective in increasing circulating ketone body concentrations and carries a significant salt load (Balasse and Ooms, 1968).”

• cites Balasse and Ooms, 1968Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The ketone ester synthesized, 1,3-butanediol acetoacetate diester, is a non-ionized sodium-free and pH-neutral precursor of acetoacetate.

“The ketone ester synthesized, 1,3-butanediol acetoacetate diester, is a non-ionized sodium-free and pH-neutral precursor of AcAc (D'Agostino et al., 2012).”

• cites D'Agostino et al., 2012Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Ketone bodies are produced in the liver mitochondria from acetyl-CoA in response to an increased mobilization of free fatty acids from adipose tissue in situations of reduced carbohydrate availability.

“Ketone bodies, namely D-β-hydroxybutyrate (βHB), acetone and acetoacetate (AcAc), are produced in the liver mitochondria from acetyl-CoA in response to an increased mobilization of free fatty acids (FFA) from adipose tissue in situations of reduced CHO availability (Robinson and Williamson, 1980).”

• cites Robinson and Williamson, 1980 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The variation in D-βHB concentrations via enzymatic analysis (serum) and whole blood is consistent with previous literature reporting a -0.5 to 0.6 mmol/L higher concentration with handheld monitors.

“This variation in D-βHB concentrations via enzymatic analysis (serum) and whole blood is consistent with previous literature reporting a –0.5 to 0.6 mmol/L higher concentration with handheld monitors (Pineda and Cardoso, 2015).”

• cites Pineda and Cardoso, 2015Not checked yet

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May combine two claims.

Gastrointestinal discomfort and/or some direct effect of ketones on the brain increased the perception of effort, and the cyclists reduced their work output to enable the TT to be completed without premature exhaustion, in accordance with the psychobiological model of pacing.

“This suggests that the gastrointestinal discomfort and/or some direct effect of ketones on the brain increased the perception of effort, and in accordance with the psychobiological model of pacing (Pageaux et al., 2014), our highly experienced cyclists reduced their work output to enable the TT to be completed without premature exhaustion.”

• cites Pageaux et al., 2014Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Under conditions of high carbohydrate availability, circulating concentrations of ketone bodies are low, but are slightly elevated (0.1-0.5 mmol/L) by an overnight fast and further raised by exercising in a fasted state (0.5-1.0 mmol/L).

“As summarized in recent reviews (Egan and D'Agostino, 2016; Pinckaers et al., 2017), under conditions of high CHO availability, circulating concentrations of ketone bodies are low, but are slightly elevated (0.1–0.5 mmol/L) by an overnight fast and further raised by exercising in a fasted state (0.5–1.0 mmol/L).”

• cites Egan and D'Agostino, 2016Not checked yet

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• cites Pinckaers et al., 2017Not checked yet

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May combine two claims.

Cox et al. (2016) found that ingesting CHO plus ketone ester (573 mg·kg−1 BM) induced higher blood D-βHB during submaximal cycling (~1.5-3 mmol/L) and improved time-trial performance by ~2% compared to CHO alone.

“Their ingestion protocol induced a higher blood D-βHB concentration during submaximal cycling (ranging between ~1.5 and 3 mmol/L) and lead to a subsequent improvement in time-trial (TT) performance by ~2% following ketone ester and CHO ingestion compared to the ingestion of only CHO.”

• cites Cox et al. (2016) sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

A ketone monoester, R-3-hydroxybutyl R-3-hydroxybutyrate, increases plasma ketone concentrations (3-6 mmol/L) within the hours following its ingestion (400-600 mg/kg BM), although this may be altered by concomitant intake of food.

“Recently, a newly produced ketone monoester, R-3-hydroxybutyl R-3-hydroxybutyrate (Clarke et al., 2012), increases in plasma ketone concentrations (3–6 mmol/L) within the hours following its ingestion (400–600 mg/kg BM), although this may be altered by concomitant intake of food (Evans et al., 2017; Pinckaers et al., 2017).”

• cites Clarke et al., 2012Not checked yet

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• cites Evans et al., 2017 sourceNot checked yet

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• cites Pinckaers et al., 2017Not checked yet

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May combine two claims.

The use of enzymatic analysis in the current study measures only the D-enantiomer, which is the main circulating form of βHB and the most likely to have a direct effect on substrate metabolism and skeletal muscle responses.

“The use of enzymatic analysis in the current study measures only the D- enantiomer which is the main circulating form of βHB and the most likely to have a direct effect on substrate metabolism and skeletal muscle responses (Yamada et al., 2010).”

• cites Yamada et al., 2010Not checked yet

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May combine two claims.

Clarke and Cox (2015) and Cox et al. (2016) reported 1-2% improvements in 30 min rowing performance and 30 min TT performance, respectively, following ingestion of a similar ketone dose to the current study (573 vs. 500 mg/kg BM, respectively) in combination with CHO, compared to CHO alone.

“Indeed, Clarke and Cox (2015) and Cox et al. (2016) reported 1–2% improvements in 30 min rowing performance and 30 min TT performance, respectively, following ingestion of a similar ketone dose to the current study (573 vs. 500 mg/kg BM, respectively) in combination with CHO, compared to CHO alone.”

• cites Clarke and Cox, 2015Not checked yet

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• cites Cox et al., 2016 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The reduction in heart rate may be associated with a slightly reduced average power output in the ketone trial.

“We also reported a modest reduction in heart rate during the TT in the ketone trial compared to the placebo trial (5 bpm) which may be associated with a slightly reduced average power output and in the ketone trial.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Cox et al. (2016) reported an increase in βHB concentrations to ~2 mmol/L within 20 min of ketone ester ingestion when co-ingested with CHO or ~4 mmol/L when ingested alone.

“Cox et al. (2016) reported an increased in βHB concentrations to ~2 mmol/L within 20 min of ketone ester ingestion when co-ingested with CHO or ~4 mmol/L when ingested alone.”

• cites Cox et al., 2016 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The world-class cyclists who participated were personally motivated to receive individual and group results, and were highly experienced in TT cycling as well as familiarized to the specific laboratory-based course simulation.

“Furthermore, the world-class cyclists from the team who participated in the study were personally motivated to receive individual and group results, and were highly experienced in TT cycling as well as familiarized to the specific laboratory-based course simulation.”

May combine two claims.

Despite optimal nutritional support, ketone ingestion was associated with an increase in perception of effort, leading to an impairment of TT performance in elite professional cyclists.

“Despite optimal nutritional support (i.e., CHO breakfast, feeding during the TT and caffeine ingestion) for performance, ketone ingestion was associated with an increase in perception of effort, leading to an impairment of TT performance in elite professional cyclists.”

May combine two claims.

The study did not estimate rates of substrate oxidation because βHB and AcAc yield respiratory exchange quotient values of 0.89 and 1.00, respectively, and without appropriate correction factors for CO2 displacement and urine volume this would lead to an inaccurate representation of substrate utilization.

“We have not estimated rates of substrate oxidation rates due to βHB and AcAc yielding respiratory exchange quotient values of 0.89 and 1.00, respectively and thus without appropriate correction factors for CO2 displacement and urine volume this would lead to an inaccurate representation of substrate utilization (Frayn, 1983; Pinckaers et al., 2017).”

• cites Frayn, 1983Not checked yet

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• cites Pinckaers et al., 2017Not checked yet

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Classified as probably not a substantial claim.

Team sports scientists provided a simulation of the profile of the 2017 World Championships TT course (Bergen, Norway) on a cycle ergometer.

“Team sports scientists were able to provide a simulation of the profile of the 2017 World Championships TT course (Bergen, Norway) on a cycle ergometer.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

These side effects have been associated with high dose of ketone ester and the consumption of the ester with a milk-based drink.

“These side effects have been associated with high dose of ketone ester and the consumption of the ester with a milk-based drink (Clarke and Cox, 2015).”

• cites Clarke and Cox, 2015Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The high ketone concentrations in the urine suggest that ketones are not being oxidized at the skeletal muscle.

“Alternatively the high ketone concentrations in the urine suggest that the ketones are not being oxidized at the skeletal muscle.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The variation in serum βHB is likely explained by a range of factors including the different ketone esters used, the elite training status of cyclists, and the different pre-ingestion nutritional strategies.

“This variation in serum βHB is likely explained by a range of factors including the different ketone esters used, the elite training status of cyclists in the current study and the different pre-ingestion nutritional strategies were the current study focused on appropriate race preparation practices.”

• AssumptionRests on an assumption: The ketone diester used in the study is sufficiently similar to the ketone monoester used by Cox et al. (2016) to allow comparison of their effects on performance and metabolism.

Probably not a substantial claim: may not pass S3 (load-bearing).

Race nutrition strategies (24 h prior, pre-race and during race) were standardized and made realistic by involving meal preparation by the team chef to suit both sports nutrition guidelines and the cultural practices of the riders.

“Race nutrition strategies (24 h prior, pre-race and during race) were standardized and made realistic by involving meal preparation by the team chef to suit both sports nutrition guidelines (Thomas et al., 2016) and the cultural practices of the riders.”

• cites Thomas et al., 2016 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The lack of RER differences could be related to the absolute exercise intensities attained by the elite subjects (155, 310, 355 W).

“No differences in RER were measured between the ketone and placebo trials, although this could be related to the absolute exercise intensities attained by our elite subjects (155, 310, 355 W).”

Probably not a substantial claim: may not pass S3 (load-bearing).

The difference in FFA concentration between the ketone and placebo trials could be related to circulating ketone bodies having the ability to suppress lipolysis via inhibition of catecholamine's.

“However, the difference in FFA concentration between the ketone and placebo trials could be related to circulating ketone bodies having the ability to suppress lipolysis via inhibition of catecholamine's (Bjorntorp and Schersten, 1967).”

• cites Bjorntorp and Schersten, 1967Not checked yet

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May combine two claims.

Participants were cycling at 340-350 W during the TT, and thus the estimated contribution of FFA oxidation to total energy expenditure would likely be low as at this intensity the muscle relies predominantly on CHO-based fuels.

“Participants were cycling at 340–350 W during the TT and thus estimated contribution of FFA oxidation to total energy expenditure would likely be low as at this intensity, the muscle relies predominately on CHO-based fuels (Hawley and Leckey, 2015).”

• cites Hawley and Leckey, 2015Not checked yet

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