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Cited by 101Diet and metabolism studiesDietary Effects on HealthNutritional Studies and Diet

Effects of ketogenic diet on health outcomes: an umbrella review of meta-analyses of randomized clinical trials

Open access
Patikorn, Chanthawat, Saidoung, Pantakarn, Pham, Tuan, Phisalprapa, Pochamana, Lee, Yeong Yeh, Varady, Krista A., Veettil, Sajesh K., Chaiyakunapruk, Nathorn·2023·BMC Medicine
DOI 10.1186/s12916-023-02874-yPMC PMC10210275
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Abstract

Background: Systematic reviews and meta-analyses of randomized clinical trials (RCTs) have reported the benefits of ketogenic diets (KD) in various participants such as patients with epilepsy and adults with overweight or obesity . Nevertheless, there has been little synthesis of the strength and quality of this evidence in aggregate. Methods: To grade the evidence from published meta-analyses of RCTs that assessed the association of KD, ketogenic low-carbohydrate high-fat diet (K-LCHF), and very low-calorie KD (VLCKD) with health outcomes, PubMed, EMBASE, Epistemonikos, and Cochrane database of systematic reviews were searched up to February 15, 2023. Meta-analyses of RCTs of KD were included. Meta-analyses were re-performed using a random-effects model. The quality of evidence per association provided in meta-analyses was rated by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) criteria as high, moderate, low, and very low. Results: We included 17 meta-analyses comprising 68 RCTs (median [interquartile range, IQR] sample size of 42 [20–104] participants and follow-up period of 13 [8–36] weeks) and 115 unique associations. There were 51 statistically significant associations (44%) of which four associations were supported by high-quality evidence (reduced triglyceride ( n = 2), seizure frequency ( n = 1) and increased low-density lipoprotein cholesterol (LDL-C) ( n = 1)) and four associations supported by moderate-quality evidence (decrease in body weight, respiratory exchange ratio (RER), hemoglobin A 1c , and increased total cholesterol). The remaining associations were supported by very low (26 associations) to low (17 associations) quality evidence. In overweight or obese adults, VLCKD was significantly associated with improvement in anthropometric and cardiometabolic outcomes without worsening muscle mass, LDL-C, and total cholesterol. K-LCHF was associated with reduced body weight and body fat percentage, but also reduced muscle mass in healthy participants. Conclusions: This umbrella review found beneficial associations of KD supported by moderate to high-quality evidence on seizure and several cardiometabolic parameters. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether the short-term effects of KD will translate to beneficial effects on clinical outcomes such as cardiovascular events and mortality.

AI snapshot

Written from the paper’s full text.

TL;DR

This umbrella review of 17 meta-analyses covering 68 RCTs and 115 unique associations found that ketogenic diets have beneficial associations supported by moderate- to high-quality evidence for seizure frequency and several cardiometabolic parameters, but also a clinically meaningful increase in LDL-C. Long-term trials are needed to determine whether short-term benefits translate into improved clinical outcomes such as cardiovascular events and mortality.

Key findings

  • Among 115 unique associations, 51 (44%) were statistically significant; only 4 were supported by high-quality evidence: reduced triglyceride in adults with T2DM at 3 months (MD −18.36 mg/dL; 95% CI −24.24 to −12.49) and 12 months (MD −24.10 mg/dL; 95% CI −33.93 to −14.27), increased LDL-C at 12 months (MD 6.35 mg/dL; 95% CI 2.02 to 10.69), and seizure frequency reduction ≥50% from baseline in children/adolescents with refractory epilepsy (RR 5.11; 95% CI 3.18 to 8.21).
  • Four statistically significant associations were supported by moderate-quality evidence: reduced HbA1c (MD −0.61%; 95% CI −0.82 to −0.40), reduced body weight with VLCKD (MD −9.33 kg; 95% CI −15.45 to −3.22), reduced respiratory exchange ratio with K-LCHF in athletes (SMD −2.66; 95% CI −3.77 to −1.54), and increased total cholesterol with K-LCHF in athletes (MD 1.32 mg/dL; 95% CI 0.64 to 1.99).
  • In healthy participants, K-LCHF for 3–12 weeks reduced body weight by 3.68 kg (95% CI −4.45 to −2.90) but also reduced muscle mass by 1.27 kg (95% CI −1.83 to −0.70; MCID threshold 1.10 kg). In overweight or obese adults, VLCKD improved anthropometric and cardiometabolic outcomes without worsening muscle mass, LDL-C, or total cholesterol.
  • Most associations were rated very low (66/115, 57%) or low (36/115, 31%) quality; among statistically significant associations, 26 were very low, 17 low, 4 moderate, and 4 high quality.

Methods

  • Umbrella review of published meta-analyses of RCTs assessing any type of ketogenic diet (KD, K-LCHF, VLCKD, MAD) against any comparator for any health outcome; PubMed, EMBASE, Epistemonikos, and Cochrane Database of Systematic Reviews were searched from inception to February 15, 2023.
  • Included 17 meta-analyses comprising 68 unique RCTs (median [IQR] sample size 42 [20–104] participants; median follow-up 13 [8–36] weeks) and 115 unique associations.
  • Meta-analyses were re-performed using random-effects models; evidence per association was graded with GRADE, meta-analysis quality with AMSTAR-2, and sensitivity analyses excluded small studies (<25th percentile) and high-risk-of-bias RCTs.

Limitations

  • Stated: the review was confined to published meta-analyses, so outcomes and populations not covered by existing meta-analyses could not be assessed; most included meta-analyses were rated AMSTAR-2 critically low confidence; dose–response analysis was not possible due to insufficient carbohydrate intake details; most RCTs had small samples and short follow-up; adherence likely decreased and carbohydrate intake increased over trials, so the precise degree of ketosis contributing to benefits is uncertain.
  • Evident from the text: most associations were downgraded because of serious imprecision, large heterogeneity, and indirectness from mixed interventions and comparators; most outcomes were surrogate measures, and RCTs were limited to selected populations such as overweight/obesity, T2DM, cancer, athletes, and refractory epilepsy.

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Integrity signals

Registry

Crossref · 10.1186/s12916-023-02874-y

Cites

68 of 68 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 51 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The included meta-analyses comprised 68 unique RCTs.

    “These meta-analyses comprised 68 unique RCTs with a median (interquartile range, IQR) sample size per RCT of 42 (20–104) participants and a median (IQR) follow-up period of 13 (8–36) weeks.”
    • Also stated in: § Results · plain
      “We included 17 meta-analyses comprising 68 RCTs (median [interquartile range, IQR] sample size of 42 [20–104] participants and follow-up period of 13 [8–36] weeks) and 115 unique associations.”
    Quote in the paperNot a substantial claim
  • Findingown data

    There were 115 unique associations of KD with health outcomes.

    “We identified 115 unique associations of KD with health outcomes (Additional file 2: Table S5).”
    • Also stated in: § Results · plain
      “and 115 unique associations.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The median sample size per RCT was 42 (IQR 20-104) participants.

    “These meta-analyses comprised 68 unique RCTs with a median (interquartile range, IQR) sample size per RCT of 42 (20–104) participants and a median (IQR) follow-up period of 13 (8–36) weeks.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Seventeen meta-analyses were included.

    “Seventeen meta-analyses were included (Fig. 1 and Additional file 2: Table S3) [1, 2, 15–17, 34–45].”
    • Also stated in: § Results · plain
      “We included 17 meta-analyses comprising 68 RCTs (median [interquartile range, IQR] sample size of 42 [20–104] participants and follow-up period of 13 [8–36] weeks) and 115 unique associations.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [1] Bueno NB, de Melo IS, de Oliveira SL, da Rocha Ataide T. Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr. 2013;110(7):1178–87. source

      Not checked in the free run.

    • cites [2] Choi YJ, Jeon SM, Shin S. Impact of a ketogenic diet on metabolic parameters in patients with obesity or overweight and with or without type 2 diabetes: a meta-analysis of randomized controlled trials. Nutrients. 2020;12(7):2005. source

      Not checked in the free run.

    • cites [15] Castellana M, Conte E, Cignarelli A, Perrini S, Giustina A, Giovanella L, et al. Efficacy and safety of very low calorie ketogenic diet (VLCKD) in patients with overweight and obesity: a systematic review and meta-analysis. Rev Endocr Metab Disord. 2020;21(1):5–16. source

      Not checked in the free run.

    • cites [16] Sourbron J, Klinkenberg S, van Kuijk SMJ, Lagae L, Lambrechts D, Braakman HMH, et al. Ketogenic diet for the treatment of pediatric epilepsy: review and meta-analysis. Childs Nerv Syst. 2020;36(6):1099–109. source

      Not checked in the free run.

    • cites [17] Lee HS, Lee J. Influences of ketogenic diet on body fat percentage, respiratory exchange rate, and total cholesterol in athletes: a systematic review and meta-analysis. Int J Environ Res Public Health. 2021;18(6):2912. source

      Not checked in the free run.

    • cites [34] Sainsbury E, Kizirian NV, Partridge SR, Gill T, Colagiuri S, Gibson AA. Effect of dietary carbohydrate restriction on glycemic control in adults with diabetes: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2018;139:239–52. source

      Not checked in the free run.

    • cites [35] Rafiullah M, Musambil M, David SK. Effect of a very low-carbohydrate ketogenic diet vs recommended diets in patients with type 2 diabetes: a meta-analysis. Nutr Rev. 2022;80(3):488–502. source

      Not checked in the free run.

    • cites [36] Alarim RA, Alasmre FA, Alotaibi HA, Alshehri MA, Hussain SA. Effects of the ketogenic diet on glycemic control in diabetic patients: meta-analysis of clinical trials. Cureus. 2020;12(10):e10796.

      Not checked in the free run.

    • cites [37] Amini MR, Aminianfar A, Naghshi S, Larijani B, Esmaillzadeh A. The effect of ketogenic diet on body composition and anthropometric measures: A systematic review and meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr. 2022;62(13):3644–57. source

      Not checked in the free run.

    • cites [38] Ashtary-Larky D, Bagheri R, Asbaghi O, Tinsley GM, Kooti W, Abbasnezhad A, et al. Effects of resistance training combined with a ketogenic diet on body composition: a systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2022;62(21):5717–32. source

      Not checked in the free run.

  • Findingown data

    Most associations between ketogenic diet and health outcomes were rated as low or very low evidence by GRADE, due to serious imprecision, large heterogeneity, and indirectness from mixed interventions and comparators.

    “Most associations were rated as low and very low evidence according to the GRADE criteria because of serious imprecision and large heterogeneity in findings, and indirectness due to a mix of different interventions and comparators.”
    Quote in the paperSubstantial claim
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingown data

    The quality of meta-analyses assessed using AMSTAR-2 found that none were rated as high confidence, 2 (12%) as moderate confidence, 2 (12%) as low confidence, and 13 (76.0%) as critically low confidence.

    “The quality of meta-analyses assessed using AMSTAR-2 found that none were rated as high confidence, 2 (12%) as moderate confidence, 2 (12%) as low confidence, and 13 (76.0%) as critically low confidence (Table 1 and Additional file 2: Table S4).”
    Quote in the paperSubstantial claim

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

    Findingown data

    The median follow-up period was 13 (IQR 8-36) weeks.

    “These meta-analyses comprised 68 unique RCTs with a median (interquartile range, IQR) sample size per RCT of 42 (20–104) participants and a median (IQR) follow-up period of 13 (8–36) weeks.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The median number of studies per association was 3 [4-6].

    “The median (IQR) number of studies per association was 3 [4–6], and the median (IQR) sample size was 244 (127–430) participants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    VLCKD for 3-96 weeks led to a clinically meaningful improvement in BMI, body weight, waist circumference, triglyceride, fat mass, and insulin resistance, while preserving muscle mass.

    “VLCKD for 3–96 weeks led to a clinically meaningful improvement in BMI, body weight, waist circumference, triglyceride, fat mass, and insulin resistance, while preserving muscle mass [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Muscogiuri G, El Ghoch M, Colao A, Hassapidou M, Yumuk V, Busetto L. European guidelines for obesity management in adults with a very low-calorie ketogenic diet: a systematic review and meta-analysis. Obes Facts. 2021;14(2):222–45. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    K-LCHF was associated with reduced body weight and body fat percentage, but also reduced muscle mass in healthy participants.

    “K-LCHF was associated with reduced body weight and body fat percentage, but also reduced muscle mass in healthy participants.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Using GRADE, 115 associations were supported by very low strength of evidence (n = 66, 57%), low (n = 36, 31%), moderate (n = 9, 8%), and high quality of evidence (n = 4, 3%).

    “Using GRADE, 115 associations were supported by very low strength of evidence (n = 66, 57%), with the remaining being low (n = 36, 31%), moderate (n = 9, 8%), and high quality of evidence (n = 4, 3%) (Additional file 2: Table S5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In overweight or obese adults, VLCKD was significantly associated with improvement in anthropometric and cardiometabolic outcomes without worsening muscle mass, LDL-C, and total cholesterol.

    “In overweight or obese adults, VLCKD was significantly associated with improvement in anthropometric and cardiometabolic outcomes without worsening muscle mass, LDL-C, and total cholesterol.”
    Quote in the paperSubstantial claim

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

    Findingown data

    The median sample size per association was 244 (IQR 127-430) participants.

    “The median (IQR) number of studies per association was 3 [4–6], and the median (IQR) sample size was 244 (127–430) participants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Very-low-calorie ketogenic diet is very effective in producing weight loss while preserving muscle mass in adults with overweight or obesity, with specific benefits on anthropometric and cardiometabolic parameters.

    “On the one hand, VLCKD is very effective in producing weight loss while preserving muscle mass in adults with overweight or obesity, with specific benefits on anthropometric and cardiometabolic parameters [15, 42].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Castellana M, Conte E, Cignarelli A, Perrini S, Giustina A, Giovanella L, et al. Efficacy and safety of very low calorie ketogenic diet (VLCKD) in patients with overweight and obesity: a systematic review and meta-analysis. Rev Endocr Metab Disord. 2020;21(1):5–16. source

      Not checked in the free run.

    • cites [42] Muscogiuri G, El Ghoch M, Colao A, Hassapidou M, Yumuk V, Busetto L. European guidelines for obesity management in adults with a very low-calorie ketogenic diet: a systematic review and meta-analysis. Obes Facts. 2021;14(2):222–45. source

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    In adults, ketogenic diet was associated with improved anthropometric measures, cardiometabolic parameters, and exercise performance.

    “In adults, KD was associated with improved anthropometric measures, cardiometabolic parameters, and exercise performance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Ketogenic diet could induce rapid weight loss in the initial 6 months, after which further weight loss was hardly achieved.

    “Our findings demonstrated that KD could induce a rapid weight loss in the initial phase of 6 months, after which time further weight loss was hardly achieved [35].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Rafiullah M, Musambil M, David SK. Effect of a very low-carbohydrate ketogenic diet vs recommended diets in patients with type 2 diabetes: a meta-analysis. Nutr Rev. 2022;80(3):488–502. source

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    Beneficial associations of practicing ketogenic diet were supported by moderate- to high-quality evidence, including weight loss, lower triglyceride levels, decreased HbA1c, decreased respiratory exchange ratio, and decreased seizure frequency.

    “Beneficial associations of practicing KD were supported by moderate- to high-quality evidence, including weight loss, lower triglyceride levels, decreased HbA1c, RER, and decreased seizure frequency.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Lowered dietary carbohydrate intake effectively reduced serum triglyceride levels at 3 months, with further reduction by month 12.

    “With regards to KD effects on lipid profiles, our results demonstrate an effective reduction in serum triglyceride levels with 3 months of lowered dietary carbohydrate intake, with even further reduction by month 12 [35].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Rafiullah M, Musambil M, David SK. Effect of a very low-carbohydrate ketogenic diet vs recommended diets in patients with type 2 diabetes: a meta-analysis. Nutr Rev. 2022;80(3):488–502. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Weight loss induced by ketogenic diet is relatively modest and appears comparable to other dietary interventions effective for short-term weight loss, such as intermittent fasting and Mediterranean diet.

    “Furthermore, weight loss induced by KD is relatively modest and appears comparable to other dietary interventions that are effective for short-term weight loss, e.g., intermittent fastingand Mediterranean diet [55–57].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [55] O’Neill B, Raggi P. The ketogenic diet: Pros and cons. Atherosclerosis. 2020;292:119–26. source

      Not checked in the free run.

    • cites [56] Freire R. Scientific evidence of diets for weight loss: different macronutrient composition, intermittent fasting, and popular diets. Nutrition. 2020;69: 110549. source

      Not checked in the free run.

    • cites [57] Becker A, Gaballa D, Roslin M, Gianos E, Kane J. Novel nutritional and dietary approaches to weight loss for the prevention of cardiovascular disease: ketogenic diet, intermittent fasting, and bariatric surgery. Curr Cardiol Rep. 2021;23(7):1–9. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The aggregate results confirm an increase in LDL-C with ketogenic diet and an increase in total cholesterol with ketogenic low-carbohydrate high-fat diet.

    “Though our aggregate results also confirm an increase in LDL-C and total cholesterol with KD and K-LCHF, respectively, it is important to note that an increase in either of these levels does not necessarily signify a potentially deleterious cardiovascular end-point.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    When more than one meta-analysis was available for the same research question, the meta-analysis with the largest data set was selected.

    “When more than 1 meta-analysis was available for the same research question, we selected the meta-analysis with the largest data set [19–21].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Dragioti E, Solmi M, Favaro A, Fusar-Poli P, Dazzan P, Thompson T, et al. Association of antidepressant use with adverse health outcomes: a systematic umbrella review. JAMA Psychiat. 2019;76(12):1241–55. source

      Not checked in the free run.

    • cites [20] Patikorn C, Roubal K, Veettil SK, Chandran V, Pham T, Lee YY, et al. Intermittent Fasting and Obesity-Related Health Outcomes: An Umbrella Review of Meta-analyses of Randomized Clinical Trials. JAMA Netw Open. 2021;4(12):e2139558-e. source

      Not checked in the free run.

    • cites [21] Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348: g2035. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    PubMed, EMBASE, Epistemonikos, and Cochrane database of systematic reviews were searched from database inception to February 15, 2023.

    “We searched PubMed, EMBASE, Epistemonikos, and the Cochrane database of systematic reviews (CDSR) from the database inception to February 15, 2023 (Additional file 2: Table S2).”
    • Also stated in: § Methods · plain
      “PubMed, EMBASE, Epistemonikos, and Cochrane database of systematic reviews were searched up to February 15, 2023.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The protocol of this study was registered with PROSPERO (CRD42022334717).

    “The protocol of this study was registered with PROSPERO (CRD42022334717).”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The study reported following the 2020 PRISMA guidelines.

    “We reported following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) (Additional file 1) [18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. source

      Not checked in the free run.

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

    Study design and conductown data

    Data extraction and quality assessment were independently performed by two reviewers.

    “Two reviewers (CP and PS) independently performed data extraction and quality assessment (Additional file 2: Method S1).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The quality of evidence per association was assessed by applying GRADE criteria.

    “We assessed the quality of evidence per association by applying the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluations) in five domains, including (1) risk of bias in the individual studies, (2) inconsistency, (3) indirectness, (4) imprecision, and (5) publication bias [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Langendam MW, Akl EA, Dahm P, Glasziou P, Guyatt G, Schünemann HJ. Assessing and presenting summaries of evidence in cochrane reviews. Syst Rev. 2013;2(1):81. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    AMSTAR-2 was used to grade the quality of meta-analyses.

    “We used AMSTAR- 2 -A Measurement Tool to Assess Systematic Reviews- to grade the quality of meta-analyses as high, moderate, low, or critically low by assessing the following elements, research question, a priori protocol, search, study selection, data extraction, quality assessment, data analysis, interpretation, heterogeneity, publication bias, source of funding, conflict of interest [22].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. source

      Not checked in the free run.

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

    Study design and conductown data

    Study selection was independently performed by two reviewers.

    “Study selection was independently performed in EndNote by two reviewers (C.P. and PS).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Discrepancies were resolved by discussion with a third reviewer.

    “Any discrepancies were resolved by discussion with the third reviewer (SKV).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Sensitivity analyses were performed by excluding small-size studies and primary studies with high risk of bias.

    “Sensitivity analyses were performed by excluding small-size studies (< 25th percentile) [32] and excluding primary studies having a high risk of bias rated by the Cochrane’s risk of bias 2 tool (RoB 2) for RCTs from the identified associations [19–21, 33].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [32] Dechartres A, Altman DG, Trinquart L, Boutron I, Ravaud P. Association between analytic strategy and estimates of treatment outcomes in meta-analyses. JAMA. 2014;312(6):623–30. source

      Not checked in the free run.

    • cites [19] Dragioti E, Solmi M, Favaro A, Fusar-Poli P, Dazzan P, Thompson T, et al. Association of antidepressant use with adverse health outcomes: a systematic umbrella review. JAMA Psychiat. 2019;76(12):1241–55. source

      Not checked in the free run.

    • cites [20] Patikorn C, Roubal K, Veettil SK, Chandran V, Pham T, Lee YY, et al. Intermittent Fasting and Obesity-Related Health Outcomes: An Umbrella Review of Meta-analyses of Randomized Clinical Trials. JAMA Netw Open. 2021;4(12):e2139558-e. source

      Not checked in the free run.

    • cites [21] Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348: g2035. source

      Not checked in the free run.

    • cites [33] Sterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Sensitivity analyses using high-quality randomized controlled trials were performed and increased the reliability of the results.

    “Sensitivity analyses were performed to provide additional evidence from high-quality RCTs, which further increased the reliability of results.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    Most randomized controlled trials of ketogenic diet had relatively small sample sizes and short-term follow-up, limiting assessment of sustained beneficial effects after stopping the diet.

    “Fourthly, most RCTs of KD were limited to a relatively small number of participants with a short-term follow-up period, which limited our assessment of sustained beneficial effects after stopping KD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The AMSTAR-2 domains of low confidence unlikely affected the review's findings.

    “However, these domains unlikely affected our findings.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    The observed aggregate effect of ketogenic diet on cholesterol levels did not account for differences in LDL particle size or distinguish sources of dietary fat.

    “Our observed aggregate effect of KD on cholesterol levels does not account for the difference in LDL particle size, nor does it distinguish the sources of dietary fat, which can also be a significant effector of LDL particle size distribution and metabolism [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Dreon DM, Fernstrom HA, Campos H, Blanche P, Williams PT, Krauss RM. Change in dietary saturated fat intake is correlated with change in mass of large low-density-lipoprotein particles in men. Am J Clin Nutr. 1998;67(5):828–36. source

      Not checked in the free run.

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  • The paper relies on this without support.

    There has been little synthesis of the strength and quality of evidence from meta-analyses of RCTs of KD in aggregate.

    “Nevertheless, there has been little synthesis of the strength and quality of this evidence in aggregate.”
    “To date, there has been little synthesis of the strength and quality of this evidence in aggregate.”
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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Castellana et al. comparators differ across tables

    Minor

    Table 1 lists a low-calorie diet as the comparator for Castellana et al. [15], while Table 2 lists a low-fat diet or regular diet for that source's body-weight association.

  • Median number of studies falls below its reported interquartile range

    Minor

    The median is reported as 3 studies per association, but the interquartile range begins at 4. A median cannot be lower than the first quartile.

  • Lee et al. intervention is classified differently across tables

    Minor

    Table 1 identifies the intervention in Lee et al. [17] as KD, whereas Table 2 identifies the total-cholesterol intervention from the same source as K-LCHF.

  • VLCKD duration attributed to Muscogiuri et al. differs from Table 1

    Minor

    The results attribute VLCKD effects over 3-96 weeks to reference [42], but Table 1 gives the diet duration for that source as 2-4 weeks.

4 of 4

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Authors
Patikorn, C., Saidoung, P., Pham, T., Phisalprapa, P., Lee, Y. Y., Varady, K. A., Veettil, S. K., & Chaiyakunapruk, N.
Affiliations
  • Chulalongkorn University (TH)
  • University of Utah (US)
  • Siriraj Hospital (TH)
  • Universiti Sains Malaysia (MY)
  • University of Illinois Chicago (US)
Corresponding author
  • Veettil, Sajesh K.
  • Chaiyakunapruk, Nathorn
ORCID
Venue
BMC Medicine
Publisher
Springer Science and Business Media LLC
Published
2023-05-25
Volume
21
Issue
1
Pages
196-196
ISSN
1741-7015 (ISSN-L)
DOI
10.1186/s12916-023-02874-y
PMC
PMC10210275
OpenAlex
W4378220711
Semantic Scholar
7804f976e2673f54ac575a886f64620c1ff14ac3
Cited by
101
References
68
Citations by year
2026: 28 · 2025: 30 · 2024: 33 · 2023: 10
FWCI
17.79
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Physiology › Diet and metabolism studies
  • Health Sciences › Medicine › Physiology › Dietary Effects on Health
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
Keywords
ketogenic diet, very low-calorie ketogenic diet, epilepsy, seizure frequency, cardiometabolic outcomes, LDL cholesterol, triglycerides, body weight, body fat percentage, muscle mass, quality of evidence, GRADE, obesity, overweight adults, health outcomes, respiratory exchange ratio
MeSH terms
Adult, Body Weight, Cardiovascular Diseases, Humans, Cholesterol, LDL, Obesity, Seizures, Meta-Analysis as Topic, Randomized Controlled Trials as Topic, Overweight, Diet, Ketogenic

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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