TABLE 1.
Overview of the comparisons included in this review1
| Study | Within/between2 | Participants, n (% male) | Sample population | Ketone supplement | Dosing of supplement | Duration of intervention | Study type3 | Outcome of interest4 | Time points included5 | Exercise? |
|---|---|---|---|---|---|---|---|---|---|---|
| Bharmal 20216 (27) | W, B | 18 (67) | Prediabetes | Monoester | 395 mg⋅(kg LBW)–1 | Acute | X | 0, 30, 60, 90, 120, 150 | No | |
| Clark 20216,7 (28) | W, B | 9 (100) | Healthy | Salt | 300 mg⋅(kg BW)–1 | Acute | X | BL, PRE, steady state, time trial | Yes | |
| Cox 20168,9 (29) | W, B | 10 (100) | Healthy | Monoester | 573 mg⋅(kg BW)–1 | Acute | X | –10, 0, 2, 5, 10, 25, 35, 45, 50, 60 | Yes | |
| Crabtree 202110 (30) | — | 25 (48) | Overweight/obesity | Salt | 2 × 11.8 g daily | 6 wk | II | Fasting glucose | — | No |
| Dearlove 20198 (31) | W, B | 12 (75) | Healthy | Monoester | 330 mg⋅(kg BW)–1 | Acute | X | –60, 0, 3, 15, 27, 39 | Yes | |
| Dearlove 2020 (I)8,11 (32) | W, B | 6 (83) | Healthy | Monoester | 252 mg⋅(kg BW)–1 | Acute | X | Pre-drink, Post-drink, 25%, 50%, 75% | Yes | |
| Dearlove 2020 (II)8,11 (32) | W, B | 6 (83) | Healthy | Monoester | 752 mg⋅(kg BW)–1 | Acute | X | Pre-drink, Post-drink, 25%, 50%, 75% | Yes | |
| Dearlove 2021 (33)8,12 | W | 6 (100) | Healthy | Monoester | 573 mg⋅(kg BW) –1 | Acute | S | Fasting glucose | –60, –30, 0 | Yes |
| Evans 2018a6,11 (34) | W, B | 19 (63) | Healthy | Salt | 468 mg⋅(kg BW)–1 | Acute | X | –60, –30, 0, 8, 16, 24, 32, 40, 48 | Yes | |
| Evans 2018b6 (35) | B | 11 (100) | Healthy | Monoester | 750 mg⋅(kg BW)–1 | Acute | X | Mean nonfasted glucose | Start, block 1, block 2, block 3, block 4, block 5, end RTE | Yes |
| Evans 20196 (36) | B | 8 (88) | Healthy | Monoester | 573 mg⋅(kg BW)–1 | Acute | X | Mean nonfasted glucose | 0, 20, 40, 60, end of time trial | Yes |
| Fischer 20188 (37) | W | 5 (60) | Healthy | Salt | 308 mg⋅(kg BW)–1 | Acute | S | 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330 | No | |
| Greaves 20206 (38) | W, B | 19 (53) | Healthy | Monoester | 482 mg⋅(kg BW) -1 | Acute | X | Glucose during MMTT | –15, 0, 15, 30, 60, 90, 120 | No |
| Holdsworth 20178,13 (39) | W, B | 12 (100) | Healthy | Monoester | 615 mg⋅(kg BW) -1 | Acute | X | –30, 0 | Yes | |
| James 2018 (40) | B | 10 (30) | Healthy | Salt | 11.7 g | Acute | X | Baseline, before exercise, after exercise | Yes | |
| McCarthy 2020 (41) | B | 12 (53) | Healthy | Monoester | 600 mg⋅(kg BW) -1 | Acute | X | 0, 35 | Yes | |
| Monzo 2020 (I)6 (42) | W | 6 (100) | Healthy | Monoester | 9.6 g | Acute | S | Fasting, after KE | No | |
| Monzo 2020 (II)6 (42) | W | 11 (83) | Heart failure | Monoester | 9.6 g | Acute | S | Fasting, after KE | No | |
| Moore 2021 (I)14 (43) | W | 13 (46) | Healthy | Salt | 7 g | Acute | S | 0, 60 | No | |
| Moore 2021 (II)14 (43) | W | 13 (46) | Healthy | Salt | 7 g | Acute | S | 0, 60 | No | |
| Mose 2021 (44)8,11,15 | B | 8 (100) | Healthy | Monoester | 50 g | Acute | X | Fasting glucose | 240, 270, 300, 330, 360, 420 | No |
| Mujica-Parodi 2020 (I)16 (45) | W | 8 (63) | Healthy | Monoester | 395 mg⋅(kg BW)–1 | Acute | S | Pre, post 10 min, post 80 min | No | |
| Mujica-Parodi 2020 (II)16 (45) | W | 30 (40) | Healthy | Monoester | 395 mg⋅(kg BW)–1 | Acute | S | Pre, post 10 min, post 80 min | No | |
| Myette-Côté 20186 (46) | W, B | 20 (50) | Healthy | Monoester | 482 mg⋅(kg BW)–1 | Acute | X | Glucose during OGTT | –30, 0, 15, 30, 60, 90, 120 | No |
| Myette-Côté 20196 (47) | W, B | 15 (33) | Overweight/obesity | Monoester | 482 mg⋅(kg BW)–1 | Acute | X | Glucose during OGTT | –30, 0, 15, 30, 60, 90, 120 | No |
| Nakagata 20216 (48) | B | 9 (56) | Prediabetes17 | Monoester | 482 mg⋅(kg BW)–1 | Acute | X | Glucose during OGTT | 15, 30, 60, 90, 120, 180 | No |
| O'Connor 2018 (I)8 (49) | W, B | 10 (20) | Healthy | Salt | 11.7 g | Acute | X | 0, 15, 30, 60, 120, 180, 240 | No | |
| O'Connor 2018 (II)8 (49) | W, B | 10 (20) | Healthy | Salt | 5.85 g | Acute | X | 0, 15, 30, 60, 120, 180, 240 | No | |
| O'Malley 20176,18 (50) | W, B | 10 (100) | Healthy | Salt | 300 mg⋅(kg BW)–1 | Acute | X | Fasting, post-supplement, post-exercise, post-time trial | Yes | |
| Poffé 20196 (51) | — | 18 (100) | Healthy | Monoester | 1–3 ⋅ 25 g daily | 3 wk | II | Nonfasted glucose | — | Yes |
| Poffé 20206,11 (52) | (W), B | 12 (100) | Healthy | Monoester | 65 g | Acute | X | Mean nonfasted glucose | –60, –30, 0, 30, 60, 90, 120, 150, 180, 200 | Yes |
| Poffé 2021a (I)6,11,19 (53) | (W), B | 9 (100) | Healthy | Monoester | 65 g | Acute | X | Mean nonfasted glucose | –60, –30, 0, 30, 60, 90, 120, 150, 180, 200 | Yes |
| Poffé 2021a (II)6,11,19 (53) | B | 9 (100) | Healthy | Monoester | 65 g | Acute | X | Mean nonfasted glucose | –60, –30, 0, 30, 60, 90, 120, 150, 180, 200 | Yes |
| Poffé 2021b (I)6,11,19 (54) | B | 12 (100) | Healthy | Monoester | 50 g | Acute | X | Mean nonfasted glucose | 0, 15, 30 | Yes |
| Poffé 2021b (II)6,11,19 (54) | B | 12 (100) | Healthy | Monoester | 50 g | Acute | X | Mean nonfasted glucose | 0, 15, 30 | Yes |
| Poffé 2021c (I)6,11,19 (55) | B | 14 (100) | Healthy | Monoester | 75 g | Acute | X | Mean nonfasted glucose | 60, 90, 120, 150, 180, 200 | Yes |
| Poffé 2021c (II)6,11,19 (55) | B | 14 (100) | Healthy | Monoester | 75 g | Acute | X | Mean nonfasted glucose | 60, 90, 120, 150, 180, 200 | Yes |
| Rittig 20206,20 (56) | W | 8 (100) | Healthy | Salt | 36.5 g | Acute | S | 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180 | No | |
| Rodger8 2017 (57) | B | 12 (100) | Healthy | Salt | 23.4 g | Acute | X | 90, post 4PT | Yes | |
| Soto-Mota 201921 (58) | (W), — | 24 (50) | Healthy | Monoester | 3 ⋅ 26.8 g daily | 28 d | S | Mean nonfasted glucose | 30 | No |
| Soto-Mota 2021a (59) | — | 21 (67) | Type 2 Diabetes | Monoester | 3 ⋅ 25 g daily | 4 wk | S | Mean daily glucose | Without ketone monoester, with ketone monoester | No |
| Soto-Mota 2021b (60)22 | W | 10 (50) | Healthy | Monoester | 25 g | Acute | S | Fasting glucose | 0, 15, 30, 45, 60, 75, 90, 120 | No |
| Stubbs 2017a6 (61) | W | 15 (67) | Healthy | Monoester | 380 mg⋅(kg BW)–1 | Acute | S | 0, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h | No | |
| Stubbs 2017b (I)6,23 (62) | W | 15 (60) | Healthy | Monoester | 141 mg⋅(kg BW)–1 | Acute | S | 0, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h | No | |
| Stubbs 2017b (II)6,23 (62) | W | 15 (60) | Healthy | Monoester | 282 mg⋅(kg BW)–1 | Acute | S | 0, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h | No | |
| Stubbs 2017b (III)6,23 (62) | W | 15 (60) | Healthy | Salt | 141 mg⋅(kg BW)–1 | Acute | S | 0, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h | No | |
| Stubbs 2017b (IV)6,23 (62) | W | 15 (60) | Healthy | Salt | 282 mg⋅(kg BW)–1 | Acute | S | 0, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h | No | |
| Stubbs 2017b (V)6,23 (62) | W | 16 (63) | Healthy | Monoester | 395 mg⋅(kg BW)–1 | Acute | S | 0, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h | No | |
| Stubbs 2017b (VI)6,23 (62) | (W) | 16 (63) | Healthy | Monoester | 395 mg⋅(kg BW)–1 | Acute | S | Mean nonfasted glucose | 0, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h | No |
| Svart 20206 (63) | B | 6 (100) | Healthy | Salt | 36.5 g | Acute | X | Glucose during clamp | 150, 180, 210, 240, 250, 260, 270 | No |
| Vandoorne 20176,11 (64) | B | 8 (100) | Healthy | Monoester | 1500 mg⋅(kg BW)–1 | Acute | X | Mean nonfasted glucose | 30, 60, 90, 120, 150, 180, 210, 240, 270, 300 | Yes |
| Vestergaard 20216,24 (65) | W, B | 10 (100) | Healthy | Monoester | 714 mg⋅(kg BW)–1 | Acute | X | 0, 30, 60, 120, 180, 240, 300 | No | |
| Waldman 2018 (66) | B | 15 (100) | Healthy | Salt | 11.38 g | Acute | X | Pre, post | Yes | |
| Waldman 20206,11 (67) | W, B | 16 (100) | Healthy | Salt | 468 mg⋅(kg BW)–1 | Acute | X | –60, –15, 10, 30 | Yes | |
| Walsh 2020 (I)6 (68) | — | 14 (29) | Overweight/obesity | Monoester | 3 ⋅ 12 g daily | 14 d | X | Fasting glucose, mean daily glucose | — | No |
| Whitfield 2021 (I)6,25 (69) | (W) | 3 (83) | Healthy | Monoester | 573 mg⋅(kg BW)–1 | Acute | S | Mean nonfasted glucose | Rest, post-KE | Yes |
| Whitfield 2021 (II)6,25 (69) | (W) | 3 (83) | Healthy | Monoester | 573 mg⋅(kg BW)–1 | Acute | S | Mean nonfasted glucose | Rest, post-KE | Yes |
| Whitfield 2021 (II)6,25 (69) | (W) | 3 (83) | Healthy | Monoester | 573 mg⋅(kg BW)–1 | Acute | S | Mean nonfasted glucose | –30, –5 | Yes |
BHB, β-hydroxybutyrate; BIC, bicarbonate; BL, baseline; BLG, beta-lactoglobulin; BW, body weight; CAT, catabolic condition; CHO, carbohydrate; CON, control; II, parallel study design;KD, ketogenic diet; KET, ketone supplementation; KS, ketone salt; LBW, lean body weight; MMTT, mixed-meal tolerance test; Monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate; OGTT, oral-glucose-tolerance test; PRE, end of the pre-exercise condition 30 minutes after supplement ingestion; RTE, shuttle run to exhaustion; S, single-arm study design; X, crossover study design; 4PT, 4-minutes maximal cycling performance test.
Refers to which main analysis the respective study is included in: B, between-condition analysis; W, within-group analysis; (W), within-group measurements in nonfasted state; therefore, included only in exploratory sensitivity analyses; —, narrative summary.
Study type refers to how the study is treated for this review (i.e., if the original study followed a crossover design but had an ineligible comparator arm, it was treated as a single-arm study for the purpose of this review and its analyses).
If nothing is indicated, outcome of interest is “mean fasted glucose” (i.e., average glucose following supplement consumption in a fasted state); “mean nonfasted glucose” refers to average glucose following supplement consumption in a nonfasted state or alongside nutrient consumption.
All time points following supplement consumption included in between-condition analyses, all time points before and following supplement consumption before onset of exercise or ingestion of nutrients included in within-group analyses (minutes, unless otherwise stated).
Data provided by authors upon request.
CON vs KET.
Data extracted via graph reader online (12).
Study 2/5.
KD + KS vs. KD + PL.
Ketone supplement was provided in multiple boluses.
KE + CHO.
Ketone vs. control drink before onset of hyperglycemic clamp.
Moore 2021 (I), racemic salts; (II), natural salts; average (mean) of both measurement devices used.
CAT-BLG vs. CAT-BLG + BHB.
Mujica-Parodi (I), MRS time course study; (II), fMRI bolus study.
Individuals had impaired glucose tolerance; treated as prediabetes for the purpose of this review.
Insulin data was provided by Neudorf et al. (70).
Poffé 2021a and 2021b and 2021c (I), KE vs. CON; (II), BIC vs. BIC + KE.
Oral condition.
Random glucose measurements before and 30 min following a 25-mL drink of ketone monoester averaged across weeks 1–4 included in (W) analysis.
KE; data extracted from preprint version of the paper (https://doi.org/10.21203/rs.3.rs-355173/v2; accessed 13 December 2021); only mean values were reported, therefore SD imputed as the average SD across studies using a similar design (no exercise, single-dose, monoester, healthy population).
Stubbs 2017b (I–IV), Study 1/3; (V), Study 2/3 in fasted state; (VI), Study 2/3 in fed state.
KE vs PBO.
Total sample size of n = 9 (in LCHF intervention arm) divided by 3 outcomes: Whitfield 2021 (I), Baseline + KE; (II), Adaptation + KE; (III), LCHF Adaptation + KE in 10,000-m race; 83% of total participants were male.