Low-Carbohydrate Diets for the Management of Pediatric Obesity: A Systematic Review and Meta-analysis

Fournier, Elora; Moore, Halim; Alghamdi, Zainab S; Thivel, David

doi:10.1093/nutrit/nuaf029

Abstract

Context

Although low-carbohydrate (LC) diets have been shown to be beneficial for weight loss and improvements in cardiometabolic health in adults with obesity, their efficacy in youth has not yet been established.

Objectives

A systematic review and meta-analysis was conducted to qualitatively and quantitively synthesize the evidence from clinical trials testing the efficacy of LC diets to improve anthropometric and cardiometabolic-related parameters in children and adolescents with obesity.

Data Sources

Searches in Medline, EMBASE, and Cochrane databases were undertaken for LC interventions with or without control comparisons.

Data Extraction and Analysis

Data before and after the LC intervention and control comparisons (if applicable) were extracted from 19 studies, 17 of which were pooled in random-effects meta-analyses.

Results

Children on LC diets (Mean = 30 [IQR: 30-60] g/d), for approximately 3 months (IQR: 3-4 months) significantly reduced their weight (mean change [MC] = -7.09 [95% CI: -9.60, -4.58] kg; P < .001), body mass index (BMI) (MC = -3.01 [-3.71, -2.30] kg/m²; P < .001), and BMI z-score (MC = -0.27 [-0.48, -0.06]; P = .020), on average, with concomitant improvements in different metabolic biomarkers, such as serum triglycerides (MC = -29.16 [-45.06, -13.26] mg/dL; P = .002) and insulin (MC = -7.13 [-9.27, -4.99] µU/mL; P < .001). Evidence from 5 out of 7 controlled trials suggests that LC diets without caloric restriction may lead to similar or greater improvements in anthropometric and lipid-related outcomes relative to caloric-restricted or low-fat diets. However, meta-analyses demonstrated high between-study heterogeneity, indicative of a wide variety of methodologies, including intervention duration and degree of carbohydrate restriction.

Conclusion

Overall, this review found that short-term LC diets can be beneficial for weight loss and improving cardiometabolic parameters with or without calorie restriction. However, the limited number of controlled trials and the demonstrable diversity in methods prevent firm conclusions regarding their efficacy relative to traditional approaches, such as energy restriction.

Systematic Review Registration

PROSPERO registration no. CRD42023440835.

ketogenic diet, low-carb diet, obesity, children, adolescent, weight loss

INTRODUCTION

Childhood obesity represents 1 of the most serious global health issues of the 21st century. In 2016, obesity affected more than 340 million (6.8%) children and adolescents aged 5 to 19 years worldwide.¹ Importantly, childhood obesity is associated with numerous short-term comorbidities. A systematic review in 2019 showed that children and adolescents with obesity are 1.4 times more likely to have prediabetes, 1.7 times more likely to have self‐reported asthma, 4.4 times more likely to have high blood pressure, and 26.1 times more likely to have nonalcoholic fatty liver disease compared with normal-weight youth.² An elevated body mass index (BMI) also represents a major risk factor for development of cardiovascular disease,³ insulin resistance, and type 2 diabetes,⁴ and often persists into adulthood, which increases the risk of premature death and disability.⁵^,⁶

With a multifactorial etiology involving sociodemographic, psychological, and lifestyle factors,⁷ various strategies are used to manage pediatric obesity. Current strategies involve not only dietary but also lifestyle interventions targeting physical activity, sleep, and mental health, as well as pharmacological interventions like glucagon-like peptide-1 agonists⁸ (eg, liraglutide, phentermine/topiramate, and semaglutide) or, for the management of severe obesity, metabolic and bariatric surgery.⁹^,¹⁰ Dietary approaches have traditionally been, and remain today, the primary intervention for obesity management, and mainly correspond to calorie restriction (CR) or macronutrient modification.¹¹ However, while most guidelines currently prescribe CR to achieve weight loss, such diets have often been associated with weight regain and poor adherence, thus may not be not optimal for long-term management of youth obesity.¹¹ Therefore, there is an urgent need for alternative therapies that can aid weight loss with better long-term efficacy, and which may have in less psychological and physiological burden.

In order to improve adherence and avoid potential long-term deleterious effects associated with CR alone, other standard dietary strategies have been used based on modification or restriction of specific macronutrients, such as low-carbohydrate (LC), ketogenic, or low-fat (LF) diets, with or without CR. In the early 20th century, LC and ketogenic diets were initially used to treat epilepsy and type 1 diabetes, but they were acknowledged as a dietary therapy for obesity and prescribed widely with the advent of the Atkins diet.¹² Low-carbohydrate diet protocols have included various degrees of carbohydrate restriction, with the ketogenic diet corresponding to the greatest degree of restriction. The ketogenic diet generally consists of limiting carbohydrate intake to 5% to 10% of daily energy intake, with a concomitant increase of fat consumption to a range from 60% to 90%, initiating ketogenesis or the production of ketone bodies (eg, β-hydroxybutyrate, acetoacetate, and acetone).¹³ Together with glucose, ketones represent the principal energy source in humans but can also serve as an anabolic substrate for various hormones.¹⁴ In lieu of fasting, an LC diet may be used to induce fatty acid oxidation and ketone production with sufficient carbohydrate restriction, although there is likely individual variation regarding the level of restriction required to elicit these metabolic adaptations.¹⁵ However, such diets may induce several physical and gastrointestinal adverse effects, at least initially, such as constipation, nausea, fatigue, electrolyte losses, and limited exercise capacity, due to the elimination of certain nutritious food items and rapid depletion of glycogen and intracellular water.¹⁶

Ketogenic diets have been shown to induce weight loss and improvements in lipid and cardiometabolic profiles in adults with obesity,¹⁷^,¹⁸ which may be more significant compared with a standard LF diet.¹⁸ A state of ketosis induced by LC diets has been clinically shown to reduce hunger,¹⁹ inflammation, oxidative stress, and serum glucose and insulin concentrations, and stimulate the formation and regeneration of mitochondria and autophagy in adults.¹³^,²⁰^,²¹ However, excessive levels of ketosis can also induce hypoglycemia, lactic acidosis, and hyperammonemia, causing nausea, vomiting, stomach pain, or flu-like symptoms, and may predispose to kidney stone formation.¹⁵^,²² However, the present body of evidence is limited and inconsistent, especially in this demographic. A previous systematic review published in 2013 indicated that weight reduction in children and adolescents with obesity can be achieved irrespective of the macronutrient distribution as long as the total energy intake is reduced.²³ Although their meta-analysis indicated a more beneficial effect of an LC diet on BMI and BMI z-score changes compared with an LF diet, they warned of the high clinical and statistical heterogeneity among the small number of available studies (n = 6).

Since most of the existing reviews addressing LC and ketogenic diets in children and adolescents focus on the treatment of epilepsy,²⁴^,²⁵ and due to the recent increasing number of studies conducted in this field, the primary aim of the present systematic review and meta-analysis was to qualitatively and quantitively synthesize the effects from clinical applications of LC diets on anthropometric and cardiometabolic parameters in children and adolescents with obesity. Secondary to this aim, we also addressed the potential practical and clinical utility of LC diets in children, along with any potential challenges and adverse effects associated with their use, with a specific focus on age, intervention duration, and diet protocols.

METHODS

Search Strategy and Screening Process

The following electronic bibliographic databases were searched between June and July 2023: Medline, EMBASE, and CENTRAL (Cochrane Library). The search terms were a combination of medical subject heading (MeSH) terms and keywords (title and abstract), which were adapted for use in each database. Briefly, the search terms included all derivations of the terms “low-carbohydrate diet”, “ketogenic diet”, “high-fat diet”, “pediatric obesity”, or “obesity in children”. Custom syntaxes were adapted to perform the search on each database. Reference lists from narrative or systematic reviews and eligible publications were also screened to find additional records. The research equations used to search the 3 databases are displayed in Table S1.

Search results were exported to a spreadsheet and duplicates removed. An initial screening was performed based on titles and abstracts according to the inclusion and exclusion criteria outlined below. The full texts of eligible articles were then evaluated to confirm their inclusion. The selection process was performed independently by 2 reviewers, and any discrepancies were collectively discussed until a consensus was reached. A third reviewer was consulted when necessary. All of the selected references were then extracted to Zotero software (6.0.26; Center for History and New Media, George-Mason University, Virginia, USA). The flow diagram presented in Figure 1 illustrates the selection process.

Flowchart of the Search and Selection Process.42 Abbreviations: BMI, body mass index; HDL, high-density-lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; LDL, low-density-lipoprotein cholesterol

Figure 1.

Flowchart of the Search and Selection Process.⁴² Abbreviations: BMI, body mass index; HDL, high-density-lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; LDL, low-density-lipoprotein cholesterol

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Inclusion and Exclusion Criteria

The eligibility criteria were adapted from the Participants, Interventions, Comparisons, Outcomes, and Study design (PICOS) framework (Table 1). Studies were eligible if they were longitudinal clinical trials published in English or French after 1980 involving children or adolescents between 6 and 18 years of age with overweight (BMI ≥85th percentile of the Centers for Disease Control and Prevention [CDC] sex-specific BMI-for-age growth charts) or obesity (BMI ≥95th percentile).²⁶ The study had to include at least 1 group following a diet with some degree of carbohydrate restriction defined here as carbohydrate intake per day under 40% of total caloric intake, corresponding to the limit indicated by the Fourth French National Nutrition and Health Program (PNNS),²⁷ and that measured at least 1 of the following outcomes at baseline and follow-up: anthropometrics (weight, height, BMI), blood pressure, body composition, lipid profiles, hormonal profiles, metabolic profiles, appetite regulation, or mental health indicators. Clinical trials could be of any duration and a control group was not required. Studies involving animal models, adults, athletes, or normal-weight youths, as well as reviews, systematic reviews, meta-analyses, conference abstracts, or acute intervention studies were not included. In order to select a sufficient number of studies for synthesis, trials including participants with any particular medical condition were not excluded.

Table 1.

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PICOS Criteria for Inclusion and Exclusion of Studies

Parameter	Inclusion criteria	Exclusion criteria
Population	Overweight children and adolescents from 6 to 18 y old or with obesity including participants with any particular medical condition	Animal models, adults, athletes, or normal-weight youth
Intervention	Including at least 1 arm with a carbohydrate-restricted diet (upper limit of 40% of carbohydrates per day of the total caloric intake)	Involving no carbohydrate-restricted diet or a carbohydrate-restricted diet with >40% of carbohydrates per day of their total caloric intake
Comparator	Another diet-intervention arm including low-fat and caloric-restricted diet
Outcome	Anthropometric or biological parameters as weight, BMI, BMI z-score, waist circumference, body composition, triglycerides, LDL and HDL cholesterol, insulin, HOMA-IR	Investigating neither anthropometric or biological parameters
Study design	We included any longitudinal clinical trials	Crossover clinical trials Reviews, systematic reviews, meta-analyses, or conference abstracts

Parameter	Inclusion criteria	Exclusion criteria
Population	Overweight children and adolescents from 6 to 18 y old or with obesity including participants with any particular medical condition	Animal models, adults, athletes, or normal-weight youth
Intervention	Including at least 1 arm with a carbohydrate-restricted diet (upper limit of 40% of carbohydrates per day of the total caloric intake)	Involving no carbohydrate-restricted diet or a carbohydrate-restricted diet with >40% of carbohydrates per day of their total caloric intake
Comparator	Another diet-intervention arm including low-fat and caloric-restricted diet
Outcome	Anthropometric or biological parameters as weight, BMI, BMI z-score, waist circumference, body composition, triglycerides, LDL and HDL cholesterol, insulin, HOMA-IR	Investigating neither anthropometric or biological parameters
Study design	We included any longitudinal clinical trials	Crossover clinical trials Reviews, systematic reviews, meta-analyses, or conference abstracts

Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; LDL, low-density lipoprotein

Table 1.

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PICOS Criteria for Inclusion and Exclusion of Studies

Parameter	Inclusion criteria	Exclusion criteria
Population	Overweight children and adolescents from 6 to 18 y old or with obesity including participants with any particular medical condition	Animal models, adults, athletes, or normal-weight youth
Intervention	Including at least 1 arm with a carbohydrate-restricted diet (upper limit of 40% of carbohydrates per day of the total caloric intake)	Involving no carbohydrate-restricted diet or a carbohydrate-restricted diet with >40% of carbohydrates per day of their total caloric intake
Comparator	Another diet-intervention arm including low-fat and caloric-restricted diet
Outcome	Anthropometric or biological parameters as weight, BMI, BMI z-score, waist circumference, body composition, triglycerides, LDL and HDL cholesterol, insulin, HOMA-IR	Investigating neither anthropometric or biological parameters
Study design	We included any longitudinal clinical trials	Crossover clinical trials Reviews, systematic reviews, meta-analyses, or conference abstracts

Parameter	Inclusion criteria	Exclusion criteria
Population	Overweight children and adolescents from 6 to 18 y old or with obesity including participants with any particular medical condition	Animal models, adults, athletes, or normal-weight youth
Intervention	Including at least 1 arm with a carbohydrate-restricted diet (upper limit of 40% of carbohydrates per day of the total caloric intake)	Involving no carbohydrate-restricted diet or a carbohydrate-restricted diet with >40% of carbohydrates per day of their total caloric intake
Comparator	Another diet-intervention arm including low-fat and caloric-restricted diet
Outcome	Anthropometric or biological parameters as weight, BMI, BMI z-score, waist circumference, body composition, triglycerides, LDL and HDL cholesterol, insulin, HOMA-IR	Investigating neither anthropometric or biological parameters
Study design	We included any longitudinal clinical trials	Crossover clinical trials Reviews, systematic reviews, meta-analyses, or conference abstracts

Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; LDL, low-density lipoprotein

Data Extraction, Synthesis, and Meta-analysis Procedure

The extracted data were synthesized using inverse variance, random-effects meta-analyses performed in the R environment (R Foundation for Statistical Computing, Vienna, Austria)²⁸ with the following packages: Tidyverse,²⁹ meta,³⁰ metafor,³¹ and dmetar.³² Random-effects models were preferred in anticipation of additional heterogeneity from salient intervention parameters, such as the duration, degree of carbohydrate restriction, and eligibility criteria for participant recruitment. Effect sizes representing the efficacy of LC diets were calculated and pooled in 2 stages due to the relatively limited availability of controlled trials. In the first stage, mean changes were calculated by subtracting post values from baseline for all relevant outcomes within LC diet arms specifically. The second phase applied only to studies including a comparator diet and consisted of calculating weighted mean differences (MDs) between post values from LC and comparator diet arms (ie, LF or CR) while adjusting for baseline values using analysis of covariance.³³ Respective means, SDs, and sample sizes for each relevant timepoint and study arm were compiled to calculate these effect sizes and their 95% CIs. All dispersion statistics were converted to SDs when needed. Units were converted when necessary into mg/dL for triglycerides (TG) and high-density-lipoprotein (HDL) and low-density-lipoprotein (LDL) cholesterol, ng/mL for leptin, and µU/mL for insulin. If postintervention means and SDs were not reported, they were calculated using means and SDs of the change and baseline values. Studies were permitted to contribute multiple effect sizes if multiple comparator arms were included, but sample sizes were adjusted commensurately to limit unit-of-analysis errors.³⁴ Correlation coefficients were estimated for each distinct outcome of interest using data from longitudinal clinical trials in pediatric samples with obesity conducted in our laboratory, and imputed in analyses to calculate effect sizes for both stages.

Between-study heterogeneity was estimated using the restricted-maximum-likelihood method, and both τ² and I² statistics were used as metrics for measuring the variance associated with pooled effects, the former being relatively more robust to small-study bias.³⁵ I² values range between 0 and 100% and are typically considered low when <25%, moderate when between 25% and 50%, and high when >50%.³⁶ Their CIs were also reported to quantify the level of certainty of the estimates. The Knapp-Hartung adjustment was applied when calculating the standard error of pooled effects as a more conservative approach in the context of considerable heterogeneity and small sample sizes.³⁷ Prediction intervals were also calculated based on the Knapp-Hartung method, which provides a range of effect estimates that incorporate the statistical heterogeneity present in the meta-analysis.³⁸ Publication bias was assessed by visual inspection of funnel plot symmetry and Duvall and Tweedie’s trim-and-fill method,³⁹ but Egger’s regression test was also conducted if K ≥ 10. Outliers and influential cases were identified by inspection of CIs and using the leave-one-out method, respectively, and removed in sensitivity analyses. Finally, meta-regressions were performed to test whether study duration and the degree of carbohydrate restriction had a significant influence on the outcome of meta-analyses. The results of the meta-analyses are visualized using forest plots sorted by carbohydrate intake per day, and also include the authors, duration, participant completion rate, comparator diet (if applicable), effect size, 95% CI, and study weight.

Quality Assessment

Quality assessment of the included studies was performed independently by 2 reviewers using the Quality Assessment Tool for Quantitative Studies developed by the Effective Public Health Practice Project.⁴⁰^,⁴¹ Studies were assessed against 6 criteria related to their design, analysis, and reporting: selection bias, study design, confounders, blinding, data collection method, and withdrawals/dropouts. Each criterion was rated as “strong,” “moderate,” or “weak.” The overall methodological quality was then rated as “strong” if there were no criteria with a “weak” rating, “moderate” if there was 1 “weak” rating, and “weak” if there were 2 or more “weak” ratings. Any discrepancies were collectively discussed between 2 reviewers until a consensus was reached, and a third reviewer was consulted when necessary. The quality assessment for each study is presented individually in addition to global quality scores using summary bar plots for each criterion and the overall quality in Figure 2.

Figure 2.

Risks-of-Bias Analysis Using the Quality Assessment Tool for Quantitative Studies developed by the Effective Public Health Practice Project.⁴⁰^,^,⁴¹ The table presents the results of the quality assessment for each criterion and the overall quality per studies classified as weak (red), medium (orange), or strong (green). A summary bar plot of the aggregate quality assessment results is presented below the table

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Ethical Considerations

This systematic review and meta-analysis followed the recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement⁴² (Table S2), and the protocol was prospectively registered in the International Prospective Register of Systematic Reviews database (PROSPERO registration number: CRD42023440835).

RESULTS

The initial database search yielded a total of 1066 publications. After removal of duplicates, 613 records were excluded after title/abstract screening according to our eligibility criteria. Finally, the remaining 27 full-text articles were screened, 19 of which met all of the eligibility criteria. A flowchart detailing the screening process, including the number of studies within the 2 meta-analyses, is illustrated in Figure 1.

Quality Assessment

The global quality assessment found 6 studies to be “strong,” 7 studies to be “moderate,” and 6 studies to be “weak.” The quality of selection bias minimization (n = 15), confounders (n = 10), and data collection (n = 11) was evaluated as “moderate” for the majority of studies, while the blinding of participants and personnel was mostly rated as “weak” (n = 12). Overall, studies were deemed to have a moderate score for selection bias as few authors reported the number of participants who agreed to participate in the study or their recruitment strategy. Most studies checked for differences in potential confounders between groups prior to the intervention (eg, gender, age, health status) (n = 12). Studies did not always use validated measurement methods (n = 11), which explains the moderate score for measurement bias. Most of the studies (n = 11) rated as strong for their design were randomized controlled trials. Although not reported in some studies (n = 3), the retention rate was generally higher than 60%. Individual quality assessment of the selected publications is detailed in Figure 2.

Participant Characteristics

All participant and study characteristics are detailed in Table 2. All studies were performed in youth with overweight/obesity presenting a weighted average BMI of 33.3 kg/m² (BMI range: 24.05⁴⁵–50.09 kg/m^{2 57}) and a weighted mean age of 12.5 years old, ranging from 9 years⁴⁵ to 15.8 years.⁴⁹ Among the 19 clinical studies included, 12 were conducted in the United States. Most studies enrolled either a majority of girls (n = 10) or an approximately equal number of females and males (±2; n = 6), except for 1 study involving only girls,⁴⁹ 1 study involving more boys than girls,⁵⁵ and 1 study that did not specify gender ratio.⁵⁶ Children in 3 studies had specific diagnosed pathologies such as NAFLD,⁴⁴ Prader-Willi syndrome,⁴⁵ or polycystic ovary syndrome.⁴⁹

Table 2.

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Summary of Study Design, Population Characteristics, Methodology, and Main Results of the Clinical Trials Selected in the Systematic Review

Study (year), country	Study design	Population characteristics	Methodology	Main anthropometric and biochemical results
Pauley et al (2021),⁴³ United States	Observational study Retrospective analysis of clinical data extracted from medical records from July 1, 2014, to June 30, 2017—Group A Collection of laboratory analyses of a smaller second group of children from the obesity clinic referred from July 1, 2018, to December 31, 2018—Group B	Children/adolescents Obesity (≥95th percentile) 5–18 y old n = 138 Group A: 130 88♀+ 42♂ Mean age: 11.5 (95% CI: 10.9 to 12.0) y Mean BMI: 34.1 (95% CI: 32.7 to 35.4) kg/m² Group B: 8 5♀+ 3♂ Mean age: 14.0 (95% CI: 11.6 to 16.4) y Mean BMI: 41.3 (95% CI: 35.0 to 47.5) kg/m²	Carbohydrate-restricted diet (≤30 g/d; 5% to 10% of total energy intake), with unlimited calories, fat, and protein Limited fruit consumption to berries No milk, juice, and sugar-sweetened drinks Multivitamin supplementation Only diet instruction provided Duration: 3–4 mo Parameters: Weight (digital scale), height (stadiometer), blood pressure, diary of daily food intake Biochemical analysis: Group B: Fasting serum analyses of total cholesterol, TG, insulin, glycated hemoglobin, blood urea nitrogen, creatinine, and 20- hydroxy-eicosatetraenoic acid No ketone measurement Data collection: Before and after the diet intervention Exercise daily	Anthropometric results: Group A ↘: Weight of 5.1 kg (P < .001) BMI of 2.5 kg/m² (P < .001) Percentage weight loss of 6.9% (P < .001). Group B ↘: Weight of 9.6 kg (P < .01) BMI of 4 kg/m² (P < .01) Percentage weight loss of 9% (P < .01) The older-group participants who completed the diet had the same percentage of weight loss compared with those <12 years (6.9% vs 6.9%) Biochemical results: Group A: No analysis Group B ↘: Fasting serum insulin (P < .01) TG (P < .01) 20-Hydroxy-eicosatetraenoic acid (P < .01)
Goss et al (2020),⁴⁴ United States	Randomized 2-arm, parallel dietary intervention Family-based diet intervention	Children/adolescents Obesity (≥85th percentile) NAFLD (ALT >45 and/or perfusely echogenic liver via ultrasound) Sedentary (<2 h/wk of intentional exercise) 9-17 y old n = 32 16♀+ 16♂ CRD group: Mean ± SD age: 14.2 ± 2.1 y Mean ± SD BMI: 35.9 ± 6.7 kg/m² FRD group: Mean ± SD age: 14.5 ± 2.6 y Mean ± SD BMI: 38.4 ± 7.3 kg/m²	Two randomized groups: Moderately CHO-restricted diet (CRD): n = 16 CRD: <25%, 25%, >50% of energy from CHO, protein, fat, respectively Fat-restricted diet (FRD): n = 16 55%, 25%, 20% of energy from CHO, protein, fat, respectively Based on the USDA MyPlate Daily Food Plan for teenagers Caloric intakes were calculated to be weight maintaining Saturated fat intake was limited to <10% total energy/d Foods and menus provided at least for a part of the study Duration: 8 wk 2-wk modified controlled-feeding phase 6-wk free-living phase Parameters: Weight, height, body composition (DXA) Biochemical analysis: Insulin resistance (fasting blood sample) REE (indirect calorimetry) Change in hepatic lipid content (magnetic resonance imaging) No ketone measurement Data collection: Before and after the diet intervention	Anthropometric results: Significant ↘ in weight, BMI, and BMI z-score after 8 wk of CRD diet only Significantly greater ↘ in abdominal fat mass (-1.5 vs 0.0, P < .01) and body fat mass (-1.1 vs -0.1, P < .01) in response to the CRD vs FRD Biochemical results: Change in hepatic lipids did not differ with diet, but declined significantly (−6.0%± 4.7%, P < .001) only within the CRD group Significantly greater ↘ in plasma insulin concentration and insulin resistance (P < .05), in response to the CRD vs FRD
Felix et al (2020),⁴⁵ United States	Clinical feasibility study	Children Overweight/obese (≥95th percentile) Prader-Willi syndrome (PWS) 6–12 y old n = 7 5♀+ 2♂ Mean ± SD age: 9 ± 2.62 y Mean ± SD BMI: 24.05 ± 5.14 kg/m²	Modified Atkins diet 10–15 g net carbohydrate limit (a calculation of total carbohydrates minus fiber) To take a general pediatric multivitamin with minerals, a vitamin D supplement (600 IU) daily, and a calcium supplement (1000 mg/d for 4–8-y-olds and 1300 mg/d for 9–13-y-olds) Menus and recipes provided Duration: ∼12 mo 4 months being on the diet 4 months being off the diet Parameters: History, weight, height Biochemical analysis: Fasting bloodwork (comprehensive metabolic panel, lipid profile, hemoglobin A1c, insulin level), urine studies (urinalysis, urine calcium, urine creatinine) Psychology questionnaires: Families and participants were also asked to comment subjectively on behavior, skin picking, and hyperphagia Urinary ketones (urine ketone sticks) Data collection: 3 study visits, 4 mo apart	Anthropometric results: 1 patient ↘ 2.9 kg; the others maintained their weight BMI z-scores improved for 3/4 of participants, ↘ by average of 0.21 points for each participant Weight gain noted in all participants after the end of the diet and especially in patients who lost weight Biochemical results: 3/4 patients: ↗ in LDL 1 patient: ↘ in TG Various and opposite impact on HOMA-IR according to patients 1 patient: hypercalciuria (with no renal stones) Results are descriptive due to the lack of participant number for statistical analysis.
Kirk et al (2017),⁴⁶ United States	Randomized trial (same population and dataset as Kirk et al, 2012)	Children Obesity (BMI z-score: 1.60–2.65) 7-12 y old n = 102 88♀+ 14♂ LC group: Mean age: 10.4 (9.4–12.1) y Mean BMI: 29.7 (26.7–32.6) kg/m² PC group PC: Mean age: 10.5 (9.2–11.3) y Mean BMI: 28.9 (25.8–31.4) kg/m² RGL group: Mean age: 10.5 (9.0–11.8) y Mean BMI: 30.1 (25.3–32.1) kg/m²	Low-carbohydrate (LC) (n = 35), reduced glycemic load (RGL) (n = 36), or standard portion-controlled PC diet (n = 31); randomized LC: ≤60 g/d (10%–20%), no limit on energy intake RGL: Limit their intake of high-glycemic index foods and drinks using a stoplight approach, no limit on energy intake PC: Age-appropriate, calorie-restricted meal plans (55%–60% CHO; 10%–15% protein, and 30% fat), resulting in a 500-kcal/d deficit relative to expected energy requirements Only diet instruction provided Duration: 12 mo 3-mo intervention 9-mo follow-up period Parameters: Weight, height, TFEQ completed by parents (TFEQ contains 3 factors: H, Hunger; D, Disinhibition; CR, Cognitive restraint), 3-d food records Urinary ketones (urine ketone sticks) Data collection: At baseline and 3, 6, and 12 mo	TFEQ results: All diet groups showed increased CR and decreased H and D from baseline to 3 mo, with differences from baseline remaining at 12 mo for CR and H Lower BMI status during study follow-up was associated with different TFEQ scores by diet group (LC and RGL: higher CR; PC: lower H), adjusting for sex, age, and race Higher CR at follow-up was predicted by race and higher baseline CR; only lower H at baseline predicted lower H at follow-up
Kirk et al (2012),⁴⁷ United States	Randomized trial (same population and dataset as Kirk et al, 2017)	Children Obesity (BMI z-score, 1.60–2.65) 7–12 y old n = 102 88♀+ 14♂ LC group: Mean age: 9.9 ± 1.6 y Mean BMI: 29.9 ± 4.4 kg/m² PC group: Mean age: 9.7 ± 1.3 y Mean BMI: 29.1 ± 3.8 kg/m² RGL group: Mean age: 9.8 ± 1.7 y Mean BMI: 29.2 ± 3.8 kg/m²	LC (n = 35), RGL (n = 36), or standard PC diet (n = 31); randomized LC: ≤60 g/d, no limit on energy intake RGL: Limit their intake of high-glycemic-index foods and drinks using a stoplight approach, no limit on energy intake PC: Age-appropriate, calorie-restricted meal plans (55%–60% CHO, 10%–15% protein, and 30% fat), resulting in a 500-kcal/d deficit relative to expected energy requirements Only diet instruction provided Duration: 12 mo 3-mo intervention 9-mo follow-up period Parameters: Body weight (weekly, digital scale), height (stadiometer), waist circumference (fiberglass tape measure), body fat (DXA), 3-d food records (3 consecutive days the week prior the assessment visit) Biochemical analyses: Fasting insulin, glucose, total cholesterol, TG, and LDL and HDL cholesterol) Blood pressure, urinary ketones (urine ketone sticks) Data collection: At baseline and 3, 6, and 12 mo One hour of exercise biweekly led by a specialist	Anthropometric results: At 3 mo: BMI z-score lower in all diet groups (LC: -0.27 ± 0.04; RGL: -0.20 ± 0.04; PC: -0.21 ± 0.04; P < .0001) and maintained at 6 mo Similar results for waist circumference and percent body fat At 12 mo: In all diet groups, lower BMI z-scores than at baseline (LC: -0.21 ± 0.04; RGL: -0.28 ± 0.04; PC: -0.31 ± 0.04; P < .0001) Lower percent of body fat No reductions in waist circumference were maintained Daily caloric intake ↘ from baseline to all time points for all diet groups (P < .0001) Biochemical results: All diets demonstrated some improved clinical measures By the 12-mo follow-up: LC group demonstrated improvements in TG and HDL cholesterol CR group had improved fasting glucose, insulin and HDL cholesterol LGL group exhibited improved fasting insulin and LDL cholesterol. At 3 mo: Insulin was significantly lower in the LC group than in the RGL and PC groups (LC vs PC, P = .04; LC vs RGL, P = .03)
Partsalaki et al (2012),⁴⁸ Greece	Randomized trial	Children/adolescents Obesity (>95th percentile) 8–18 y old n = 58 31♀+ 27♂ Ketogenic diet group: Mean age: 13.6 ± 2.5 y Mean BMI: 30.8 ± 8.1 kg/m² Hypocaloric diet group: Mean age: 12.3 ± 2.7 y Mean BMI: 28.0 ± 4.2 kg/m²	Two diets: (50% of subjects each) Ketogenic diet: <20 g/d carbohydrates, with a gradual ↗ towards 30–40 g/d, if the measurements of urinary ketones continued to indicate ketosis No restrictions on caloric intake or the type of fat or cholesterol concentration of the foods Hypocaloric diet: Reduce their caloric intake by 500 calories daily while deriving 28%–33% and 50%–55 % of these calories from fat and carbohydrates, respectively Both have daily multivitamins with minerals supplements Only diet instruction provided Duration: 6 mo Parameters: Weight (electronic scale), height (stadiometer), waist circumference, body composition (impedance analyzer) Biochemical analyses: Lipidemic profile, HMW adiponectin, WBISI, and HOMA-IR were determined before and after each diet Daily urinary ketone measurements (dipsticks), food diaries, oral-glucose/insulin-tolerance test Data collection: At baseline and after a weight loss of ≥10% from the initial body weight Recommendation to perform at least 1 h daily of vigorous exercise	Anthropometric results: Both groups significantly ↘ their: Weight (mean: -8 kg for the ketogenic diet, P = .001, and -5.7 kg for the hypocaloric diet, P = .001) Fat mass (mean: -7 kg for the ketogenic diet, P = .001, and -5.1 kg for the hypocaloric diet, P = .003) Waist circumference (mean: -9.2 cm for the ketogenic diet, P = .002, and -7.4 cm for the hypocaloric diet, P = .003, respectively) The differences were greater in the ketogenic group Biochemical results: Both groups significantly ↘ their: Fasting insulin (P = .017 for the ketogenic diet, and P = .009 for the hypocaloric diet) HOMA-IR (P = .009 for ketogenic diet, and P = .014 for the hypocaloric diet) The differences were greater in the ketogenic group Only the ketogenic group increased HMW adiponectin significantly (P = .025)
Ornstein et al (2011),⁴⁹ United States	Randomized pilot trial of 2 diets in a prospective study	Adolescent/young-adult females Overweight (≥85th percentile) Polycystic ovary syndrome 12–22 y n = 24 ♀ Mean age: 15.8 ± 2.2 y Mean BMI: 35.7 ± 6 kg/m²	Two diets: (50% of subjects each) Very-low-carbohydrate diet (LC): ≤20 g/d of carbohydrate and an ad libitum intake of protein, fat, and energy for the initial 2 weeks. For weeks 3 through 12, carbohydrate ↗ to 40 g daily by adding additional low-glycemic-index foods. Hypocaloric low-fat diet (LF): ≤40 g/d of fat, with 5 servings of starch (15 g of carbohydrate per serving) per day and an ad libitum intake of fat-free dairy foods, fruits, and vegetables. No juices and sweetened beverages. Multivitamin supplements in both diets Menus and recipes provided Duration: 12 wk Parameters: Dietary compliance, menstrual history, and weight and waist circumference Urinary ketones (urine ketone sticks) Data collection: Weight (2×/wk), waist circumference (at baseline and at the end) Perform 30 min of aerobic exercise 3 times per week	Anthropometric results: Weight loss averaged 6.5% (P < .0001) Waist circumference ↘ by an average of 5.7 ± 7.7 cm (P = .01). The sample size did not have adequate power to show a difference between the 2 diet treatment groups (0.13 for the LC group and 0.08 for the LF group).
Truby et al (2016),⁵⁰ Australia	Randomized controlled trial, “Eat Smart” study	Youth Obesity (>90th percentile) 10–17 y old n = 87 63♀+ 24♂ SLF group: Mean age: 13.2 ± 2.1 y Mean BMI: 32.62 ± 5.9 kg/m² SMC group: Mean age: 13.2 ± 1.9 y Mean BMI: 32.47 ± 4.9 kg/m² Control group: Mean age: 13.6 ± 1.9 y Mean BMI: 35.17 ± 8.54 kg/m²	3 groups: “Structured modified carbohydrate” (SMC; 35% carbohydrate, 30% protein, 35% fat; n = 37 including 27 females) “Structured low fat” (SLF; 55% carbohydrate, 20% protein, 25% fat; n = 36 including 26 females) Wait-listed control group (n = 14 including 10 females) 20% energy reduction when compared with their estimated energy expenditure except for the control group Only diet instruction provided Duration: 12 wk Parameters: Weight, height, waist circumference, body composition (impedance analysis) Biochemical parameters: Liver function, lipid profiles, insulin and glucose, leptin, resistin, adiponectin, PAI-1 and soluble ICAM-1, TNF-α, IL-6, and CRP At baseline, estimation of the energy expenditure through resting energy expenditure measurement and physical activity level through self-reported activity diary. No ketone measurement Data collection: Before and after the diet intervention Encouraged to set a goal to ↘ sedentary behavior	Anthropometric results: Weight was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -4.15; 95% CI = -5.50, -2.81; P < .001; SMC vs control, -4.51; 95% CI: -6.41, -2.60; P < .001) BMI z-scores were significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -0.13; 95% CI = -0.18, -0.07; P < .001; SMC vs control, -0.14; 95% CI: -0.19, -0.09; P < .001) Waist circumference was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -3.07; 95% CI = -4.54, -1.61; P < .001; SMC vs control, -3.74; 95% CI: -6.29, -1.19; P = .005) There was no difference in BMI z-scores, weight, and waist circumference losses between the 2 diet intervention groups Biochemical results: HOMA-IR was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -0.7; 95% CI = -1.2, -0.2; P = .009; SMC vs control, -0.7; 95% CI: -1.3, -0.2; P = .01) Leptin was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -0.4; 95% CI = -0.7, -0.2; P = .001; SMC vs control, -0.4; 95% CI: -0.7, -0.1; P = .005) Adiponectin was significantly higher only in the SMC group compared with control after adjusting for baseline values (SMC vs control, mean difference = 0.1; 95% CI = -0.0, 0.3; P = .04) Metabolic measurement results: REE was significantly higher only in the SLF group compared with control after adjusting for baseline values (SLF vs control, mean difference = -132; 95% CI = -237, -28; P = .01) There was a significantly higher REE in the SLF group compared with the SMC group after adjusting for baseline (SLF vs SMC, mean difference = 116; 95% CI = 25, 208; P = .01)
Siegel et al (2009),⁵¹ United States	Clinical office–based study	Adolescents Obesity (>95th percentile) 12–18 y old n = 71 53♀+ 18♂ Mean ± SD age: 14.5 ± 1.71 y Mean ± SEM BMI: 34.9 ± 0.81 kg/m²	One group: low-carbohydrate diet (LCD; 20 g < carbohydrates < 50 g daily and no restriction on fat or protein intake) Only diet instruction provided Duration: 6 mo Parameters: Weight, height, 3-d diary of dietary intake Biochemical parameters: CBC, renal profile, fasting serum glucose, fasting insulin level, and total cholesterol, HDL, LDL, and TG levels Self-esteem (Rosenberg Self-Esteem Survey) No ketone measurement Data collection: Diary of dietary intake at baseline, 2 wk, and at 1, 2, 4, and 6 mo Biochemical data analyzed at baseline and after 6 mo Self-esteem survey (at baseline, at 2 mo, and at 6 mo) General recommendation to engage in regular physical activity	Anthropometric results: 32 (84%) lost weight (range from a gain of 5.5 kg to a loss of 23.9 kg) Significant decrease in mean BMI (34.9 to 32.5 kg/m²) Biochemical results: Hematocrit and hemoglobin significantly ↗ over the study period (P < .05).
Demol et al (2009),⁵² Israel	Open-label randomized controlled trial	Adolescents Obesity (>95th percentile) 12–18 y old n = 55 34♀+ 21♂ Low-carbohydrate/low-fat group: Mean ± SE age: 14.0 ± 1.8 y Mean ± SE BMI: 35.2 ± 1.6 kg/m² Low-carbohydrate/high-fat group: Mean ± SE age: 14.3 ± 1.6 y Mean ± SE BMI: 33.7 ± 1.6 kg/m² High-carbohydrate/low-fat group: Mean ± SE age: 14.9 ± 1.8 y Mean ± SE BMI: 33.8 ± 1.5 kg/m²	Three isoenergetic diet regimens (1200–1500 kcal/d): Group 1: Low-carbohydrate, low-fat, protein-rich diet: 60 g carbohydrates (up to 20%), 30% fats, and 50% proteins; n = 18 Group 2: Low-carbohydrate, high-fat diet: 60 g carbohydrates (up to 20%), 60% fats, and 20% proteins; n = 17 Group 3: High-carbohydrate, low-fat diet: 50%–60% carbohydrates, 30% fats, and 20% proteins; n = 20 Menus and recipes provided Duration: 1 y 12 wk intervention 9 mo follow-up Parameters: Weight (standard scale), height (stadiometer), body composition (bioimpedance analysis system), some sessions: food records Biochemical parameters: Total cholesterol, LDL cholesterol, HDL cholesterol, TG, glucose, insulin, blood urea nitrogen, creatinine, total protein, liver enzymes (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase), renal functions (urea, creatinine, electrolytes, uric acid), electrolyte level, hemoglobin, CRP, TSH, free thyroxine, iron, vitamin B₁₂, folic acid, and leptin Ketone and protein levels in urine (reagent strips) Data collection: At baseline, 12 wk and after 1 y, anthropometric (1 time/wk during intervention and once every 3 mo during follow-up) Ketone and protein levels (every week in urine) Biochemical parameters: At baseline, after the 12-wk intervention, and after 9 mo of follow-up General recommendation to engage in regular physical activity	Anthropometric results: All diet regimens were associated with a significant ↘ in BMI, BMI percentile, and body fat percentage at the end of the intervention period No significant differences were found among the groups in changes in BMI, BMI percentile, or fat percentage at the end of the intervention and at the end of follow-up No significant interaction between time and group effect was found for anthropometric After 9 mo of follow-up, all groups maintained the lower BMI and BMI percentile but had significant ↗ in fat percentage compared with at the end of the intervention but still lower than baseline Biochemical results: Insulin and HOMA-IR levels ↘ significantly at both time points only in the 2 low-carbohydrate diet groups. Almost all parameters (glucose, cholesterol, HDL, LDL, TG, leptin), except CRP and ghrelin, ↘ significantly during the intervention and stayed at a similar lower level by the end of the follow-up period (time effect) No significant differences were found among the groups in metabolic markers at the end of the intervention and at the end of follow-up No significant interaction between time and group effect was found for biochemical parameters Only traces of ketones in urine were detected (5 mg/dL), with no significant difference among the 3 study groups meaning no ketosis
Yackobovitch-Gavan et al (2008),⁵³ Israel	Open-label randomized controlled trial	Adolescents Obesity (>95th percentile) 12–18 y old n = 71 42♀+ 29♂ Low-carbohydrate/low-fat group: Mean ± SE age: 14.9 ± 1.8 y Mean ± SE BMI: 36.0 ± 7.7 kg/m² Low-carbohydrate/high-fat group: Mean ± SE age: 14.3 ± 1.6 y Mean ± SE BMI: 33.6 ± 5.5 kg/m² High-carbohydrate/low-fat group: Mean ± SE age: 14.1 ± 1.8 y Mean ± SE BMI: 34.4 ± 6.2 kg/m²	Three isoenergetic diet regimens (1200 kcal/d): Group a: Low-carbohydrate (60 g, 20%), high-protein (150 g, 50%), low-fat (40 g, 30%) (LCLF); n = 15 Group b: Low-carbohydrate (60 g, 20%), low-protein (60 g, 20%), high-fat (80 g, 60%) (LCHF); n = 12 Group c: High-carbohydrate (150–180 g, 50%–60%), low-protein (60 g, 20%), low-fat (40 g, 30%) (HCLF); n = 25 Menus and recipes provided Duration: 12 wk Parameters: Weight (standard scale), height (stadiometer), body composition (bioimpedance analysis system), some sessions: food records HRQOL (Pediatric Quality of Life Inventory) No ketone measurement Data collection: Anthropometric (1 time/wk during intervention), HRQOL (before and at the end of the intervention) General recommendation to engage in regular physical activity	Anthropometric results: Significant similar ↘ in BMI, BMI-SDS, and fat percentage occurred in all groups
Sunehag et al (2005),⁵⁴ Italy	Randomized crossover study	Adolescents Obesity (>95th percentile and body fat content ≤30%) 13–17 y old n = 13 7♀+ 6♂ Mean ± SE age: 14.7 ± 0.3 y Mean ± SE BMI: 34.0 ± 1 kg/m²	Two isocaloric, isonitrogenous diets randomized during 2 visits High-CHO: 60% CHO and 25% fat Low-CHO: 30% CHO and 55% fat Foods and menus provided Participant consumed the selected diet during 7 d before the intervention day and followed the same protocol with the other diet 8 wk after Results compared to lean subjects from a previous study Parameters: Weight, height, visceral fat (magnetic resonance imaging), 24-h calorimeter study (energy expenditure and substrate oxidation rates) with the diet selected Biochemical analysis: Glucose metabolism (gluconeogenesis, glucose production, and glycerol turnover), insulin sensitivity, and first- and second-phase insulin secretory indices, substrate and hormone blood concentration (glucose, insulin, C-peptides, adiponectin, CRP, lipids) No ketone measurement Reported physical activity at baseline used to assess energy requirement only	Biochemical results: Obese adolescents ↗ first- and second-phase insulin secretory indices by 18% (P = .05) and 36% (P = .05), respectively, to maintain normoglycemia during the high-CHO diet because they failed to increase insulin sensitivity as did the lean adolescents Obese adolescents following the CRD had significantly higher total cholesterol and β-OH butyrate compared with the control group Regardless of diet, in obese adolescents, insulin sensitivity was half (P < .05) and first- and second-phase insulin secretory indices twice (P < .01) those compared with the corresponding values in lean participants In obese adolescents, gluconeogenesis increased by 32% during the low-CHO (high-fat diet) (P < .01)
Bailes et al (2003),⁵⁵ United States	Prospective non-randomized controlled study	Children Obesity (>95th percentile) 5–18 y old n = 37 14♀+ 23♂ High-protein, low-CHO-diet group: Mean ± SD age: 12 ± 3 y Mean ± SE BMI: 36.68 ± 4.0 kg/m² Low-cal-diet group: Mean ± SD age: 11 ± 2 y Mean ± SD BMI: 36.0 ± 3.1 kg/m²	Choose between 2 dietary interventions: (1) High-protein, carbohydrate-restricted diet (High Protein, Low CHO diet): <30 g of carbohydrates per day; no limitation on total calories or for other macronutrients; n = 27 (2) Calorie-restricted diet (Low Cal Diet): 20% ↘ in their energy needs based on ideal weight, fat (<30%), protein (15%–20%), and carbohydrates (50%–55%); n = 10 Only diet instruction provided Duration: 2 mo Parameters: Weight, height No ketone measurement	Anthropometric results: At 2 mo, children in the High Protein, Low CHO Diet group lost an average weight of 5.21 ± 3.44 kg (P < .001) and decreased their BMI by 2.42 ± 1.3 points (P < .001) Children in the Low Cal Diet group gained an average weight of 2.36 ± 2.54 kg and 1.00 point on the BMI value (P < .001)
Sondike et al (2003),⁵⁶ United States	Randomized, nonblinded controlled trial	Adolescents Obesity (>95th percentile) 12–18 y old n = 39 ?♀+ ?♂ LC group: Mean ± SD age: 14.4 ± 1.9 y Mean ± SD BMI: 35.4 ± 5.0 kg/m² LF group: Mean ± SD age: 15.0 ± 1.8 y Mean ± SD BMI: 35.6 ± 5.8 kg/m²	Two groups: Low-carbohydrates (LC): <20 g of carbohydrate per day for 2 wk, then <40 g/d for 10 wk, and to eat LC foods according to hunger (n = 20) Low-fat (LF): <30% of energy from fat (n = 19)—control Menus and recipes provided Duration: 12 wk Parameters: Weight (triple-beam balance scale), height (stadiometer), diet composition (food records) Biochemical analysis: Serum lipid profiles Urinary ketones (urine ketone sticks) Data collection: Diet composition and weight (every 2 wk), serum lipid profiles (at baseline and at the end of study), urinary ketones (daily)	Anthropometric results: The LC group lost more weight (mean, 9.9 ± 9.3 kg vs 4.1 ± 4.9 kg; P < .05) and ↘ more the BMI (mean, 3.3 ± 3.0 kg/m² vs 1.5 ± 1.7 kg/m², P < .05) and the BMI T-scores than the LF group Higher reported EI in the LC group compared with the LF group. Biochemical results: There was improvement in LDL-cholesterol levels (P < .05) in the LF group but not in the LC group There was improvement in non–HDL-cholesterol levels (P < .05) in the LC group TG also ↘ significantly in the LC group from baseline There were no adverse effects on the lipid profiles of participants in either group All patients in the LC group had ketonuria on most days Ketonuria developed in the LC group by the third day, on average
Willi et al (1998),⁵⁷ United States	Clinical trial	Adolescents Obesity (200% of the ideal body weight) 12–15 y old n = 6 3♀+ 3♂ Mean ± SEM age: 13.7 ± 0.49 y Mean ± SEM BMI: 50.9 ± 3.4 kg/m²	One diet: K diet (high protein low in carbohydrates and fat) Daily intake (650–725 calories), high in protein (80–100 g), very low in carbohydrates (25 g) and fat (25 g) This was followed by 12 wk of the K diet (carbohydrates [30 g] per meal) called the K + 2 diet Foods and menus provided Duration: 20 wk 8 wk 12 wk (K + 2 diet) Parameters: Weight (single scale), body composition (DXA, bioelectrical impedance, creatinine excretion) Food records Biochemical analysis: Complete blood chemistries as well as electrolytes, hematology profile, lipid profile, IGF-1, IGFBP-3, and serum leptin levels Urinary nitrogen and electrolyte balance (urine ketone test), REE (indirect calorimetry), nocturnal polysomnography (electrocardiogram, electroencephalogram, electromyogram, chest wall pneumography, and pulse oximetry), and multiple sleep latency Data collection: Anthropometric data, blood and urine (at baseline, at week 1, and at 4-wk intervals throughout the course of the study), body composition and urinary creatinine excretion (at baseline and each phase of the diet), sleep studies (at baseline and after an average weight loss of 18.7 kg)	Anthropometric results: Participants lost 15.4 ± 1.4 kg (mean ± SEM) of body weight during the K diet and an additional 2.3 ± 2.9 kg during the K + 2 diet One participant regained weight while others lost weight during the K + 2 diet BMI ↘ 5.4 ± 0.4 kg/m² during the K diet and an additional 1.1 ± 1.2 kg/m² during the K + 2 diet Weight was lost equally from all areas of the body and was predominantly fat DXA showed a ↘ from 51.1% ± 2.1% body fat to 44.2% ± 2.9% during the K diet and then to 41.6% ± 4.5% during the K + 2 diet Lean body mass was not significantly affected Biochemical results: Blood chemistries remained normal throughout the study and included a ↘ in serum cholesterol from 162 ± 12 to 121 ± 8 mg/dL in the initial 4 wk of the K diet Leptin levels were considerably lower than found in similarly obese adults and showed no consistent decline with weight loss Within 72 h of starting the K diet, urine testing revealed the presence of small to moderate amounts of ketone bodies Ketosis was quickly suppressed with the daily addition of 90 g of carbohydrate during the K + 2 diet An ↗ in calcium excretion was accompanied by a ↘ in total-body bone mineral content Metabolic measurement results: Weight loss was accompanied by a reduction in REE of 5.2 ± 1.8 kcal/kg of fat-free mass per day
Krebs et al (2010),⁵⁸ United States	Randomized controlled trial	Adolescents Severe obesity (body weight estimated to be ≥175% of ideal body weight) 12–18 y old n = 33 25♀+ 21♂ HPLC group: Mean ± SEM age: 14.2 ± 0.4 y Mean ± SEM BMI: 38.0 ± 1.2 kg/m² LF group: Mean ± SEM age: 13.7 ± 0.3 y Mean ± SEM BMI: 40.1 ± 1.8 kg/m²	High protein (2.0–2.5 g protein/kg ideal body weight per day), low carbohydrate (≤20 g/d) diet (HPLC); n = 18 Fat and energy intake not restricted Low fat (≤30% of calories/d) (LF); n = 15 Daily energy intake goal of 70% of REE (Harris-Benedict equation) Only diet instruction provided Duration: 13 wk Follow-up at weeks 24 and 36 from baseline Parameters: Weight (scale), height (stadiometer), body composition (DXA), 3-d diet records at random times Biochemical analysis: Lipid profile, 2-h oral-glucose-tolerance test Blood β-hydroxybutyrate measurement 3-d diet records including subjective feelings of hunger and fullness 9 times throughout the day (visual analog scale) Safety and potential adverse effects tests: Serum electrolytes, blood urea nitrogen, creatinine, serum calcium, phosphorus, and magnesium; liver function test and urine pregnancy test (β-HCG) for the female participants, electrocardiogram, and abdominal ultrasounds Data collection: 3-d diet records (random times throughout the intervention, varied among participants), body composition (at baseline and at 13 wk) Exercise program (at least 30 min of daily moderately vigorous physical activity)	Anthropometric results: Significant ↘ in BMI-Z was achieved in both groups during the intervention The ↘ BMI-Z was significantly greater for the HPLC group (P = .03) Both groups maintained significant BMI-Z reduction at follow-up; changes were not significantly different between groups Loss of lean body mass was not spared in the HPLC group Biochemical results: Both groups had significant ↘ in TG and LDL-cholesterol levels Mean TG ↘ was 3-fold greater in the HPLC group (P = .0003), whereas there was only a marginal reduction for the LF group (P = .10) Modest HDL cholesterol ↘ was significant for LF but not for the HPLC group None of these cholesterol changes were significantly different between the groups. The mean ↘ in 2-h insulin concentration at 13 wk was significant in the HPLC group (P = .03) but showed only a trend for the LF group (P = .07) The proportions of HOMA-IR scores >3.16 in both groups were ↘ to approximately one-third of participants at 13 wk compared with >50% of participants at study initiation The 13-wk serum β-hydroxybutyrate concentrations increased in the HPLC group compared with the LF group: 2.28 ± 0.34 mmol/L vs 1.0 ± 0.12 mmol/L, for the HPLC and LF groups, respectively (P = .002)
Zeybek et al (2010),⁵⁹ Turkey	Clinical study	34 Children with obesity (≥95th percentile) 17♀+ 17♂ 24 sex-matched lean controls (≤85th percentile) 12♀+ 12♂ Obese group: Mean ± SD age: 11.75 ± 2.23 y Mean ± SD BMI: 32.55 ± 2.96 kg/m² Lean group: Mean ± SD age: 11.25 ± 1.75 y Mean ± SD BMI: 17.52 ± 1.72 kg/m²	Only the obese group (n = 31) follow a low-carbohydrate diet: ≤30% of the total calories from simple carbohydrates Intake of protein and fat not limited but avoid trans-fat No caloric restriction (1500 and 2500 kcal/d) Only diet instruction provided Duration: 6 mo Parameters: Weight, height Biochemical analysis: Serum fasting glucose and plasma insulin Systolic and diastolic blood pressures, echocardiographic imaging and measurements No ketone measurement Data collection: At baseline and at the end of the intervention General recommendation to engage in regular physical activity	Anthropometric results: The mean weight of obese children was ↘ from 70.73 ± 14.85 to 65.03 ± 11.88 kg (P < .0001) BMI was ↘ from 33.20 ± 3.86 to 29.26 ± 3.38 kg/m² (P < .05) Biochemical results: Insulin and HOMA-IR levels were higher in obese patients Plasma fasting insulin level ↘ from 19.07 ± 26.41 to 14.14 ± 10.77 mIU/mL (P < .0001) after diet in obese patients HOMA-IR level ↘ from 4.36 ± 8.83 to 2.85 ± 2.64 (P < .0001) after diet in obese patients
Zeybek et al (2009),⁶⁰ Turkey	Clinical study	Overweight group: n = 28 (BMI: 25–30 kg/m²) 15♀+ 13♂ Mean ± SD age: 10.95 ± 2.11 y Mean ± SD BMI: 27.31 ± 1.25 kg/m² Obese group: n = 34 (BMI: ≥30 kg/m²) 16♀+ 18♂ Mean ± SD age: 12.19 ± 2.66 y Mean ± SD BMI: 35.15 ± 3.03 kg/m² Lean group: n = 29 (BMI: 17–25 kg/m²) 14♀+ 15♂ Mean± SD age: 11.33 ± 2.05 y Mean± SD BMI: 18.87 ± 2.43 kg/m²	Only the obese group (n = 30) follow a low-carbohydrate diet: ≤30% of the total calories from simple carbohydrates Intake of protein and fat not limited but avoid trans-fat No caloric restriction (1500 and 2500 kcal/d) Only diet instruction provided Duration: 6 mo Parameters: Weight, height Biochemical analysis: Serum fasting glucose, plasma insulin, uric acid, total cholesterol, TG, LDL and HDL cholesterol levels Systolic and diastolic blood pressures, echocardiographic imaging and measurements No ketone measurement Data collection: At baseline and at the end of the intervention General recommendation to engage in regular physical activity	Anthropometric results: The mean weight of these obese children was ↘ from 77.99 ± 14.72 to 73.01 ± 12.42 kg (P < .0001) Their height was ↗ from 1.49 ± 0.14 to 1.54 ± 0.11 m (P < .05) Their BMI was ↘ from 35.13 ± 4.65 to 30.80 ± 4.10 kg/m² (P < .0001)
Dunlap and Bailes (2008),⁶¹ United States	Pilot study	Children Overweight (BMI <97%) 6–12 y old n = 18 8♀+ 10♂ Mean age: 9.3 y ± 3 y Mean BMI: 32.6 ± 5.7 kg/m²	Restricted-carbohydrate (≤30 g daily) diet Unlimited protein and energy Only diet instruction provided Duration: 10 wk Parameters: Weight (digital scale), height (stadiometer) Biochemical analysis: Fasting lipid profiles (including total cholesterol, HDL, LDL, and TG) No ketone measurement Data collection: At baseline and at the end of the intervention	Anthropometric results: Average weight loss was 7.1 kg BMI ↘ by 3.2 kg/m² but did not reach statistical significance Biochemical results: Both total serum cholesterol and TG levels showed a significant ↘: 24.2 (P = .018) and 56.9 (P = .015) mg/dL, respectively

Study (year), country	Study design	Population characteristics	Methodology	Main anthropometric and biochemical results
Pauley et al (2021),⁴³ United States	Observational study Retrospective analysis of clinical data extracted from medical records from July 1, 2014, to June 30, 2017—Group A Collection of laboratory analyses of a smaller second group of children from the obesity clinic referred from July 1, 2018, to December 31, 2018—Group B	Children/adolescents Obesity (≥95th percentile) 5–18 y old n = 138 Group A: 130 88♀+ 42♂ Mean age: 11.5 (95% CI: 10.9 to 12.0) y Mean BMI: 34.1 (95% CI: 32.7 to 35.4) kg/m² Group B: 8 5♀+ 3♂ Mean age: 14.0 (95% CI: 11.6 to 16.4) y Mean BMI: 41.3 (95% CI: 35.0 to 47.5) kg/m²	Carbohydrate-restricted diet (≤30 g/d; 5% to 10% of total energy intake), with unlimited calories, fat, and protein Limited fruit consumption to berries No milk, juice, and sugar-sweetened drinks Multivitamin supplementation Only diet instruction provided Duration: 3–4 mo Parameters: Weight (digital scale), height (stadiometer), blood pressure, diary of daily food intake Biochemical analysis: Group B: Fasting serum analyses of total cholesterol, TG, insulin, glycated hemoglobin, blood urea nitrogen, creatinine, and 20- hydroxy-eicosatetraenoic acid No ketone measurement Data collection: Before and after the diet intervention Exercise daily	Anthropometric results: Group A ↘: Weight of 5.1 kg (P < .001) BMI of 2.5 kg/m² (P < .001) Percentage weight loss of 6.9% (P < .001). Group B ↘: Weight of 9.6 kg (P < .01) BMI of 4 kg/m² (P < .01) Percentage weight loss of 9% (P < .01) The older-group participants who completed the diet had the same percentage of weight loss compared with those <12 years (6.9% vs 6.9%) Biochemical results: Group A: No analysis Group B ↘: Fasting serum insulin (P < .01) TG (P < .01) 20-Hydroxy-eicosatetraenoic acid (P < .01)
Goss et al (2020),⁴⁴ United States	Randomized 2-arm, parallel dietary intervention Family-based diet intervention	Children/adolescents Obesity (≥85th percentile) NAFLD (ALT >45 and/or perfusely echogenic liver via ultrasound) Sedentary (<2 h/wk of intentional exercise) 9-17 y old n = 32 16♀+ 16♂ CRD group: Mean ± SD age: 14.2 ± 2.1 y Mean ± SD BMI: 35.9 ± 6.7 kg/m² FRD group: Mean ± SD age: 14.5 ± 2.6 y Mean ± SD BMI: 38.4 ± 7.3 kg/m²	Two randomized groups: Moderately CHO-restricted diet (CRD): n = 16 CRD: <25%, 25%, >50% of energy from CHO, protein, fat, respectively Fat-restricted diet (FRD): n = 16 55%, 25%, 20% of energy from CHO, protein, fat, respectively Based on the USDA MyPlate Daily Food Plan for teenagers Caloric intakes were calculated to be weight maintaining Saturated fat intake was limited to <10% total energy/d Foods and menus provided at least for a part of the study Duration: 8 wk 2-wk modified controlled-feeding phase 6-wk free-living phase Parameters: Weight, height, body composition (DXA) Biochemical analysis: Insulin resistance (fasting blood sample) REE (indirect calorimetry) Change in hepatic lipid content (magnetic resonance imaging) No ketone measurement Data collection: Before and after the diet intervention	Anthropometric results: Significant ↘ in weight, BMI, and BMI z-score after 8 wk of CRD diet only Significantly greater ↘ in abdominal fat mass (-1.5 vs 0.0, P < .01) and body fat mass (-1.1 vs -0.1, P < .01) in response to the CRD vs FRD Biochemical results: Change in hepatic lipids did not differ with diet, but declined significantly (−6.0%± 4.7%, P < .001) only within the CRD group Significantly greater ↘ in plasma insulin concentration and insulin resistance (P < .05), in response to the CRD vs FRD
Felix et al (2020),⁴⁵ United States	Clinical feasibility study	Children Overweight/obese (≥95th percentile) Prader-Willi syndrome (PWS) 6–12 y old n = 7 5♀+ 2♂ Mean ± SD age: 9 ± 2.62 y Mean ± SD BMI: 24.05 ± 5.14 kg/m²	Modified Atkins diet 10–15 g net carbohydrate limit (a calculation of total carbohydrates minus fiber) To take a general pediatric multivitamin with minerals, a vitamin D supplement (600 IU) daily, and a calcium supplement (1000 mg/d for 4–8-y-olds and 1300 mg/d for 9–13-y-olds) Menus and recipes provided Duration: ∼12 mo 4 months being on the diet 4 months being off the diet Parameters: History, weight, height Biochemical analysis: Fasting bloodwork (comprehensive metabolic panel, lipid profile, hemoglobin A1c, insulin level), urine studies (urinalysis, urine calcium, urine creatinine) Psychology questionnaires: Families and participants were also asked to comment subjectively on behavior, skin picking, and hyperphagia Urinary ketones (urine ketone sticks) Data collection: 3 study visits, 4 mo apart	Anthropometric results: 1 patient ↘ 2.9 kg; the others maintained their weight BMI z-scores improved for 3/4 of participants, ↘ by average of 0.21 points for each participant Weight gain noted in all participants after the end of the diet and especially in patients who lost weight Biochemical results: 3/4 patients: ↗ in LDL 1 patient: ↘ in TG Various and opposite impact on HOMA-IR according to patients 1 patient: hypercalciuria (with no renal stones) Results are descriptive due to the lack of participant number for statistical analysis.
Kirk et al (2017),⁴⁶ United States	Randomized trial (same population and dataset as Kirk et al, 2012)	Children Obesity (BMI z-score: 1.60–2.65) 7-12 y old n = 102 88♀+ 14♂ LC group: Mean age: 10.4 (9.4–12.1) y Mean BMI: 29.7 (26.7–32.6) kg/m² PC group PC: Mean age: 10.5 (9.2–11.3) y Mean BMI: 28.9 (25.8–31.4) kg/m² RGL group: Mean age: 10.5 (9.0–11.8) y Mean BMI: 30.1 (25.3–32.1) kg/m²	Low-carbohydrate (LC) (n = 35), reduced glycemic load (RGL) (n = 36), or standard portion-controlled PC diet (n = 31); randomized LC: ≤60 g/d (10%–20%), no limit on energy intake RGL: Limit their intake of high-glycemic index foods and drinks using a stoplight approach, no limit on energy intake PC: Age-appropriate, calorie-restricted meal plans (55%–60% CHO; 10%–15% protein, and 30% fat), resulting in a 500-kcal/d deficit relative to expected energy requirements Only diet instruction provided Duration: 12 mo 3-mo intervention 9-mo follow-up period Parameters: Weight, height, TFEQ completed by parents (TFEQ contains 3 factors: H, Hunger; D, Disinhibition; CR, Cognitive restraint), 3-d food records Urinary ketones (urine ketone sticks) Data collection: At baseline and 3, 6, and 12 mo	TFEQ results: All diet groups showed increased CR and decreased H and D from baseline to 3 mo, with differences from baseline remaining at 12 mo for CR and H Lower BMI status during study follow-up was associated with different TFEQ scores by diet group (LC and RGL: higher CR; PC: lower H), adjusting for sex, age, and race Higher CR at follow-up was predicted by race and higher baseline CR; only lower H at baseline predicted lower H at follow-up
Kirk et al (2012),⁴⁷ United States	Randomized trial (same population and dataset as Kirk et al, 2017)	Children Obesity (BMI z-score, 1.60–2.65) 7–12 y old n = 102 88♀+ 14♂ LC group: Mean age: 9.9 ± 1.6 y Mean BMI: 29.9 ± 4.4 kg/m² PC group: Mean age: 9.7 ± 1.3 y Mean BMI: 29.1 ± 3.8 kg/m² RGL group: Mean age: 9.8 ± 1.7 y Mean BMI: 29.2 ± 3.8 kg/m²	LC (n = 35), RGL (n = 36), or standard PC diet (n = 31); randomized LC: ≤60 g/d, no limit on energy intake RGL: Limit their intake of high-glycemic-index foods and drinks using a stoplight approach, no limit on energy intake PC: Age-appropriate, calorie-restricted meal plans (55%–60% CHO, 10%–15% protein, and 30% fat), resulting in a 500-kcal/d deficit relative to expected energy requirements Only diet instruction provided Duration: 12 mo 3-mo intervention 9-mo follow-up period Parameters: Body weight (weekly, digital scale), height (stadiometer), waist circumference (fiberglass tape measure), body fat (DXA), 3-d food records (3 consecutive days the week prior the assessment visit) Biochemical analyses: Fasting insulin, glucose, total cholesterol, TG, and LDL and HDL cholesterol) Blood pressure, urinary ketones (urine ketone sticks) Data collection: At baseline and 3, 6, and 12 mo One hour of exercise biweekly led by a specialist	Anthropometric results: At 3 mo: BMI z-score lower in all diet groups (LC: -0.27 ± 0.04; RGL: -0.20 ± 0.04; PC: -0.21 ± 0.04; P < .0001) and maintained at 6 mo Similar results for waist circumference and percent body fat At 12 mo: In all diet groups, lower BMI z-scores than at baseline (LC: -0.21 ± 0.04; RGL: -0.28 ± 0.04; PC: -0.31 ± 0.04; P < .0001) Lower percent of body fat No reductions in waist circumference were maintained Daily caloric intake ↘ from baseline to all time points for all diet groups (P < .0001) Biochemical results: All diets demonstrated some improved clinical measures By the 12-mo follow-up: LC group demonstrated improvements in TG and HDL cholesterol CR group had improved fasting glucose, insulin and HDL cholesterol LGL group exhibited improved fasting insulin and LDL cholesterol. At 3 mo: Insulin was significantly lower in the LC group than in the RGL and PC groups (LC vs PC, P = .04; LC vs RGL, P = .03)
Partsalaki et al (2012),⁴⁸ Greece	Randomized trial	Children/adolescents Obesity (>95th percentile) 8–18 y old n = 58 31♀+ 27♂ Ketogenic diet group: Mean age: 13.6 ± 2.5 y Mean BMI: 30.8 ± 8.1 kg/m² Hypocaloric diet group: Mean age: 12.3 ± 2.7 y Mean BMI: 28.0 ± 4.2 kg/m²	Two diets: (50% of subjects each) Ketogenic diet: <20 g/d carbohydrates, with a gradual ↗ towards 30–40 g/d, if the measurements of urinary ketones continued to indicate ketosis No restrictions on caloric intake or the type of fat or cholesterol concentration of the foods Hypocaloric diet: Reduce their caloric intake by 500 calories daily while deriving 28%–33% and 50%–55 % of these calories from fat and carbohydrates, respectively Both have daily multivitamins with minerals supplements Only diet instruction provided Duration: 6 mo Parameters: Weight (electronic scale), height (stadiometer), waist circumference, body composition (impedance analyzer) Biochemical analyses: Lipidemic profile, HMW adiponectin, WBISI, and HOMA-IR were determined before and after each diet Daily urinary ketone measurements (dipsticks), food diaries, oral-glucose/insulin-tolerance test Data collection: At baseline and after a weight loss of ≥10% from the initial body weight Recommendation to perform at least 1 h daily of vigorous exercise	Anthropometric results: Both groups significantly ↘ their: Weight (mean: -8 kg for the ketogenic diet, P = .001, and -5.7 kg for the hypocaloric diet, P = .001) Fat mass (mean: -7 kg for the ketogenic diet, P = .001, and -5.1 kg for the hypocaloric diet, P = .003) Waist circumference (mean: -9.2 cm for the ketogenic diet, P = .002, and -7.4 cm for the hypocaloric diet, P = .003, respectively) The differences were greater in the ketogenic group Biochemical results: Both groups significantly ↘ their: Fasting insulin (P = .017 for the ketogenic diet, and P = .009 for the hypocaloric diet) HOMA-IR (P = .009 for ketogenic diet, and P = .014 for the hypocaloric diet) The differences were greater in the ketogenic group Only the ketogenic group increased HMW adiponectin significantly (P = .025)
Ornstein et al (2011),⁴⁹ United States	Randomized pilot trial of 2 diets in a prospective study	Adolescent/young-adult females Overweight (≥85th percentile) Polycystic ovary syndrome 12–22 y n = 24 ♀ Mean age: 15.8 ± 2.2 y Mean BMI: 35.7 ± 6 kg/m²	Two diets: (50% of subjects each) Very-low-carbohydrate diet (LC): ≤20 g/d of carbohydrate and an ad libitum intake of protein, fat, and energy for the initial 2 weeks. For weeks 3 through 12, carbohydrate ↗ to 40 g daily by adding additional low-glycemic-index foods. Hypocaloric low-fat diet (LF): ≤40 g/d of fat, with 5 servings of starch (15 g of carbohydrate per serving) per day and an ad libitum intake of fat-free dairy foods, fruits, and vegetables. No juices and sweetened beverages. Multivitamin supplements in both diets Menus and recipes provided Duration: 12 wk Parameters: Dietary compliance, menstrual history, and weight and waist circumference Urinary ketones (urine ketone sticks) Data collection: Weight (2×/wk), waist circumference (at baseline and at the end) Perform 30 min of aerobic exercise 3 times per week	Anthropometric results: Weight loss averaged 6.5% (P < .0001) Waist circumference ↘ by an average of 5.7 ± 7.7 cm (P = .01). The sample size did not have adequate power to show a difference between the 2 diet treatment groups (0.13 for the LC group and 0.08 for the LF group).
Truby et al (2016),⁵⁰ Australia	Randomized controlled trial, “Eat Smart” study	Youth Obesity (>90th percentile) 10–17 y old n = 87 63♀+ 24♂ SLF group: Mean age: 13.2 ± 2.1 y Mean BMI: 32.62 ± 5.9 kg/m² SMC group: Mean age: 13.2 ± 1.9 y Mean BMI: 32.47 ± 4.9 kg/m² Control group: Mean age: 13.6 ± 1.9 y Mean BMI: 35.17 ± 8.54 kg/m²	3 groups: “Structured modified carbohydrate” (SMC; 35% carbohydrate, 30% protein, 35% fat; n = 37 including 27 females) “Structured low fat” (SLF; 55% carbohydrate, 20% protein, 25% fat; n = 36 including 26 females) Wait-listed control group (n = 14 including 10 females) 20% energy reduction when compared with their estimated energy expenditure except for the control group Only diet instruction provided Duration: 12 wk Parameters: Weight, height, waist circumference, body composition (impedance analysis) Biochemical parameters: Liver function, lipid profiles, insulin and glucose, leptin, resistin, adiponectin, PAI-1 and soluble ICAM-1, TNF-α, IL-6, and CRP At baseline, estimation of the energy expenditure through resting energy expenditure measurement and physical activity level through self-reported activity diary. No ketone measurement Data collection: Before and after the diet intervention Encouraged to set a goal to ↘ sedentary behavior	Anthropometric results: Weight was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -4.15; 95% CI = -5.50, -2.81; P < .001; SMC vs control, -4.51; 95% CI: -6.41, -2.60; P < .001) BMI z-scores were significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -0.13; 95% CI = -0.18, -0.07; P < .001; SMC vs control, -0.14; 95% CI: -0.19, -0.09; P < .001) Waist circumference was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -3.07; 95% CI = -4.54, -1.61; P < .001; SMC vs control, -3.74; 95% CI: -6.29, -1.19; P = .005) There was no difference in BMI z-scores, weight, and waist circumference losses between the 2 diet intervention groups Biochemical results: HOMA-IR was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -0.7; 95% CI = -1.2, -0.2; P = .009; SMC vs control, -0.7; 95% CI: -1.3, -0.2; P = .01) Leptin was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -0.4; 95% CI = -0.7, -0.2; P = .001; SMC vs control, -0.4; 95% CI: -0.7, -0.1; P = .005) Adiponectin was significantly higher only in the SMC group compared with control after adjusting for baseline values (SMC vs control, mean difference = 0.1; 95% CI = -0.0, 0.3; P = .04) Metabolic measurement results: REE was significantly higher only in the SLF group compared with control after adjusting for baseline values (SLF vs control, mean difference = -132; 95% CI = -237, -28; P = .01) There was a significantly higher REE in the SLF group compared with the SMC group after adjusting for baseline (SLF vs SMC, mean difference = 116; 95% CI = 25, 208; P = .01)
Siegel et al (2009),⁵¹ United States	Clinical office–based study	Adolescents Obesity (>95th percentile) 12–18 y old n = 71 53♀+ 18♂ Mean ± SD age: 14.5 ± 1.71 y Mean ± SEM BMI: 34.9 ± 0.81 kg/m²	One group: low-carbohydrate diet (LCD; 20 g < carbohydrates < 50 g daily and no restriction on fat or protein intake) Only diet instruction provided Duration: 6 mo Parameters: Weight, height, 3-d diary of dietary intake Biochemical parameters: CBC, renal profile, fasting serum glucose, fasting insulin level, and total cholesterol, HDL, LDL, and TG levels Self-esteem (Rosenberg Self-Esteem Survey) No ketone measurement Data collection: Diary of dietary intake at baseline, 2 wk, and at 1, 2, 4, and 6 mo Biochemical data analyzed at baseline and after 6 mo Self-esteem survey (at baseline, at 2 mo, and at 6 mo) General recommendation to engage in regular physical activity	Anthropometric results: 32 (84%) lost weight (range from a gain of 5.5 kg to a loss of 23.9 kg) Significant decrease in mean BMI (34.9 to 32.5 kg/m²) Biochemical results: Hematocrit and hemoglobin significantly ↗ over the study period (P < .05).
Demol et al (2009),⁵² Israel	Open-label randomized controlled trial	Adolescents Obesity (>95th percentile) 12–18 y old n = 55 34♀+ 21♂ Low-carbohydrate/low-fat group: Mean ± SE age: 14.0 ± 1.8 y Mean ± SE BMI: 35.2 ± 1.6 kg/m² Low-carbohydrate/high-fat group: Mean ± SE age: 14.3 ± 1.6 y Mean ± SE BMI: 33.7 ± 1.6 kg/m² High-carbohydrate/low-fat group: Mean ± SE age: 14.9 ± 1.8 y Mean ± SE BMI: 33.8 ± 1.5 kg/m²	Three isoenergetic diet regimens (1200–1500 kcal/d): Group 1: Low-carbohydrate, low-fat, protein-rich diet: 60 g carbohydrates (up to 20%), 30% fats, and 50% proteins; n = 18 Group 2: Low-carbohydrate, high-fat diet: 60 g carbohydrates (up to 20%), 60% fats, and 20% proteins; n = 17 Group 3: High-carbohydrate, low-fat diet: 50%–60% carbohydrates, 30% fats, and 20% proteins; n = 20 Menus and recipes provided Duration: 1 y 12 wk intervention 9 mo follow-up Parameters: Weight (standard scale), height (stadiometer), body composition (bioimpedance analysis system), some sessions: food records Biochemical parameters: Total cholesterol, LDL cholesterol, HDL cholesterol, TG, glucose, insulin, blood urea nitrogen, creatinine, total protein, liver enzymes (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase), renal functions (urea, creatinine, electrolytes, uric acid), electrolyte level, hemoglobin, CRP, TSH, free thyroxine, iron, vitamin B₁₂, folic acid, and leptin Ketone and protein levels in urine (reagent strips) Data collection: At baseline, 12 wk and after 1 y, anthropometric (1 time/wk during intervention and once every 3 mo during follow-up) Ketone and protein levels (every week in urine) Biochemical parameters: At baseline, after the 12-wk intervention, and after 9 mo of follow-up General recommendation to engage in regular physical activity	Anthropometric results: All diet regimens were associated with a significant ↘ in BMI, BMI percentile, and body fat percentage at the end of the intervention period No significant differences were found among the groups in changes in BMI, BMI percentile, or fat percentage at the end of the intervention and at the end of follow-up No significant interaction between time and group effect was found for anthropometric After 9 mo of follow-up, all groups maintained the lower BMI and BMI percentile but had significant ↗ in fat percentage compared with at the end of the intervention but still lower than baseline Biochemical results: Insulin and HOMA-IR levels ↘ significantly at both time points only in the 2 low-carbohydrate diet groups. Almost all parameters (glucose, cholesterol, HDL, LDL, TG, leptin), except CRP and ghrelin, ↘ significantly during the intervention and stayed at a similar lower level by the end of the follow-up period (time effect) No significant differences were found among the groups in metabolic markers at the end of the intervention and at the end of follow-up No significant interaction between time and group effect was found for biochemical parameters Only traces of ketones in urine were detected (5 mg/dL), with no significant difference among the 3 study groups meaning no ketosis
Yackobovitch-Gavan et al (2008),⁵³ Israel	Open-label randomized controlled trial	Adolescents Obesity (>95th percentile) 12–18 y old n = 71 42♀+ 29♂ Low-carbohydrate/low-fat group: Mean ± SE age: 14.9 ± 1.8 y Mean ± SE BMI: 36.0 ± 7.7 kg/m² Low-carbohydrate/high-fat group: Mean ± SE age: 14.3 ± 1.6 y Mean ± SE BMI: 33.6 ± 5.5 kg/m² High-carbohydrate/low-fat group: Mean ± SE age: 14.1 ± 1.8 y Mean ± SE BMI: 34.4 ± 6.2 kg/m²	Three isoenergetic diet regimens (1200 kcal/d): Group a: Low-carbohydrate (60 g, 20%), high-protein (150 g, 50%), low-fat (40 g, 30%) (LCLF); n = 15 Group b: Low-carbohydrate (60 g, 20%), low-protein (60 g, 20%), high-fat (80 g, 60%) (LCHF); n = 12 Group c: High-carbohydrate (150–180 g, 50%–60%), low-protein (60 g, 20%), low-fat (40 g, 30%) (HCLF); n = 25 Menus and recipes provided Duration: 12 wk Parameters: Weight (standard scale), height (stadiometer), body composition (bioimpedance analysis system), some sessions: food records HRQOL (Pediatric Quality of Life Inventory) No ketone measurement Data collection: Anthropometric (1 time/wk during intervention), HRQOL (before and at the end of the intervention) General recommendation to engage in regular physical activity	Anthropometric results: Significant similar ↘ in BMI, BMI-SDS, and fat percentage occurred in all groups
Sunehag et al (2005),⁵⁴ Italy	Randomized crossover study	Adolescents Obesity (>95th percentile and body fat content ≤30%) 13–17 y old n = 13 7♀+ 6♂ Mean ± SE age: 14.7 ± 0.3 y Mean ± SE BMI: 34.0 ± 1 kg/m²	Two isocaloric, isonitrogenous diets randomized during 2 visits High-CHO: 60% CHO and 25% fat Low-CHO: 30% CHO and 55% fat Foods and menus provided Participant consumed the selected diet during 7 d before the intervention day and followed the same protocol with the other diet 8 wk after Results compared to lean subjects from a previous study Parameters: Weight, height, visceral fat (magnetic resonance imaging), 24-h calorimeter study (energy expenditure and substrate oxidation rates) with the diet selected Biochemical analysis: Glucose metabolism (gluconeogenesis, glucose production, and glycerol turnover), insulin sensitivity, and first- and second-phase insulin secretory indices, substrate and hormone blood concentration (glucose, insulin, C-peptides, adiponectin, CRP, lipids) No ketone measurement Reported physical activity at baseline used to assess energy requirement only	Biochemical results: Obese adolescents ↗ first- and second-phase insulin secretory indices by 18% (P = .05) and 36% (P = .05), respectively, to maintain normoglycemia during the high-CHO diet because they failed to increase insulin sensitivity as did the lean adolescents Obese adolescents following the CRD had significantly higher total cholesterol and β-OH butyrate compared with the control group Regardless of diet, in obese adolescents, insulin sensitivity was half (P < .05) and first- and second-phase insulin secretory indices twice (P < .01) those compared with the corresponding values in lean participants In obese adolescents, gluconeogenesis increased by 32% during the low-CHO (high-fat diet) (P < .01)
Bailes et al (2003),⁵⁵ United States	Prospective non-randomized controlled study	Children Obesity (>95th percentile) 5–18 y old n = 37 14♀+ 23♂ High-protein, low-CHO-diet group: Mean ± SD age: 12 ± 3 y Mean ± SE BMI: 36.68 ± 4.0 kg/m² Low-cal-diet group: Mean ± SD age: 11 ± 2 y Mean ± SD BMI: 36.0 ± 3.1 kg/m²	Choose between 2 dietary interventions: (1) High-protein, carbohydrate-restricted diet (High Protein, Low CHO diet): <30 g of carbohydrates per day; no limitation on total calories or for other macronutrients; n = 27 (2) Calorie-restricted diet (Low Cal Diet): 20% ↘ in their energy needs based on ideal weight, fat (<30%), protein (15%–20%), and carbohydrates (50%–55%); n = 10 Only diet instruction provided Duration: 2 mo Parameters: Weight, height No ketone measurement	Anthropometric results: At 2 mo, children in the High Protein, Low CHO Diet group lost an average weight of 5.21 ± 3.44 kg (P < .001) and decreased their BMI by 2.42 ± 1.3 points (P < .001) Children in the Low Cal Diet group gained an average weight of 2.36 ± 2.54 kg and 1.00 point on the BMI value (P < .001)
Sondike et al (2003),⁵⁶ United States	Randomized, nonblinded controlled trial	Adolescents Obesity (>95th percentile) 12–18 y old n = 39 ?♀+ ?♂ LC group: Mean ± SD age: 14.4 ± 1.9 y Mean ± SD BMI: 35.4 ± 5.0 kg/m² LF group: Mean ± SD age: 15.0 ± 1.8 y Mean ± SD BMI: 35.6 ± 5.8 kg/m²	Two groups: Low-carbohydrates (LC): <20 g of carbohydrate per day for 2 wk, then <40 g/d for 10 wk, and to eat LC foods according to hunger (n = 20) Low-fat (LF): <30% of energy from fat (n = 19)—control Menus and recipes provided Duration: 12 wk Parameters: Weight (triple-beam balance scale), height (stadiometer), diet composition (food records) Biochemical analysis: Serum lipid profiles Urinary ketones (urine ketone sticks) Data collection: Diet composition and weight (every 2 wk), serum lipid profiles (at baseline and at the end of study), urinary ketones (daily)	Anthropometric results: The LC group lost more weight (mean, 9.9 ± 9.3 kg vs 4.1 ± 4.9 kg; P < .05) and ↘ more the BMI (mean, 3.3 ± 3.0 kg/m² vs 1.5 ± 1.7 kg/m², P < .05) and the BMI T-scores than the LF group Higher reported EI in the LC group compared with the LF group. Biochemical results: There was improvement in LDL-cholesterol levels (P < .05) in the LF group but not in the LC group There was improvement in non–HDL-cholesterol levels (P < .05) in the LC group TG also ↘ significantly in the LC group from baseline There were no adverse effects on the lipid profiles of participants in either group All patients in the LC group had ketonuria on most days Ketonuria developed in the LC group by the third day, on average
Willi et al (1998),⁵⁷ United States	Clinical trial	Adolescents Obesity (200% of the ideal body weight) 12–15 y old n = 6 3♀+ 3♂ Mean ± SEM age: 13.7 ± 0.49 y Mean ± SEM BMI: 50.9 ± 3.4 kg/m²	One diet: K diet (high protein low in carbohydrates and fat) Daily intake (650–725 calories), high in protein (80–100 g), very low in carbohydrates (25 g) and fat (25 g) This was followed by 12 wk of the K diet (carbohydrates [30 g] per meal) called the K + 2 diet Foods and menus provided Duration: 20 wk 8 wk 12 wk (K + 2 diet) Parameters: Weight (single scale), body composition (DXA, bioelectrical impedance, creatinine excretion) Food records Biochemical analysis: Complete blood chemistries as well as electrolytes, hematology profile, lipid profile, IGF-1, IGFBP-3, and serum leptin levels Urinary nitrogen and electrolyte balance (urine ketone test), REE (indirect calorimetry), nocturnal polysomnography (electrocardiogram, electroencephalogram, electromyogram, chest wall pneumography, and pulse oximetry), and multiple sleep latency Data collection: Anthropometric data, blood and urine (at baseline, at week 1, and at 4-wk intervals throughout the course of the study), body composition and urinary creatinine excretion (at baseline and each phase of the diet), sleep studies (at baseline and after an average weight loss of 18.7 kg)	Anthropometric results: Participants lost 15.4 ± 1.4 kg (mean ± SEM) of body weight during the K diet and an additional 2.3 ± 2.9 kg during the K + 2 diet One participant regained weight while others lost weight during the K + 2 diet BMI ↘ 5.4 ± 0.4 kg/m² during the K diet and an additional 1.1 ± 1.2 kg/m² during the K + 2 diet Weight was lost equally from all areas of the body and was predominantly fat DXA showed a ↘ from 51.1% ± 2.1% body fat to 44.2% ± 2.9% during the K diet and then to 41.6% ± 4.5% during the K + 2 diet Lean body mass was not significantly affected Biochemical results: Blood chemistries remained normal throughout the study and included a ↘ in serum cholesterol from 162 ± 12 to 121 ± 8 mg/dL in the initial 4 wk of the K diet Leptin levels were considerably lower than found in similarly obese adults and showed no consistent decline with weight loss Within 72 h of starting the K diet, urine testing revealed the presence of small to moderate amounts of ketone bodies Ketosis was quickly suppressed with the daily addition of 90 g of carbohydrate during the K + 2 diet An ↗ in calcium excretion was accompanied by a ↘ in total-body bone mineral content Metabolic measurement results: Weight loss was accompanied by a reduction in REE of 5.2 ± 1.8 kcal/kg of fat-free mass per day
Krebs et al (2010),⁵⁸ United States	Randomized controlled trial	Adolescents Severe obesity (body weight estimated to be ≥175% of ideal body weight) 12–18 y old n = 33 25♀+ 21♂ HPLC group: Mean ± SEM age: 14.2 ± 0.4 y Mean ± SEM BMI: 38.0 ± 1.2 kg/m² LF group: Mean ± SEM age: 13.7 ± 0.3 y Mean ± SEM BMI: 40.1 ± 1.8 kg/m²	High protein (2.0–2.5 g protein/kg ideal body weight per day), low carbohydrate (≤20 g/d) diet (HPLC); n = 18 Fat and energy intake not restricted Low fat (≤30% of calories/d) (LF); n = 15 Daily energy intake goal of 70% of REE (Harris-Benedict equation) Only diet instruction provided Duration: 13 wk Follow-up at weeks 24 and 36 from baseline Parameters: Weight (scale), height (stadiometer), body composition (DXA), 3-d diet records at random times Biochemical analysis: Lipid profile, 2-h oral-glucose-tolerance test Blood β-hydroxybutyrate measurement 3-d diet records including subjective feelings of hunger and fullness 9 times throughout the day (visual analog scale) Safety and potential adverse effects tests: Serum electrolytes, blood urea nitrogen, creatinine, serum calcium, phosphorus, and magnesium; liver function test and urine pregnancy test (β-HCG) for the female participants, electrocardiogram, and abdominal ultrasounds Data collection: 3-d diet records (random times throughout the intervention, varied among participants), body composition (at baseline and at 13 wk) Exercise program (at least 30 min of daily moderately vigorous physical activity)	Anthropometric results: Significant ↘ in BMI-Z was achieved in both groups during the intervention The ↘ BMI-Z was significantly greater for the HPLC group (P = .03) Both groups maintained significant BMI-Z reduction at follow-up; changes were not significantly different between groups Loss of lean body mass was not spared in the HPLC group Biochemical results: Both groups had significant ↘ in TG and LDL-cholesterol levels Mean TG ↘ was 3-fold greater in the HPLC group (P = .0003), whereas there was only a marginal reduction for the LF group (P = .10) Modest HDL cholesterol ↘ was significant for LF but not for the HPLC group None of these cholesterol changes were significantly different between the groups. The mean ↘ in 2-h insulin concentration at 13 wk was significant in the HPLC group (P = .03) but showed only a trend for the LF group (P = .07) The proportions of HOMA-IR scores >3.16 in both groups were ↘ to approximately one-third of participants at 13 wk compared with >50% of participants at study initiation The 13-wk serum β-hydroxybutyrate concentrations increased in the HPLC group compared with the LF group: 2.28 ± 0.34 mmol/L vs 1.0 ± 0.12 mmol/L, for the HPLC and LF groups, respectively (P = .002)
Zeybek et al (2010),⁵⁹ Turkey	Clinical study	34 Children with obesity (≥95th percentile) 17♀+ 17♂ 24 sex-matched lean controls (≤85th percentile) 12♀+ 12♂ Obese group: Mean ± SD age: 11.75 ± 2.23 y Mean ± SD BMI: 32.55 ± 2.96 kg/m² Lean group: Mean ± SD age: 11.25 ± 1.75 y Mean ± SD BMI: 17.52 ± 1.72 kg/m²	Only the obese group (n = 31) follow a low-carbohydrate diet: ≤30% of the total calories from simple carbohydrates Intake of protein and fat not limited but avoid trans-fat No caloric restriction (1500 and 2500 kcal/d) Only diet instruction provided Duration: 6 mo Parameters: Weight, height Biochemical analysis: Serum fasting glucose and plasma insulin Systolic and diastolic blood pressures, echocardiographic imaging and measurements No ketone measurement Data collection: At baseline and at the end of the intervention General recommendation to engage in regular physical activity	Anthropometric results: The mean weight of obese children was ↘ from 70.73 ± 14.85 to 65.03 ± 11.88 kg (P < .0001) BMI was ↘ from 33.20 ± 3.86 to 29.26 ± 3.38 kg/m² (P < .05) Biochemical results: Insulin and HOMA-IR levels were higher in obese patients Plasma fasting insulin level ↘ from 19.07 ± 26.41 to 14.14 ± 10.77 mIU/mL (P < .0001) after diet in obese patients HOMA-IR level ↘ from 4.36 ± 8.83 to 2.85 ± 2.64 (P < .0001) after diet in obese patients
Zeybek et al (2009),⁶⁰ Turkey	Clinical study	Overweight group: n = 28 (BMI: 25–30 kg/m²) 15♀+ 13♂ Mean ± SD age: 10.95 ± 2.11 y Mean ± SD BMI: 27.31 ± 1.25 kg/m² Obese group: n = 34 (BMI: ≥30 kg/m²) 16♀+ 18♂ Mean ± SD age: 12.19 ± 2.66 y Mean ± SD BMI: 35.15 ± 3.03 kg/m² Lean group: n = 29 (BMI: 17–25 kg/m²) 14♀+ 15♂ Mean± SD age: 11.33 ± 2.05 y Mean± SD BMI: 18.87 ± 2.43 kg/m²	Only the obese group (n = 30) follow a low-carbohydrate diet: ≤30% of the total calories from simple carbohydrates Intake of protein and fat not limited but avoid trans-fat No caloric restriction (1500 and 2500 kcal/d) Only diet instruction provided Duration: 6 mo Parameters: Weight, height Biochemical analysis: Serum fasting glucose, plasma insulin, uric acid, total cholesterol, TG, LDL and HDL cholesterol levels Systolic and diastolic blood pressures, echocardiographic imaging and measurements No ketone measurement Data collection: At baseline and at the end of the intervention General recommendation to engage in regular physical activity	Anthropometric results: The mean weight of these obese children was ↘ from 77.99 ± 14.72 to 73.01 ± 12.42 kg (P < .0001) Their height was ↗ from 1.49 ± 0.14 to 1.54 ± 0.11 m (P < .05) Their BMI was ↘ from 35.13 ± 4.65 to 30.80 ± 4.10 kg/m² (P < .0001)
Dunlap and Bailes (2008),⁶¹ United States	Pilot study	Children Overweight (BMI <97%) 6–12 y old n = 18 8♀+ 10♂ Mean age: 9.3 y ± 3 y Mean BMI: 32.6 ± 5.7 kg/m²	Restricted-carbohydrate (≤30 g daily) diet Unlimited protein and energy Only diet instruction provided Duration: 10 wk Parameters: Weight (digital scale), height (stadiometer) Biochemical analysis: Fasting lipid profiles (including total cholesterol, HDL, LDL, and TG) No ketone measurement Data collection: At baseline and at the end of the intervention	Anthropometric results: Average weight loss was 7.1 kg BMI ↘ by 3.2 kg/m² but did not reach statistical significance Biochemical results: Both total serum cholesterol and TG levels showed a significant ↘: 24.2 (P = .018) and 56.9 (P = .015) mg/dL, respectively

Abbreviations: ALT, alanine transaminase; BMI, body mass index; BMI-Z, BMI z-score or for-age; CBC, complete blood count; CEBQ, Children's Eating Behaviour Questionnaire; CHO, carbohydrate; CR, calorie-restricted diet; CRD, carbohydrate-restricted diet; CRP, C-reactive protein; DXA, dual-energy X-ray absorptiometry; EI, energy intake; FRD, fat-restricted diet, HDL, high-density lipoprotein; HMW, high-molecular-weight; HOMA-IR, homeostatic model assessment of insulin resistance; HRQOL, health-related quality of life; ICAM-1, intercellular adhesion molecule 1; IGF-1, insulin-like growth factor 1; IGFBP-3, insulin-like growth factor binding protein-3; IL-6, interleukin-6; LDL, low-density lipoprotein; LGL, low-glycemic-load diet; NAFLD, nonalcoholic fatty liver disease; PAI-1, plasminogen activator inhibitor-1; REE, resting energy expenditure; TFEQ, Three-Factor Eating Questionnaire; TG, triglycerides; TNF-α, tumor necrosis factor α; TSH, thyroid-stimulating hormone; WBISI, Whole-Body Insulin Sensitivity Index; β-HCG, Human chorionic gonadotropin ♀, female; ♂, male; ↘, decrease(d); ↗, increase(d).

Table 2.

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Summary of Study Design, Population Characteristics, Methodology, and Main Results of the Clinical Trials Selected in the Systematic Review

Study (year), country	Study design	Population characteristics	Methodology	Main anthropometric and biochemical results
Pauley et al (2021),⁴³ United States	Observational study Retrospective analysis of clinical data extracted from medical records from July 1, 2014, to June 30, 2017—Group A Collection of laboratory analyses of a smaller second group of children from the obesity clinic referred from July 1, 2018, to December 31, 2018—Group B	Children/adolescents Obesity (≥95th percentile) 5–18 y old n = 138 Group A: 130 88♀+ 42♂ Mean age: 11.5 (95% CI: 10.9 to 12.0) y Mean BMI: 34.1 (95% CI: 32.7 to 35.4) kg/m² Group B: 8 5♀+ 3♂ Mean age: 14.0 (95% CI: 11.6 to 16.4) y Mean BMI: 41.3 (95% CI: 35.0 to 47.5) kg/m²	Carbohydrate-restricted diet (≤30 g/d; 5% to 10% of total energy intake), with unlimited calories, fat, and protein Limited fruit consumption to berries No milk, juice, and sugar-sweetened drinks Multivitamin supplementation Only diet instruction provided Duration: 3–4 mo Parameters: Weight (digital scale), height (stadiometer), blood pressure, diary of daily food intake Biochemical analysis: Group B: Fasting serum analyses of total cholesterol, TG, insulin, glycated hemoglobin, blood urea nitrogen, creatinine, and 20- hydroxy-eicosatetraenoic acid No ketone measurement Data collection: Before and after the diet intervention Exercise daily	Anthropometric results: Group A ↘: Weight of 5.1 kg (P < .001) BMI of 2.5 kg/m² (P < .001) Percentage weight loss of 6.9% (P < .001). Group B ↘: Weight of 9.6 kg (P < .01) BMI of 4 kg/m² (P < .01) Percentage weight loss of 9% (P < .01) The older-group participants who completed the diet had the same percentage of weight loss compared with those <12 years (6.9% vs 6.9%) Biochemical results: Group A: No analysis Group B ↘: Fasting serum insulin (P < .01) TG (P < .01) 20-Hydroxy-eicosatetraenoic acid (P < .01)
Goss et al (2020),⁴⁴ United States	Randomized 2-arm, parallel dietary intervention Family-based diet intervention	Children/adolescents Obesity (≥85th percentile) NAFLD (ALT >45 and/or perfusely echogenic liver via ultrasound) Sedentary (<2 h/wk of intentional exercise) 9-17 y old n = 32 16♀+ 16♂ CRD group: Mean ± SD age: 14.2 ± 2.1 y Mean ± SD BMI: 35.9 ± 6.7 kg/m² FRD group: Mean ± SD age: 14.5 ± 2.6 y Mean ± SD BMI: 38.4 ± 7.3 kg/m²	Two randomized groups: Moderately CHO-restricted diet (CRD): n = 16 CRD: <25%, 25%, >50% of energy from CHO, protein, fat, respectively Fat-restricted diet (FRD): n = 16 55%, 25%, 20% of energy from CHO, protein, fat, respectively Based on the USDA MyPlate Daily Food Plan for teenagers Caloric intakes were calculated to be weight maintaining Saturated fat intake was limited to <10% total energy/d Foods and menus provided at least for a part of the study Duration: 8 wk 2-wk modified controlled-feeding phase 6-wk free-living phase Parameters: Weight, height, body composition (DXA) Biochemical analysis: Insulin resistance (fasting blood sample) REE (indirect calorimetry) Change in hepatic lipid content (magnetic resonance imaging) No ketone measurement Data collection: Before and after the diet intervention	Anthropometric results: Significant ↘ in weight, BMI, and BMI z-score after 8 wk of CRD diet only Significantly greater ↘ in abdominal fat mass (-1.5 vs 0.0, P < .01) and body fat mass (-1.1 vs -0.1, P < .01) in response to the CRD vs FRD Biochemical results: Change in hepatic lipids did not differ with diet, but declined significantly (−6.0%± 4.7%, P < .001) only within the CRD group Significantly greater ↘ in plasma insulin concentration and insulin resistance (P < .05), in response to the CRD vs FRD
Felix et al (2020),⁴⁵ United States	Clinical feasibility study	Children Overweight/obese (≥95th percentile) Prader-Willi syndrome (PWS) 6–12 y old n = 7 5♀+ 2♂ Mean ± SD age: 9 ± 2.62 y Mean ± SD BMI: 24.05 ± 5.14 kg/m²	Modified Atkins diet 10–15 g net carbohydrate limit (a calculation of total carbohydrates minus fiber) To take a general pediatric multivitamin with minerals, a vitamin D supplement (600 IU) daily, and a calcium supplement (1000 mg/d for 4–8-y-olds and 1300 mg/d for 9–13-y-olds) Menus and recipes provided Duration: ∼12 mo 4 months being on the diet 4 months being off the diet Parameters: History, weight, height Biochemical analysis: Fasting bloodwork (comprehensive metabolic panel, lipid profile, hemoglobin A1c, insulin level), urine studies (urinalysis, urine calcium, urine creatinine) Psychology questionnaires: Families and participants were also asked to comment subjectively on behavior, skin picking, and hyperphagia Urinary ketones (urine ketone sticks) Data collection: 3 study visits, 4 mo apart	Anthropometric results: 1 patient ↘ 2.9 kg; the others maintained their weight BMI z-scores improved for 3/4 of participants, ↘ by average of 0.21 points for each participant Weight gain noted in all participants after the end of the diet and especially in patients who lost weight Biochemical results: 3/4 patients: ↗ in LDL 1 patient: ↘ in TG Various and opposite impact on HOMA-IR according to patients 1 patient: hypercalciuria (with no renal stones) Results are descriptive due to the lack of participant number for statistical analysis.
Kirk et al (2017),⁴⁶ United States	Randomized trial (same population and dataset as Kirk et al, 2012)	Children Obesity (BMI z-score: 1.60–2.65) 7-12 y old n = 102 88♀+ 14♂ LC group: Mean age: 10.4 (9.4–12.1) y Mean BMI: 29.7 (26.7–32.6) kg/m² PC group PC: Mean age: 10.5 (9.2–11.3) y Mean BMI: 28.9 (25.8–31.4) kg/m² RGL group: Mean age: 10.5 (9.0–11.8) y Mean BMI: 30.1 (25.3–32.1) kg/m²	Low-carbohydrate (LC) (n = 35), reduced glycemic load (RGL) (n = 36), or standard portion-controlled PC diet (n = 31); randomized LC: ≤60 g/d (10%–20%), no limit on energy intake RGL: Limit their intake of high-glycemic index foods and drinks using a stoplight approach, no limit on energy intake PC: Age-appropriate, calorie-restricted meal plans (55%–60% CHO; 10%–15% protein, and 30% fat), resulting in a 500-kcal/d deficit relative to expected energy requirements Only diet instruction provided Duration: 12 mo 3-mo intervention 9-mo follow-up period Parameters: Weight, height, TFEQ completed by parents (TFEQ contains 3 factors: H, Hunger; D, Disinhibition; CR, Cognitive restraint), 3-d food records Urinary ketones (urine ketone sticks) Data collection: At baseline and 3, 6, and 12 mo	TFEQ results: All diet groups showed increased CR and decreased H and D from baseline to 3 mo, with differences from baseline remaining at 12 mo for CR and H Lower BMI status during study follow-up was associated with different TFEQ scores by diet group (LC and RGL: higher CR; PC: lower H), adjusting for sex, age, and race Higher CR at follow-up was predicted by race and higher baseline CR; only lower H at baseline predicted lower H at follow-up
Kirk et al (2012),⁴⁷ United States	Randomized trial (same population and dataset as Kirk et al, 2017)	Children Obesity (BMI z-score, 1.60–2.65) 7–12 y old n = 102 88♀+ 14♂ LC group: Mean age: 9.9 ± 1.6 y Mean BMI: 29.9 ± 4.4 kg/m² PC group: Mean age: 9.7 ± 1.3 y Mean BMI: 29.1 ± 3.8 kg/m² RGL group: Mean age: 9.8 ± 1.7 y Mean BMI: 29.2 ± 3.8 kg/m²	LC (n = 35), RGL (n = 36), or standard PC diet (n = 31); randomized LC: ≤60 g/d, no limit on energy intake RGL: Limit their intake of high-glycemic-index foods and drinks using a stoplight approach, no limit on energy intake PC: Age-appropriate, calorie-restricted meal plans (55%–60% CHO, 10%–15% protein, and 30% fat), resulting in a 500-kcal/d deficit relative to expected energy requirements Only diet instruction provided Duration: 12 mo 3-mo intervention 9-mo follow-up period Parameters: Body weight (weekly, digital scale), height (stadiometer), waist circumference (fiberglass tape measure), body fat (DXA), 3-d food records (3 consecutive days the week prior the assessment visit) Biochemical analyses: Fasting insulin, glucose, total cholesterol, TG, and LDL and HDL cholesterol) Blood pressure, urinary ketones (urine ketone sticks) Data collection: At baseline and 3, 6, and 12 mo One hour of exercise biweekly led by a specialist	Anthropometric results: At 3 mo: BMI z-score lower in all diet groups (LC: -0.27 ± 0.04; RGL: -0.20 ± 0.04; PC: -0.21 ± 0.04; P < .0001) and maintained at 6 mo Similar results for waist circumference and percent body fat At 12 mo: In all diet groups, lower BMI z-scores than at baseline (LC: -0.21 ± 0.04; RGL: -0.28 ± 0.04; PC: -0.31 ± 0.04; P < .0001) Lower percent of body fat No reductions in waist circumference were maintained Daily caloric intake ↘ from baseline to all time points for all diet groups (P < .0001) Biochemical results: All diets demonstrated some improved clinical measures By the 12-mo follow-up: LC group demonstrated improvements in TG and HDL cholesterol CR group had improved fasting glucose, insulin and HDL cholesterol LGL group exhibited improved fasting insulin and LDL cholesterol. At 3 mo: Insulin was significantly lower in the LC group than in the RGL and PC groups (LC vs PC, P = .04; LC vs RGL, P = .03)
Partsalaki et al (2012),⁴⁸ Greece	Randomized trial	Children/adolescents Obesity (>95th percentile) 8–18 y old n = 58 31♀+ 27♂ Ketogenic diet group: Mean age: 13.6 ± 2.5 y Mean BMI: 30.8 ± 8.1 kg/m² Hypocaloric diet group: Mean age: 12.3 ± 2.7 y Mean BMI: 28.0 ± 4.2 kg/m²	Two diets: (50% of subjects each) Ketogenic diet: <20 g/d carbohydrates, with a gradual ↗ towards 30–40 g/d, if the measurements of urinary ketones continued to indicate ketosis No restrictions on caloric intake or the type of fat or cholesterol concentration of the foods Hypocaloric diet: Reduce their caloric intake by 500 calories daily while deriving 28%–33% and 50%–55 % of these calories from fat and carbohydrates, respectively Both have daily multivitamins with minerals supplements Only diet instruction provided Duration: 6 mo Parameters: Weight (electronic scale), height (stadiometer), waist circumference, body composition (impedance analyzer) Biochemical analyses: Lipidemic profile, HMW adiponectin, WBISI, and HOMA-IR were determined before and after each diet Daily urinary ketone measurements (dipsticks), food diaries, oral-glucose/insulin-tolerance test Data collection: At baseline and after a weight loss of ≥10% from the initial body weight Recommendation to perform at least 1 h daily of vigorous exercise	Anthropometric results: Both groups significantly ↘ their: Weight (mean: -8 kg for the ketogenic diet, P = .001, and -5.7 kg for the hypocaloric diet, P = .001) Fat mass (mean: -7 kg for the ketogenic diet, P = .001, and -5.1 kg for the hypocaloric diet, P = .003) Waist circumference (mean: -9.2 cm for the ketogenic diet, P = .002, and -7.4 cm for the hypocaloric diet, P = .003, respectively) The differences were greater in the ketogenic group Biochemical results: Both groups significantly ↘ their: Fasting insulin (P = .017 for the ketogenic diet, and P = .009 for the hypocaloric diet) HOMA-IR (P = .009 for ketogenic diet, and P = .014 for the hypocaloric diet) The differences were greater in the ketogenic group Only the ketogenic group increased HMW adiponectin significantly (P = .025)
Ornstein et al (2011),⁴⁹ United States	Randomized pilot trial of 2 diets in a prospective study	Adolescent/young-adult females Overweight (≥85th percentile) Polycystic ovary syndrome 12–22 y n = 24 ♀ Mean age: 15.8 ± 2.2 y Mean BMI: 35.7 ± 6 kg/m²	Two diets: (50% of subjects each) Very-low-carbohydrate diet (LC): ≤20 g/d of carbohydrate and an ad libitum intake of protein, fat, and energy for the initial 2 weeks. For weeks 3 through 12, carbohydrate ↗ to 40 g daily by adding additional low-glycemic-index foods. Hypocaloric low-fat diet (LF): ≤40 g/d of fat, with 5 servings of starch (15 g of carbohydrate per serving) per day and an ad libitum intake of fat-free dairy foods, fruits, and vegetables. No juices and sweetened beverages. Multivitamin supplements in both diets Menus and recipes provided Duration: 12 wk Parameters: Dietary compliance, menstrual history, and weight and waist circumference Urinary ketones (urine ketone sticks) Data collection: Weight (2×/wk), waist circumference (at baseline and at the end) Perform 30 min of aerobic exercise 3 times per week	Anthropometric results: Weight loss averaged 6.5% (P < .0001) Waist circumference ↘ by an average of 5.7 ± 7.7 cm (P = .01). The sample size did not have adequate power to show a difference between the 2 diet treatment groups (0.13 for the LC group and 0.08 for the LF group).
Truby et al (2016),⁵⁰ Australia	Randomized controlled trial, “Eat Smart” study	Youth Obesity (>90th percentile) 10–17 y old n = 87 63♀+ 24♂ SLF group: Mean age: 13.2 ± 2.1 y Mean BMI: 32.62 ± 5.9 kg/m² SMC group: Mean age: 13.2 ± 1.9 y Mean BMI: 32.47 ± 4.9 kg/m² Control group: Mean age: 13.6 ± 1.9 y Mean BMI: 35.17 ± 8.54 kg/m²	3 groups: “Structured modified carbohydrate” (SMC; 35% carbohydrate, 30% protein, 35% fat; n = 37 including 27 females) “Structured low fat” (SLF; 55% carbohydrate, 20% protein, 25% fat; n = 36 including 26 females) Wait-listed control group (n = 14 including 10 females) 20% energy reduction when compared with their estimated energy expenditure except for the control group Only diet instruction provided Duration: 12 wk Parameters: Weight, height, waist circumference, body composition (impedance analysis) Biochemical parameters: Liver function, lipid profiles, insulin and glucose, leptin, resistin, adiponectin, PAI-1 and soluble ICAM-1, TNF-α, IL-6, and CRP At baseline, estimation of the energy expenditure through resting energy expenditure measurement and physical activity level through self-reported activity diary. No ketone measurement Data collection: Before and after the diet intervention Encouraged to set a goal to ↘ sedentary behavior	Anthropometric results: Weight was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -4.15; 95% CI = -5.50, -2.81; P < .001; SMC vs control, -4.51; 95% CI: -6.41, -2.60; P < .001) BMI z-scores were significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -0.13; 95% CI = -0.18, -0.07; P < .001; SMC vs control, -0.14; 95% CI: -0.19, -0.09; P < .001) Waist circumference was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -3.07; 95% CI = -4.54, -1.61; P < .001; SMC vs control, -3.74; 95% CI: -6.29, -1.19; P = .005) There was no difference in BMI z-scores, weight, and waist circumference losses between the 2 diet intervention groups Biochemical results: HOMA-IR was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -0.7; 95% CI = -1.2, -0.2; P = .009; SMC vs control, -0.7; 95% CI: -1.3, -0.2; P = .01) Leptin was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -0.4; 95% CI = -0.7, -0.2; P = .001; SMC vs control, -0.4; 95% CI: -0.7, -0.1; P = .005) Adiponectin was significantly higher only in the SMC group compared with control after adjusting for baseline values (SMC vs control, mean difference = 0.1; 95% CI = -0.0, 0.3; P = .04) Metabolic measurement results: REE was significantly higher only in the SLF group compared with control after adjusting for baseline values (SLF vs control, mean difference = -132; 95% CI = -237, -28; P = .01) There was a significantly higher REE in the SLF group compared with the SMC group after adjusting for baseline (SLF vs SMC, mean difference = 116; 95% CI = 25, 208; P = .01)
Siegel et al (2009),⁵¹ United States	Clinical office–based study	Adolescents Obesity (>95th percentile) 12–18 y old n = 71 53♀+ 18♂ Mean ± SD age: 14.5 ± 1.71 y Mean ± SEM BMI: 34.9 ± 0.81 kg/m²	One group: low-carbohydrate diet (LCD; 20 g < carbohydrates < 50 g daily and no restriction on fat or protein intake) Only diet instruction provided Duration: 6 mo Parameters: Weight, height, 3-d diary of dietary intake Biochemical parameters: CBC, renal profile, fasting serum glucose, fasting insulin level, and total cholesterol, HDL, LDL, and TG levels Self-esteem (Rosenberg Self-Esteem Survey) No ketone measurement Data collection: Diary of dietary intake at baseline, 2 wk, and at 1, 2, 4, and 6 mo Biochemical data analyzed at baseline and after 6 mo Self-esteem survey (at baseline, at 2 mo, and at 6 mo) General recommendation to engage in regular physical activity	Anthropometric results: 32 (84%) lost weight (range from a gain of 5.5 kg to a loss of 23.9 kg) Significant decrease in mean BMI (34.9 to 32.5 kg/m²) Biochemical results: Hematocrit and hemoglobin significantly ↗ over the study period (P < .05).
Demol et al (2009),⁵² Israel	Open-label randomized controlled trial	Adolescents Obesity (>95th percentile) 12–18 y old n = 55 34♀+ 21♂ Low-carbohydrate/low-fat group: Mean ± SE age: 14.0 ± 1.8 y Mean ± SE BMI: 35.2 ± 1.6 kg/m² Low-carbohydrate/high-fat group: Mean ± SE age: 14.3 ± 1.6 y Mean ± SE BMI: 33.7 ± 1.6 kg/m² High-carbohydrate/low-fat group: Mean ± SE age: 14.9 ± 1.8 y Mean ± SE BMI: 33.8 ± 1.5 kg/m²	Three isoenergetic diet regimens (1200–1500 kcal/d): Group 1: Low-carbohydrate, low-fat, protein-rich diet: 60 g carbohydrates (up to 20%), 30% fats, and 50% proteins; n = 18 Group 2: Low-carbohydrate, high-fat diet: 60 g carbohydrates (up to 20%), 60% fats, and 20% proteins; n = 17 Group 3: High-carbohydrate, low-fat diet: 50%–60% carbohydrates, 30% fats, and 20% proteins; n = 20 Menus and recipes provided Duration: 1 y 12 wk intervention 9 mo follow-up Parameters: Weight (standard scale), height (stadiometer), body composition (bioimpedance analysis system), some sessions: food records Biochemical parameters: Total cholesterol, LDL cholesterol, HDL cholesterol, TG, glucose, insulin, blood urea nitrogen, creatinine, total protein, liver enzymes (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase), renal functions (urea, creatinine, electrolytes, uric acid), electrolyte level, hemoglobin, CRP, TSH, free thyroxine, iron, vitamin B₁₂, folic acid, and leptin Ketone and protein levels in urine (reagent strips) Data collection: At baseline, 12 wk and after 1 y, anthropometric (1 time/wk during intervention and once every 3 mo during follow-up) Ketone and protein levels (every week in urine) Biochemical parameters: At baseline, after the 12-wk intervention, and after 9 mo of follow-up General recommendation to engage in regular physical activity	Anthropometric results: All diet regimens were associated with a significant ↘ in BMI, BMI percentile, and body fat percentage at the end of the intervention period No significant differences were found among the groups in changes in BMI, BMI percentile, or fat percentage at the end of the intervention and at the end of follow-up No significant interaction between time and group effect was found for anthropometric After 9 mo of follow-up, all groups maintained the lower BMI and BMI percentile but had significant ↗ in fat percentage compared with at the end of the intervention but still lower than baseline Biochemical results: Insulin and HOMA-IR levels ↘ significantly at both time points only in the 2 low-carbohydrate diet groups. Almost all parameters (glucose, cholesterol, HDL, LDL, TG, leptin), except CRP and ghrelin, ↘ significantly during the intervention and stayed at a similar lower level by the end of the follow-up period (time effect) No significant differences were found among the groups in metabolic markers at the end of the intervention and at the end of follow-up No significant interaction between time and group effect was found for biochemical parameters Only traces of ketones in urine were detected (5 mg/dL), with no significant difference among the 3 study groups meaning no ketosis
Yackobovitch-Gavan et al (2008),⁵³ Israel	Open-label randomized controlled trial	Adolescents Obesity (>95th percentile) 12–18 y old n = 71 42♀+ 29♂ Low-carbohydrate/low-fat group: Mean ± SE age: 14.9 ± 1.8 y Mean ± SE BMI: 36.0 ± 7.7 kg/m² Low-carbohydrate/high-fat group: Mean ± SE age: 14.3 ± 1.6 y Mean ± SE BMI: 33.6 ± 5.5 kg/m² High-carbohydrate/low-fat group: Mean ± SE age: 14.1 ± 1.8 y Mean ± SE BMI: 34.4 ± 6.2 kg/m²	Three isoenergetic diet regimens (1200 kcal/d): Group a: Low-carbohydrate (60 g, 20%), high-protein (150 g, 50%), low-fat (40 g, 30%) (LCLF); n = 15 Group b: Low-carbohydrate (60 g, 20%), low-protein (60 g, 20%), high-fat (80 g, 60%) (LCHF); n = 12 Group c: High-carbohydrate (150–180 g, 50%–60%), low-protein (60 g, 20%), low-fat (40 g, 30%) (HCLF); n = 25 Menus and recipes provided Duration: 12 wk Parameters: Weight (standard scale), height (stadiometer), body composition (bioimpedance analysis system), some sessions: food records HRQOL (Pediatric Quality of Life Inventory) No ketone measurement Data collection: Anthropometric (1 time/wk during intervention), HRQOL (before and at the end of the intervention) General recommendation to engage in regular physical activity	Anthropometric results: Significant similar ↘ in BMI, BMI-SDS, and fat percentage occurred in all groups
Sunehag et al (2005),⁵⁴ Italy	Randomized crossover study	Adolescents Obesity (>95th percentile and body fat content ≤30%) 13–17 y old n = 13 7♀+ 6♂ Mean ± SE age: 14.7 ± 0.3 y Mean ± SE BMI: 34.0 ± 1 kg/m²	Two isocaloric, isonitrogenous diets randomized during 2 visits High-CHO: 60% CHO and 25% fat Low-CHO: 30% CHO and 55% fat Foods and menus provided Participant consumed the selected diet during 7 d before the intervention day and followed the same protocol with the other diet 8 wk after Results compared to lean subjects from a previous study Parameters: Weight, height, visceral fat (magnetic resonance imaging), 24-h calorimeter study (energy expenditure and substrate oxidation rates) with the diet selected Biochemical analysis: Glucose metabolism (gluconeogenesis, glucose production, and glycerol turnover), insulin sensitivity, and first- and second-phase insulin secretory indices, substrate and hormone blood concentration (glucose, insulin, C-peptides, adiponectin, CRP, lipids) No ketone measurement Reported physical activity at baseline used to assess energy requirement only	Biochemical results: Obese adolescents ↗ first- and second-phase insulin secretory indices by 18% (P = .05) and 36% (P = .05), respectively, to maintain normoglycemia during the high-CHO diet because they failed to increase insulin sensitivity as did the lean adolescents Obese adolescents following the CRD had significantly higher total cholesterol and β-OH butyrate compared with the control group Regardless of diet, in obese adolescents, insulin sensitivity was half (P < .05) and first- and second-phase insulin secretory indices twice (P < .01) those compared with the corresponding values in lean participants In obese adolescents, gluconeogenesis increased by 32% during the low-CHO (high-fat diet) (P < .01)
Bailes et al (2003),⁵⁵ United States	Prospective non-randomized controlled study	Children Obesity (>95th percentile) 5–18 y old n = 37 14♀+ 23♂ High-protein, low-CHO-diet group: Mean ± SD age: 12 ± 3 y Mean ± SE BMI: 36.68 ± 4.0 kg/m² Low-cal-diet group: Mean ± SD age: 11 ± 2 y Mean ± SD BMI: 36.0 ± 3.1 kg/m²	Choose between 2 dietary interventions: (1) High-protein, carbohydrate-restricted diet (High Protein, Low CHO diet): <30 g of carbohydrates per day; no limitation on total calories or for other macronutrients; n = 27 (2) Calorie-restricted diet (Low Cal Diet): 20% ↘ in their energy needs based on ideal weight, fat (<30%), protein (15%–20%), and carbohydrates (50%–55%); n = 10 Only diet instruction provided Duration: 2 mo Parameters: Weight, height No ketone measurement	Anthropometric results: At 2 mo, children in the High Protein, Low CHO Diet group lost an average weight of 5.21 ± 3.44 kg (P < .001) and decreased their BMI by 2.42 ± 1.3 points (P < .001) Children in the Low Cal Diet group gained an average weight of 2.36 ± 2.54 kg and 1.00 point on the BMI value (P < .001)
Sondike et al (2003),⁵⁶ United States	Randomized, nonblinded controlled trial	Adolescents Obesity (>95th percentile) 12–18 y old n = 39 ?♀+ ?♂ LC group: Mean ± SD age: 14.4 ± 1.9 y Mean ± SD BMI: 35.4 ± 5.0 kg/m² LF group: Mean ± SD age: 15.0 ± 1.8 y Mean ± SD BMI: 35.6 ± 5.8 kg/m²	Two groups: Low-carbohydrates (LC): <20 g of carbohydrate per day for 2 wk, then <40 g/d for 10 wk, and to eat LC foods according to hunger (n = 20) Low-fat (LF): <30% of energy from fat (n = 19)—control Menus and recipes provided Duration: 12 wk Parameters: Weight (triple-beam balance scale), height (stadiometer), diet composition (food records) Biochemical analysis: Serum lipid profiles Urinary ketones (urine ketone sticks) Data collection: Diet composition and weight (every 2 wk), serum lipid profiles (at baseline and at the end of study), urinary ketones (daily)	Anthropometric results: The LC group lost more weight (mean, 9.9 ± 9.3 kg vs 4.1 ± 4.9 kg; P < .05) and ↘ more the BMI (mean, 3.3 ± 3.0 kg/m² vs 1.5 ± 1.7 kg/m², P < .05) and the BMI T-scores than the LF group Higher reported EI in the LC group compared with the LF group. Biochemical results: There was improvement in LDL-cholesterol levels (P < .05) in the LF group but not in the LC group There was improvement in non–HDL-cholesterol levels (P < .05) in the LC group TG also ↘ significantly in the LC group from baseline There were no adverse effects on the lipid profiles of participants in either group All patients in the LC group had ketonuria on most days Ketonuria developed in the LC group by the third day, on average
Willi et al (1998),⁵⁷ United States	Clinical trial	Adolescents Obesity (200% of the ideal body weight) 12–15 y old n = 6 3♀+ 3♂ Mean ± SEM age: 13.7 ± 0.49 y Mean ± SEM BMI: 50.9 ± 3.4 kg/m²	One diet: K diet (high protein low in carbohydrates and fat) Daily intake (650–725 calories), high in protein (80–100 g), very low in carbohydrates (25 g) and fat (25 g) This was followed by 12 wk of the K diet (carbohydrates [30 g] per meal) called the K + 2 diet Foods and menus provided Duration: 20 wk 8 wk 12 wk (K + 2 diet) Parameters: Weight (single scale), body composition (DXA, bioelectrical impedance, creatinine excretion) Food records Biochemical analysis: Complete blood chemistries as well as electrolytes, hematology profile, lipid profile, IGF-1, IGFBP-3, and serum leptin levels Urinary nitrogen and electrolyte balance (urine ketone test), REE (indirect calorimetry), nocturnal polysomnography (electrocardiogram, electroencephalogram, electromyogram, chest wall pneumography, and pulse oximetry), and multiple sleep latency Data collection: Anthropometric data, blood and urine (at baseline, at week 1, and at 4-wk intervals throughout the course of the study), body composition and urinary creatinine excretion (at baseline and each phase of the diet), sleep studies (at baseline and after an average weight loss of 18.7 kg)	Anthropometric results: Participants lost 15.4 ± 1.4 kg (mean ± SEM) of body weight during the K diet and an additional 2.3 ± 2.9 kg during the K + 2 diet One participant regained weight while others lost weight during the K + 2 diet BMI ↘ 5.4 ± 0.4 kg/m² during the K diet and an additional 1.1 ± 1.2 kg/m² during the K + 2 diet Weight was lost equally from all areas of the body and was predominantly fat DXA showed a ↘ from 51.1% ± 2.1% body fat to 44.2% ± 2.9% during the K diet and then to 41.6% ± 4.5% during the K + 2 diet Lean body mass was not significantly affected Biochemical results: Blood chemistries remained normal throughout the study and included a ↘ in serum cholesterol from 162 ± 12 to 121 ± 8 mg/dL in the initial 4 wk of the K diet Leptin levels were considerably lower than found in similarly obese adults and showed no consistent decline with weight loss Within 72 h of starting the K diet, urine testing revealed the presence of small to moderate amounts of ketone bodies Ketosis was quickly suppressed with the daily addition of 90 g of carbohydrate during the K + 2 diet An ↗ in calcium excretion was accompanied by a ↘ in total-body bone mineral content Metabolic measurement results: Weight loss was accompanied by a reduction in REE of 5.2 ± 1.8 kcal/kg of fat-free mass per day
Krebs et al (2010),⁵⁸ United States	Randomized controlled trial	Adolescents Severe obesity (body weight estimated to be ≥175% of ideal body weight) 12–18 y old n = 33 25♀+ 21♂ HPLC group: Mean ± SEM age: 14.2 ± 0.4 y Mean ± SEM BMI: 38.0 ± 1.2 kg/m² LF group: Mean ± SEM age: 13.7 ± 0.3 y Mean ± SEM BMI: 40.1 ± 1.8 kg/m²	High protein (2.0–2.5 g protein/kg ideal body weight per day), low carbohydrate (≤20 g/d) diet (HPLC); n = 18 Fat and energy intake not restricted Low fat (≤30% of calories/d) (LF); n = 15 Daily energy intake goal of 70% of REE (Harris-Benedict equation) Only diet instruction provided Duration: 13 wk Follow-up at weeks 24 and 36 from baseline Parameters: Weight (scale), height (stadiometer), body composition (DXA), 3-d diet records at random times Biochemical analysis: Lipid profile, 2-h oral-glucose-tolerance test Blood β-hydroxybutyrate measurement 3-d diet records including subjective feelings of hunger and fullness 9 times throughout the day (visual analog scale) Safety and potential adverse effects tests: Serum electrolytes, blood urea nitrogen, creatinine, serum calcium, phosphorus, and magnesium; liver function test and urine pregnancy test (β-HCG) for the female participants, electrocardiogram, and abdominal ultrasounds Data collection: 3-d diet records (random times throughout the intervention, varied among participants), body composition (at baseline and at 13 wk) Exercise program (at least 30 min of daily moderately vigorous physical activity)	Anthropometric results: Significant ↘ in BMI-Z was achieved in both groups during the intervention The ↘ BMI-Z was significantly greater for the HPLC group (P = .03) Both groups maintained significant BMI-Z reduction at follow-up; changes were not significantly different between groups Loss of lean body mass was not spared in the HPLC group Biochemical results: Both groups had significant ↘ in TG and LDL-cholesterol levels Mean TG ↘ was 3-fold greater in the HPLC group (P = .0003), whereas there was only a marginal reduction for the LF group (P = .10) Modest HDL cholesterol ↘ was significant for LF but not for the HPLC group None of these cholesterol changes were significantly different between the groups. The mean ↘ in 2-h insulin concentration at 13 wk was significant in the HPLC group (P = .03) but showed only a trend for the LF group (P = .07) The proportions of HOMA-IR scores >3.16 in both groups were ↘ to approximately one-third of participants at 13 wk compared with >50% of participants at study initiation The 13-wk serum β-hydroxybutyrate concentrations increased in the HPLC group compared with the LF group: 2.28 ± 0.34 mmol/L vs 1.0 ± 0.12 mmol/L, for the HPLC and LF groups, respectively (P = .002)
Zeybek et al (2010),⁵⁹ Turkey	Clinical study	34 Children with obesity (≥95th percentile) 17♀+ 17♂ 24 sex-matched lean controls (≤85th percentile) 12♀+ 12♂ Obese group: Mean ± SD age: 11.75 ± 2.23 y Mean ± SD BMI: 32.55 ± 2.96 kg/m² Lean group: Mean ± SD age: 11.25 ± 1.75 y Mean ± SD BMI: 17.52 ± 1.72 kg/m²	Only the obese group (n = 31) follow a low-carbohydrate diet: ≤30% of the total calories from simple carbohydrates Intake of protein and fat not limited but avoid trans-fat No caloric restriction (1500 and 2500 kcal/d) Only diet instruction provided Duration: 6 mo Parameters: Weight, height Biochemical analysis: Serum fasting glucose and plasma insulin Systolic and diastolic blood pressures, echocardiographic imaging and measurements No ketone measurement Data collection: At baseline and at the end of the intervention General recommendation to engage in regular physical activity	Anthropometric results: The mean weight of obese children was ↘ from 70.73 ± 14.85 to 65.03 ± 11.88 kg (P < .0001) BMI was ↘ from 33.20 ± 3.86 to 29.26 ± 3.38 kg/m² (P < .05) Biochemical results: Insulin and HOMA-IR levels were higher in obese patients Plasma fasting insulin level ↘ from 19.07 ± 26.41 to 14.14 ± 10.77 mIU/mL (P < .0001) after diet in obese patients HOMA-IR level ↘ from 4.36 ± 8.83 to 2.85 ± 2.64 (P < .0001) after diet in obese patients
Zeybek et al (2009),⁶⁰ Turkey	Clinical study	Overweight group: n = 28 (BMI: 25–30 kg/m²) 15♀+ 13♂ Mean ± SD age: 10.95 ± 2.11 y Mean ± SD BMI: 27.31 ± 1.25 kg/m² Obese group: n = 34 (BMI: ≥30 kg/m²) 16♀+ 18♂ Mean ± SD age: 12.19 ± 2.66 y Mean ± SD BMI: 35.15 ± 3.03 kg/m² Lean group: n = 29 (BMI: 17–25 kg/m²) 14♀+ 15♂ Mean± SD age: 11.33 ± 2.05 y Mean± SD BMI: 18.87 ± 2.43 kg/m²	Only the obese group (n = 30) follow a low-carbohydrate diet: ≤30% of the total calories from simple carbohydrates Intake of protein and fat not limited but avoid trans-fat No caloric restriction (1500 and 2500 kcal/d) Only diet instruction provided Duration: 6 mo Parameters: Weight, height Biochemical analysis: Serum fasting glucose, plasma insulin, uric acid, total cholesterol, TG, LDL and HDL cholesterol levels Systolic and diastolic blood pressures, echocardiographic imaging and measurements No ketone measurement Data collection: At baseline and at the end of the intervention General recommendation to engage in regular physical activity	Anthropometric results: The mean weight of these obese children was ↘ from 77.99 ± 14.72 to 73.01 ± 12.42 kg (P < .0001) Their height was ↗ from 1.49 ± 0.14 to 1.54 ± 0.11 m (P < .05) Their BMI was ↘ from 35.13 ± 4.65 to 30.80 ± 4.10 kg/m² (P < .0001)
Dunlap and Bailes (2008),⁶¹ United States	Pilot study	Children Overweight (BMI <97%) 6–12 y old n = 18 8♀+ 10♂ Mean age: 9.3 y ± 3 y Mean BMI: 32.6 ± 5.7 kg/m²	Restricted-carbohydrate (≤30 g daily) diet Unlimited protein and energy Only diet instruction provided Duration: 10 wk Parameters: Weight (digital scale), height (stadiometer) Biochemical analysis: Fasting lipid profiles (including total cholesterol, HDL, LDL, and TG) No ketone measurement Data collection: At baseline and at the end of the intervention	Anthropometric results: Average weight loss was 7.1 kg BMI ↘ by 3.2 kg/m² but did not reach statistical significance Biochemical results: Both total serum cholesterol and TG levels showed a significant ↘: 24.2 (P = .018) and 56.9 (P = .015) mg/dL, respectively

Study (year), country	Study design	Population characteristics	Methodology	Main anthropometric and biochemical results
Pauley et al (2021),⁴³ United States	Observational study Retrospective analysis of clinical data extracted from medical records from July 1, 2014, to June 30, 2017—Group A Collection of laboratory analyses of a smaller second group of children from the obesity clinic referred from July 1, 2018, to December 31, 2018—Group B	Children/adolescents Obesity (≥95th percentile) 5–18 y old n = 138 Group A: 130 88♀+ 42♂ Mean age: 11.5 (95% CI: 10.9 to 12.0) y Mean BMI: 34.1 (95% CI: 32.7 to 35.4) kg/m² Group B: 8 5♀+ 3♂ Mean age: 14.0 (95% CI: 11.6 to 16.4) y Mean BMI: 41.3 (95% CI: 35.0 to 47.5) kg/m²	Carbohydrate-restricted diet (≤30 g/d; 5% to 10% of total energy intake), with unlimited calories, fat, and protein Limited fruit consumption to berries No milk, juice, and sugar-sweetened drinks Multivitamin supplementation Only diet instruction provided Duration: 3–4 mo Parameters: Weight (digital scale), height (stadiometer), blood pressure, diary of daily food intake Biochemical analysis: Group B: Fasting serum analyses of total cholesterol, TG, insulin, glycated hemoglobin, blood urea nitrogen, creatinine, and 20- hydroxy-eicosatetraenoic acid No ketone measurement Data collection: Before and after the diet intervention Exercise daily	Anthropometric results: Group A ↘: Weight of 5.1 kg (P < .001) BMI of 2.5 kg/m² (P < .001) Percentage weight loss of 6.9% (P < .001). Group B ↘: Weight of 9.6 kg (P < .01) BMI of 4 kg/m² (P < .01) Percentage weight loss of 9% (P < .01) The older-group participants who completed the diet had the same percentage of weight loss compared with those <12 years (6.9% vs 6.9%) Biochemical results: Group A: No analysis Group B ↘: Fasting serum insulin (P < .01) TG (P < .01) 20-Hydroxy-eicosatetraenoic acid (P < .01)
Goss et al (2020),⁴⁴ United States	Randomized 2-arm, parallel dietary intervention Family-based diet intervention	Children/adolescents Obesity (≥85th percentile) NAFLD (ALT >45 and/or perfusely echogenic liver via ultrasound) Sedentary (<2 h/wk of intentional exercise) 9-17 y old n = 32 16♀+ 16♂ CRD group: Mean ± SD age: 14.2 ± 2.1 y Mean ± SD BMI: 35.9 ± 6.7 kg/m² FRD group: Mean ± SD age: 14.5 ± 2.6 y Mean ± SD BMI: 38.4 ± 7.3 kg/m²	Two randomized groups: Moderately CHO-restricted diet (CRD): n = 16 CRD: <25%, 25%, >50% of energy from CHO, protein, fat, respectively Fat-restricted diet (FRD): n = 16 55%, 25%, 20% of energy from CHO, protein, fat, respectively Based on the USDA MyPlate Daily Food Plan for teenagers Caloric intakes were calculated to be weight maintaining Saturated fat intake was limited to <10% total energy/d Foods and menus provided at least for a part of the study Duration: 8 wk 2-wk modified controlled-feeding phase 6-wk free-living phase Parameters: Weight, height, body composition (DXA) Biochemical analysis: Insulin resistance (fasting blood sample) REE (indirect calorimetry) Change in hepatic lipid content (magnetic resonance imaging) No ketone measurement Data collection: Before and after the diet intervention	Anthropometric results: Significant ↘ in weight, BMI, and BMI z-score after 8 wk of CRD diet only Significantly greater ↘ in abdominal fat mass (-1.5 vs 0.0, P < .01) and body fat mass (-1.1 vs -0.1, P < .01) in response to the CRD vs FRD Biochemical results: Change in hepatic lipids did not differ with diet, but declined significantly (−6.0%± 4.7%, P < .001) only within the CRD group Significantly greater ↘ in plasma insulin concentration and insulin resistance (P < .05), in response to the CRD vs FRD
Felix et al (2020),⁴⁵ United States	Clinical feasibility study	Children Overweight/obese (≥95th percentile) Prader-Willi syndrome (PWS) 6–12 y old n = 7 5♀+ 2♂ Mean ± SD age: 9 ± 2.62 y Mean ± SD BMI: 24.05 ± 5.14 kg/m²	Modified Atkins diet 10–15 g net carbohydrate limit (a calculation of total carbohydrates minus fiber) To take a general pediatric multivitamin with minerals, a vitamin D supplement (600 IU) daily, and a calcium supplement (1000 mg/d for 4–8-y-olds and 1300 mg/d for 9–13-y-olds) Menus and recipes provided Duration: ∼12 mo 4 months being on the diet 4 months being off the diet Parameters: History, weight, height Biochemical analysis: Fasting bloodwork (comprehensive metabolic panel, lipid profile, hemoglobin A1c, insulin level), urine studies (urinalysis, urine calcium, urine creatinine) Psychology questionnaires: Families and participants were also asked to comment subjectively on behavior, skin picking, and hyperphagia Urinary ketones (urine ketone sticks) Data collection: 3 study visits, 4 mo apart	Anthropometric results: 1 patient ↘ 2.9 kg; the others maintained their weight BMI z-scores improved for 3/4 of participants, ↘ by average of 0.21 points for each participant Weight gain noted in all participants after the end of the diet and especially in patients who lost weight Biochemical results: 3/4 patients: ↗ in LDL 1 patient: ↘ in TG Various and opposite impact on HOMA-IR according to patients 1 patient: hypercalciuria (with no renal stones) Results are descriptive due to the lack of participant number for statistical analysis.
Kirk et al (2017),⁴⁶ United States	Randomized trial (same population and dataset as Kirk et al, 2012)	Children Obesity (BMI z-score: 1.60–2.65) 7-12 y old n = 102 88♀+ 14♂ LC group: Mean age: 10.4 (9.4–12.1) y Mean BMI: 29.7 (26.7–32.6) kg/m² PC group PC: Mean age: 10.5 (9.2–11.3) y Mean BMI: 28.9 (25.8–31.4) kg/m² RGL group: Mean age: 10.5 (9.0–11.8) y Mean BMI: 30.1 (25.3–32.1) kg/m²	Low-carbohydrate (LC) (n = 35), reduced glycemic load (RGL) (n = 36), or standard portion-controlled PC diet (n = 31); randomized LC: ≤60 g/d (10%–20%), no limit on energy intake RGL: Limit their intake of high-glycemic index foods and drinks using a stoplight approach, no limit on energy intake PC: Age-appropriate, calorie-restricted meal plans (55%–60% CHO; 10%–15% protein, and 30% fat), resulting in a 500-kcal/d deficit relative to expected energy requirements Only diet instruction provided Duration: 12 mo 3-mo intervention 9-mo follow-up period Parameters: Weight, height, TFEQ completed by parents (TFEQ contains 3 factors: H, Hunger; D, Disinhibition; CR, Cognitive restraint), 3-d food records Urinary ketones (urine ketone sticks) Data collection: At baseline and 3, 6, and 12 mo	TFEQ results: All diet groups showed increased CR and decreased H and D from baseline to 3 mo, with differences from baseline remaining at 12 mo for CR and H Lower BMI status during study follow-up was associated with different TFEQ scores by diet group (LC and RGL: higher CR; PC: lower H), adjusting for sex, age, and race Higher CR at follow-up was predicted by race and higher baseline CR; only lower H at baseline predicted lower H at follow-up
Kirk et al (2012),⁴⁷ United States	Randomized trial (same population and dataset as Kirk et al, 2017)	Children Obesity (BMI z-score, 1.60–2.65) 7–12 y old n = 102 88♀+ 14♂ LC group: Mean age: 9.9 ± 1.6 y Mean BMI: 29.9 ± 4.4 kg/m² PC group: Mean age: 9.7 ± 1.3 y Mean BMI: 29.1 ± 3.8 kg/m² RGL group: Mean age: 9.8 ± 1.7 y Mean BMI: 29.2 ± 3.8 kg/m²	LC (n = 35), RGL (n = 36), or standard PC diet (n = 31); randomized LC: ≤60 g/d, no limit on energy intake RGL: Limit their intake of high-glycemic-index foods and drinks using a stoplight approach, no limit on energy intake PC: Age-appropriate, calorie-restricted meal plans (55%–60% CHO, 10%–15% protein, and 30% fat), resulting in a 500-kcal/d deficit relative to expected energy requirements Only diet instruction provided Duration: 12 mo 3-mo intervention 9-mo follow-up period Parameters: Body weight (weekly, digital scale), height (stadiometer), waist circumference (fiberglass tape measure), body fat (DXA), 3-d food records (3 consecutive days the week prior the assessment visit) Biochemical analyses: Fasting insulin, glucose, total cholesterol, TG, and LDL and HDL cholesterol) Blood pressure, urinary ketones (urine ketone sticks) Data collection: At baseline and 3, 6, and 12 mo One hour of exercise biweekly led by a specialist	Anthropometric results: At 3 mo: BMI z-score lower in all diet groups (LC: -0.27 ± 0.04; RGL: -0.20 ± 0.04; PC: -0.21 ± 0.04; P < .0001) and maintained at 6 mo Similar results for waist circumference and percent body fat At 12 mo: In all diet groups, lower BMI z-scores than at baseline (LC: -0.21 ± 0.04; RGL: -0.28 ± 0.04; PC: -0.31 ± 0.04; P < .0001) Lower percent of body fat No reductions in waist circumference were maintained Daily caloric intake ↘ from baseline to all time points for all diet groups (P < .0001) Biochemical results: All diets demonstrated some improved clinical measures By the 12-mo follow-up: LC group demonstrated improvements in TG and HDL cholesterol CR group had improved fasting glucose, insulin and HDL cholesterol LGL group exhibited improved fasting insulin and LDL cholesterol. At 3 mo: Insulin was significantly lower in the LC group than in the RGL and PC groups (LC vs PC, P = .04; LC vs RGL, P = .03)
Partsalaki et al (2012),⁴⁸ Greece	Randomized trial	Children/adolescents Obesity (>95th percentile) 8–18 y old n = 58 31♀+ 27♂ Ketogenic diet group: Mean age: 13.6 ± 2.5 y Mean BMI: 30.8 ± 8.1 kg/m² Hypocaloric diet group: Mean age: 12.3 ± 2.7 y Mean BMI: 28.0 ± 4.2 kg/m²	Two diets: (50% of subjects each) Ketogenic diet: <20 g/d carbohydrates, with a gradual ↗ towards 30–40 g/d, if the measurements of urinary ketones continued to indicate ketosis No restrictions on caloric intake or the type of fat or cholesterol concentration of the foods Hypocaloric diet: Reduce their caloric intake by 500 calories daily while deriving 28%–33% and 50%–55 % of these calories from fat and carbohydrates, respectively Both have daily multivitamins with minerals supplements Only diet instruction provided Duration: 6 mo Parameters: Weight (electronic scale), height (stadiometer), waist circumference, body composition (impedance analyzer) Biochemical analyses: Lipidemic profile, HMW adiponectin, WBISI, and HOMA-IR were determined before and after each diet Daily urinary ketone measurements (dipsticks), food diaries, oral-glucose/insulin-tolerance test Data collection: At baseline and after a weight loss of ≥10% from the initial body weight Recommendation to perform at least 1 h daily of vigorous exercise	Anthropometric results: Both groups significantly ↘ their: Weight (mean: -8 kg for the ketogenic diet, P = .001, and -5.7 kg for the hypocaloric diet, P = .001) Fat mass (mean: -7 kg for the ketogenic diet, P = .001, and -5.1 kg for the hypocaloric diet, P = .003) Waist circumference (mean: -9.2 cm for the ketogenic diet, P = .002, and -7.4 cm for the hypocaloric diet, P = .003, respectively) The differences were greater in the ketogenic group Biochemical results: Both groups significantly ↘ their: Fasting insulin (P = .017 for the ketogenic diet, and P = .009 for the hypocaloric diet) HOMA-IR (P = .009 for ketogenic diet, and P = .014 for the hypocaloric diet) The differences were greater in the ketogenic group Only the ketogenic group increased HMW adiponectin significantly (P = .025)
Ornstein et al (2011),⁴⁹ United States	Randomized pilot trial of 2 diets in a prospective study	Adolescent/young-adult females Overweight (≥85th percentile) Polycystic ovary syndrome 12–22 y n = 24 ♀ Mean age: 15.8 ± 2.2 y Mean BMI: 35.7 ± 6 kg/m²	Two diets: (50% of subjects each) Very-low-carbohydrate diet (LC): ≤20 g/d of carbohydrate and an ad libitum intake of protein, fat, and energy for the initial 2 weeks. For weeks 3 through 12, carbohydrate ↗ to 40 g daily by adding additional low-glycemic-index foods. Hypocaloric low-fat diet (LF): ≤40 g/d of fat, with 5 servings of starch (15 g of carbohydrate per serving) per day and an ad libitum intake of fat-free dairy foods, fruits, and vegetables. No juices and sweetened beverages. Multivitamin supplements in both diets Menus and recipes provided Duration: 12 wk Parameters: Dietary compliance, menstrual history, and weight and waist circumference Urinary ketones (urine ketone sticks) Data collection: Weight (2×/wk), waist circumference (at baseline and at the end) Perform 30 min of aerobic exercise 3 times per week	Anthropometric results: Weight loss averaged 6.5% (P < .0001) Waist circumference ↘ by an average of 5.7 ± 7.7 cm (P = .01). The sample size did not have adequate power to show a difference between the 2 diet treatment groups (0.13 for the LC group and 0.08 for the LF group).
Truby et al (2016),⁵⁰ Australia	Randomized controlled trial, “Eat Smart” study	Youth Obesity (>90th percentile) 10–17 y old n = 87 63♀+ 24♂ SLF group: Mean age: 13.2 ± 2.1 y Mean BMI: 32.62 ± 5.9 kg/m² SMC group: Mean age: 13.2 ± 1.9 y Mean BMI: 32.47 ± 4.9 kg/m² Control group: Mean age: 13.6 ± 1.9 y Mean BMI: 35.17 ± 8.54 kg/m²	3 groups: “Structured modified carbohydrate” (SMC; 35% carbohydrate, 30% protein, 35% fat; n = 37 including 27 females) “Structured low fat” (SLF; 55% carbohydrate, 20% protein, 25% fat; n = 36 including 26 females) Wait-listed control group (n = 14 including 10 females) 20% energy reduction when compared with their estimated energy expenditure except for the control group Only diet instruction provided Duration: 12 wk Parameters: Weight, height, waist circumference, body composition (impedance analysis) Biochemical parameters: Liver function, lipid profiles, insulin and glucose, leptin, resistin, adiponectin, PAI-1 and soluble ICAM-1, TNF-α, IL-6, and CRP At baseline, estimation of the energy expenditure through resting energy expenditure measurement and physical activity level through self-reported activity diary. No ketone measurement Data collection: Before and after the diet intervention Encouraged to set a goal to ↘ sedentary behavior	Anthropometric results: Weight was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -4.15; 95% CI = -5.50, -2.81; P < .001; SMC vs control, -4.51; 95% CI: -6.41, -2.60; P < .001) BMI z-scores were significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -0.13; 95% CI = -0.18, -0.07; P < .001; SMC vs control, -0.14; 95% CI: -0.19, -0.09; P < .001) Waist circumference was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -3.07; 95% CI = -4.54, -1.61; P < .001; SMC vs control, -3.74; 95% CI: -6.29, -1.19; P = .005) There was no difference in BMI z-scores, weight, and waist circumference losses between the 2 diet intervention groups Biochemical results: HOMA-IR was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -0.7; 95% CI = -1.2, -0.2; P = .009; SMC vs control, -0.7; 95% CI: -1.3, -0.2; P = .01) Leptin was significantly lower in both intervention groups compared with control after adjusting for baseline values (SLF vs control, mean difference = -0.4; 95% CI = -0.7, -0.2; P = .001; SMC vs control, -0.4; 95% CI: -0.7, -0.1; P = .005) Adiponectin was significantly higher only in the SMC group compared with control after adjusting for baseline values (SMC vs control, mean difference = 0.1; 95% CI = -0.0, 0.3; P = .04) Metabolic measurement results: REE was significantly higher only in the SLF group compared with control after adjusting for baseline values (SLF vs control, mean difference = -132; 95% CI = -237, -28; P = .01) There was a significantly higher REE in the SLF group compared with the SMC group after adjusting for baseline (SLF vs SMC, mean difference = 116; 95% CI = 25, 208; P = .01)
Siegel et al (2009),⁵¹ United States	Clinical office–based study	Adolescents Obesity (>95th percentile) 12–18 y old n = 71 53♀+ 18♂ Mean ± SD age: 14.5 ± 1.71 y Mean ± SEM BMI: 34.9 ± 0.81 kg/m²	One group: low-carbohydrate diet (LCD; 20 g < carbohydrates < 50 g daily and no restriction on fat or protein intake) Only diet instruction provided Duration: 6 mo Parameters: Weight, height, 3-d diary of dietary intake Biochemical parameters: CBC, renal profile, fasting serum glucose, fasting insulin level, and total cholesterol, HDL, LDL, and TG levels Self-esteem (Rosenberg Self-Esteem Survey) No ketone measurement Data collection: Diary of dietary intake at baseline, 2 wk, and at 1, 2, 4, and 6 mo Biochemical data analyzed at baseline and after 6 mo Self-esteem survey (at baseline, at 2 mo, and at 6 mo) General recommendation to engage in regular physical activity	Anthropometric results: 32 (84%) lost weight (range from a gain of 5.5 kg to a loss of 23.9 kg) Significant decrease in mean BMI (34.9 to 32.5 kg/m²) Biochemical results: Hematocrit and hemoglobin significantly ↗ over the study period (P < .05).
Demol et al (2009),⁵² Israel	Open-label randomized controlled trial	Adolescents Obesity (>95th percentile) 12–18 y old n = 55 34♀+ 21♂ Low-carbohydrate/low-fat group: Mean ± SE age: 14.0 ± 1.8 y Mean ± SE BMI: 35.2 ± 1.6 kg/m² Low-carbohydrate/high-fat group: Mean ± SE age: 14.3 ± 1.6 y Mean ± SE BMI: 33.7 ± 1.6 kg/m² High-carbohydrate/low-fat group: Mean ± SE age: 14.9 ± 1.8 y Mean ± SE BMI: 33.8 ± 1.5 kg/m²	Three isoenergetic diet regimens (1200–1500 kcal/d): Group 1: Low-carbohydrate, low-fat, protein-rich diet: 60 g carbohydrates (up to 20%), 30% fats, and 50% proteins; n = 18 Group 2: Low-carbohydrate, high-fat diet: 60 g carbohydrates (up to 20%), 60% fats, and 20% proteins; n = 17 Group 3: High-carbohydrate, low-fat diet: 50%–60% carbohydrates, 30% fats, and 20% proteins; n = 20 Menus and recipes provided Duration: 1 y 12 wk intervention 9 mo follow-up Parameters: Weight (standard scale), height (stadiometer), body composition (bioimpedance analysis system), some sessions: food records Biochemical parameters: Total cholesterol, LDL cholesterol, HDL cholesterol, TG, glucose, insulin, blood urea nitrogen, creatinine, total protein, liver enzymes (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase), renal functions (urea, creatinine, electrolytes, uric acid), electrolyte level, hemoglobin, CRP, TSH, free thyroxine, iron, vitamin B₁₂, folic acid, and leptin Ketone and protein levels in urine (reagent strips) Data collection: At baseline, 12 wk and after 1 y, anthropometric (1 time/wk during intervention and once every 3 mo during follow-up) Ketone and protein levels (every week in urine) Biochemical parameters: At baseline, after the 12-wk intervention, and after 9 mo of follow-up General recommendation to engage in regular physical activity	Anthropometric results: All diet regimens were associated with a significant ↘ in BMI, BMI percentile, and body fat percentage at the end of the intervention period No significant differences were found among the groups in changes in BMI, BMI percentile, or fat percentage at the end of the intervention and at the end of follow-up No significant interaction between time and group effect was found for anthropometric After 9 mo of follow-up, all groups maintained the lower BMI and BMI percentile but had significant ↗ in fat percentage compared with at the end of the intervention but still lower than baseline Biochemical results: Insulin and HOMA-IR levels ↘ significantly at both time points only in the 2 low-carbohydrate diet groups. Almost all parameters (glucose, cholesterol, HDL, LDL, TG, leptin), except CRP and ghrelin, ↘ significantly during the intervention and stayed at a similar lower level by the end of the follow-up period (time effect) No significant differences were found among the groups in metabolic markers at the end of the intervention and at the end of follow-up No significant interaction between time and group effect was found for biochemical parameters Only traces of ketones in urine were detected (5 mg/dL), with no significant difference among the 3 study groups meaning no ketosis
Yackobovitch-Gavan et al (2008),⁵³ Israel	Open-label randomized controlled trial	Adolescents Obesity (>95th percentile) 12–18 y old n = 71 42♀+ 29♂ Low-carbohydrate/low-fat group: Mean ± SE age: 14.9 ± 1.8 y Mean ± SE BMI: 36.0 ± 7.7 kg/m² Low-carbohydrate/high-fat group: Mean ± SE age: 14.3 ± 1.6 y Mean ± SE BMI: 33.6 ± 5.5 kg/m² High-carbohydrate/low-fat group: Mean ± SE age: 14.1 ± 1.8 y Mean ± SE BMI: 34.4 ± 6.2 kg/m²	Three isoenergetic diet regimens (1200 kcal/d): Group a: Low-carbohydrate (60 g, 20%), high-protein (150 g, 50%), low-fat (40 g, 30%) (LCLF); n = 15 Group b: Low-carbohydrate (60 g, 20%), low-protein (60 g, 20%), high-fat (80 g, 60%) (LCHF); n = 12 Group c: High-carbohydrate (150–180 g, 50%–60%), low-protein (60 g, 20%), low-fat (40 g, 30%) (HCLF); n = 25 Menus and recipes provided Duration: 12 wk Parameters: Weight (standard scale), height (stadiometer), body composition (bioimpedance analysis system), some sessions: food records HRQOL (Pediatric Quality of Life Inventory) No ketone measurement Data collection: Anthropometric (1 time/wk during intervention), HRQOL (before and at the end of the intervention) General recommendation to engage in regular physical activity	Anthropometric results: Significant similar ↘ in BMI, BMI-SDS, and fat percentage occurred in all groups
Sunehag et al (2005),⁵⁴ Italy	Randomized crossover study	Adolescents Obesity (>95th percentile and body fat content ≤30%) 13–17 y old n = 13 7♀+ 6♂ Mean ± SE age: 14.7 ± 0.3 y Mean ± SE BMI: 34.0 ± 1 kg/m²	Two isocaloric, isonitrogenous diets randomized during 2 visits High-CHO: 60% CHO and 25% fat Low-CHO: 30% CHO and 55% fat Foods and menus provided Participant consumed the selected diet during 7 d before the intervention day and followed the same protocol with the other diet 8 wk after Results compared to lean subjects from a previous study Parameters: Weight, height, visceral fat (magnetic resonance imaging), 24-h calorimeter study (energy expenditure and substrate oxidation rates) with the diet selected Biochemical analysis: Glucose metabolism (gluconeogenesis, glucose production, and glycerol turnover), insulin sensitivity, and first- and second-phase insulin secretory indices, substrate and hormone blood concentration (glucose, insulin, C-peptides, adiponectin, CRP, lipids) No ketone measurement Reported physical activity at baseline used to assess energy requirement only	Biochemical results: Obese adolescents ↗ first- and second-phase insulin secretory indices by 18% (P = .05) and 36% (P = .05), respectively, to maintain normoglycemia during the high-CHO diet because they failed to increase insulin sensitivity as did the lean adolescents Obese adolescents following the CRD had significantly higher total cholesterol and β-OH butyrate compared with the control group Regardless of diet, in obese adolescents, insulin sensitivity was half (P < .05) and first- and second-phase insulin secretory indices twice (P < .01) those compared with the corresponding values in lean participants In obese adolescents, gluconeogenesis increased by 32% during the low-CHO (high-fat diet) (P < .01)
Bailes et al (2003),⁵⁵ United States	Prospective non-randomized controlled study	Children Obesity (>95th percentile) 5–18 y old n = 37 14♀+ 23♂ High-protein, low-CHO-diet group: Mean ± SD age: 12 ± 3 y Mean ± SE BMI: 36.68 ± 4.0 kg/m² Low-cal-diet group: Mean ± SD age: 11 ± 2 y Mean ± SD BMI: 36.0 ± 3.1 kg/m²	Choose between 2 dietary interventions: (1) High-protein, carbohydrate-restricted diet (High Protein, Low CHO diet): <30 g of carbohydrates per day; no limitation on total calories or for other macronutrients; n = 27 (2) Calorie-restricted diet (Low Cal Diet): 20% ↘ in their energy needs based on ideal weight, fat (<30%), protein (15%–20%), and carbohydrates (50%–55%); n = 10 Only diet instruction provided Duration: 2 mo Parameters: Weight, height No ketone measurement	Anthropometric results: At 2 mo, children in the High Protein, Low CHO Diet group lost an average weight of 5.21 ± 3.44 kg (P < .001) and decreased their BMI by 2.42 ± 1.3 points (P < .001) Children in the Low Cal Diet group gained an average weight of 2.36 ± 2.54 kg and 1.00 point on the BMI value (P < .001)
Sondike et al (2003),⁵⁶ United States	Randomized, nonblinded controlled trial	Adolescents Obesity (>95th percentile) 12–18 y old n = 39 ?♀+ ?♂ LC group: Mean ± SD age: 14.4 ± 1.9 y Mean ± SD BMI: 35.4 ± 5.0 kg/m² LF group: Mean ± SD age: 15.0 ± 1.8 y Mean ± SD BMI: 35.6 ± 5.8 kg/m²	Two groups: Low-carbohydrates (LC): <20 g of carbohydrate per day for 2 wk, then <40 g/d for 10 wk, and to eat LC foods according to hunger (n = 20) Low-fat (LF): <30% of energy from fat (n = 19)—control Menus and recipes provided Duration: 12 wk Parameters: Weight (triple-beam balance scale), height (stadiometer), diet composition (food records) Biochemical analysis: Serum lipid profiles Urinary ketones (urine ketone sticks) Data collection: Diet composition and weight (every 2 wk), serum lipid profiles (at baseline and at the end of study), urinary ketones (daily)	Anthropometric results: The LC group lost more weight (mean, 9.9 ± 9.3 kg vs 4.1 ± 4.9 kg; P < .05) and ↘ more the BMI (mean, 3.3 ± 3.0 kg/m² vs 1.5 ± 1.7 kg/m², P < .05) and the BMI T-scores than the LF group Higher reported EI in the LC group compared with the LF group. Biochemical results: There was improvement in LDL-cholesterol levels (P < .05) in the LF group but not in the LC group There was improvement in non–HDL-cholesterol levels (P < .05) in the LC group TG also ↘ significantly in the LC group from baseline There were no adverse effects on the lipid profiles of participants in either group All patients in the LC group had ketonuria on most days Ketonuria developed in the LC group by the third day, on average
Willi et al (1998),⁵⁷ United States	Clinical trial	Adolescents Obesity (200% of the ideal body weight) 12–15 y old n = 6 3♀+ 3♂ Mean ± SEM age: 13.7 ± 0.49 y Mean ± SEM BMI: 50.9 ± 3.4 kg/m²	One diet: K diet (high protein low in carbohydrates and fat) Daily intake (650–725 calories), high in protein (80–100 g), very low in carbohydrates (25 g) and fat (25 g) This was followed by 12 wk of the K diet (carbohydrates [30 g] per meal) called the K + 2 diet Foods and menus provided Duration: 20 wk 8 wk 12 wk (K + 2 diet) Parameters: Weight (single scale), body composition (DXA, bioelectrical impedance, creatinine excretion) Food records Biochemical analysis: Complete blood chemistries as well as electrolytes, hematology profile, lipid profile, IGF-1, IGFBP-3, and serum leptin levels Urinary nitrogen and electrolyte balance (urine ketone test), REE (indirect calorimetry), nocturnal polysomnography (electrocardiogram, electroencephalogram, electromyogram, chest wall pneumography, and pulse oximetry), and multiple sleep latency Data collection: Anthropometric data, blood and urine (at baseline, at week 1, and at 4-wk intervals throughout the course of the study), body composition and urinary creatinine excretion (at baseline and each phase of the diet), sleep studies (at baseline and after an average weight loss of 18.7 kg)	Anthropometric results: Participants lost 15.4 ± 1.4 kg (mean ± SEM) of body weight during the K diet and an additional 2.3 ± 2.9 kg during the K + 2 diet One participant regained weight while others lost weight during the K + 2 diet BMI ↘ 5.4 ± 0.4 kg/m² during the K diet and an additional 1.1 ± 1.2 kg/m² during the K + 2 diet Weight was lost equally from all areas of the body and was predominantly fat DXA showed a ↘ from 51.1% ± 2.1% body fat to 44.2% ± 2.9% during the K diet and then to 41.6% ± 4.5% during the K + 2 diet Lean body mass was not significantly affected Biochemical results: Blood chemistries remained normal throughout the study and included a ↘ in serum cholesterol from 162 ± 12 to 121 ± 8 mg/dL in the initial 4 wk of the K diet Leptin levels were considerably lower than found in similarly obese adults and showed no consistent decline with weight loss Within 72 h of starting the K diet, urine testing revealed the presence of small to moderate amounts of ketone bodies Ketosis was quickly suppressed with the daily addition of 90 g of carbohydrate during the K + 2 diet An ↗ in calcium excretion was accompanied by a ↘ in total-body bone mineral content Metabolic measurement results: Weight loss was accompanied by a reduction in REE of 5.2 ± 1.8 kcal/kg of fat-free mass per day
Krebs et al (2010),⁵⁸ United States	Randomized controlled trial	Adolescents Severe obesity (body weight estimated to be ≥175% of ideal body weight) 12–18 y old n = 33 25♀+ 21♂ HPLC group: Mean ± SEM age: 14.2 ± 0.4 y Mean ± SEM BMI: 38.0 ± 1.2 kg/m² LF group: Mean ± SEM age: 13.7 ± 0.3 y Mean ± SEM BMI: 40.1 ± 1.8 kg/m²	High protein (2.0–2.5 g protein/kg ideal body weight per day), low carbohydrate (≤20 g/d) diet (HPLC); n = 18 Fat and energy intake not restricted Low fat (≤30% of calories/d) (LF); n = 15 Daily energy intake goal of 70% of REE (Harris-Benedict equation) Only diet instruction provided Duration: 13 wk Follow-up at weeks 24 and 36 from baseline Parameters: Weight (scale), height (stadiometer), body composition (DXA), 3-d diet records at random times Biochemical analysis: Lipid profile, 2-h oral-glucose-tolerance test Blood β-hydroxybutyrate measurement 3-d diet records including subjective feelings of hunger and fullness 9 times throughout the day (visual analog scale) Safety and potential adverse effects tests: Serum electrolytes, blood urea nitrogen, creatinine, serum calcium, phosphorus, and magnesium; liver function test and urine pregnancy test (β-HCG) for the female participants, electrocardiogram, and abdominal ultrasounds Data collection: 3-d diet records (random times throughout the intervention, varied among participants), body composition (at baseline and at 13 wk) Exercise program (at least 30 min of daily moderately vigorous physical activity)	Anthropometric results: Significant ↘ in BMI-Z was achieved in both groups during the intervention The ↘ BMI-Z was significantly greater for the HPLC group (P = .03) Both groups maintained significant BMI-Z reduction at follow-up; changes were not significantly different between groups Loss of lean body mass was not spared in the HPLC group Biochemical results: Both groups had significant ↘ in TG and LDL-cholesterol levels Mean TG ↘ was 3-fold greater in the HPLC group (P = .0003), whereas there was only a marginal reduction for the LF group (P = .10) Modest HDL cholesterol ↘ was significant for LF but not for the HPLC group None of these cholesterol changes were significantly different between the groups. The mean ↘ in 2-h insulin concentration at 13 wk was significant in the HPLC group (P = .03) but showed only a trend for the LF group (P = .07) The proportions of HOMA-IR scores >3.16 in both groups were ↘ to approximately one-third of participants at 13 wk compared with >50% of participants at study initiation The 13-wk serum β-hydroxybutyrate concentrations increased in the HPLC group compared with the LF group: 2.28 ± 0.34 mmol/L vs 1.0 ± 0.12 mmol/L, for the HPLC and LF groups, respectively (P = .002)
Zeybek et al (2010),⁵⁹ Turkey	Clinical study	34 Children with obesity (≥95th percentile) 17♀+ 17♂ 24 sex-matched lean controls (≤85th percentile) 12♀+ 12♂ Obese group: Mean ± SD age: 11.75 ± 2.23 y Mean ± SD BMI: 32.55 ± 2.96 kg/m² Lean group: Mean ± SD age: 11.25 ± 1.75 y Mean ± SD BMI: 17.52 ± 1.72 kg/m²	Only the obese group (n = 31) follow a low-carbohydrate diet: ≤30% of the total calories from simple carbohydrates Intake of protein and fat not limited but avoid trans-fat No caloric restriction (1500 and 2500 kcal/d) Only diet instruction provided Duration: 6 mo Parameters: Weight, height Biochemical analysis: Serum fasting glucose and plasma insulin Systolic and diastolic blood pressures, echocardiographic imaging and measurements No ketone measurement Data collection: At baseline and at the end of the intervention General recommendation to engage in regular physical activity	Anthropometric results: The mean weight of obese children was ↘ from 70.73 ± 14.85 to 65.03 ± 11.88 kg (P < .0001) BMI was ↘ from 33.20 ± 3.86 to 29.26 ± 3.38 kg/m² (P < .05) Biochemical results: Insulin and HOMA-IR levels were higher in obese patients Plasma fasting insulin level ↘ from 19.07 ± 26.41 to 14.14 ± 10.77 mIU/mL (P < .0001) after diet in obese patients HOMA-IR level ↘ from 4.36 ± 8.83 to 2.85 ± 2.64 (P < .0001) after diet in obese patients
Zeybek et al (2009),⁶⁰ Turkey	Clinical study	Overweight group: n = 28 (BMI: 25–30 kg/m²) 15♀+ 13♂ Mean ± SD age: 10.95 ± 2.11 y Mean ± SD BMI: 27.31 ± 1.25 kg/m² Obese group: n = 34 (BMI: ≥30 kg/m²) 16♀+ 18♂ Mean ± SD age: 12.19 ± 2.66 y Mean ± SD BMI: 35.15 ± 3.03 kg/m² Lean group: n = 29 (BMI: 17–25 kg/m²) 14♀+ 15♂ Mean± SD age: 11.33 ± 2.05 y Mean± SD BMI: 18.87 ± 2.43 kg/m²	Only the obese group (n = 30) follow a low-carbohydrate diet: ≤30% of the total calories from simple carbohydrates Intake of protein and fat not limited but avoid trans-fat No caloric restriction (1500 and 2500 kcal/d) Only diet instruction provided Duration: 6 mo Parameters: Weight, height Biochemical analysis: Serum fasting glucose, plasma insulin, uric acid, total cholesterol, TG, LDL and HDL cholesterol levels Systolic and diastolic blood pressures, echocardiographic imaging and measurements No ketone measurement Data collection: At baseline and at the end of the intervention General recommendation to engage in regular physical activity	Anthropometric results: The mean weight of these obese children was ↘ from 77.99 ± 14.72 to 73.01 ± 12.42 kg (P < .0001) Their height was ↗ from 1.49 ± 0.14 to 1.54 ± 0.11 m (P < .05) Their BMI was ↘ from 35.13 ± 4.65 to 30.80 ± 4.10 kg/m² (P < .0001)
Dunlap and Bailes (2008),⁶¹ United States	Pilot study	Children Overweight (BMI <97%) 6–12 y old n = 18 8♀+ 10♂ Mean age: 9.3 y ± 3 y Mean BMI: 32.6 ± 5.7 kg/m²	Restricted-carbohydrate (≤30 g daily) diet Unlimited protein and energy Only diet instruction provided Duration: 10 wk Parameters: Weight (digital scale), height (stadiometer) Biochemical analysis: Fasting lipid profiles (including total cholesterol, HDL, LDL, and TG) No ketone measurement Data collection: At baseline and at the end of the intervention	Anthropometric results: Average weight loss was 7.1 kg BMI ↘ by 3.2 kg/m² but did not reach statistical significance Biochemical results: Both total serum cholesterol and TG levels showed a significant ↘: 24.2 (P = .018) and 56.9 (P = .015) mg/dL, respectively

Abbreviations: ALT, alanine transaminase; BMI, body mass index; BMI-Z, BMI z-score or for-age; CBC, complete blood count; CEBQ, Children's Eating Behaviour Questionnaire; CHO, carbohydrate; CR, calorie-restricted diet; CRD, carbohydrate-restricted diet; CRP, C-reactive protein; DXA, dual-energy X-ray absorptiometry; EI, energy intake; FRD, fat-restricted diet, HDL, high-density lipoprotein; HMW, high-molecular-weight; HOMA-IR, homeostatic model assessment of insulin resistance; HRQOL, health-related quality of life; ICAM-1, intercellular adhesion molecule 1; IGF-1, insulin-like growth factor 1; IGFBP-3, insulin-like growth factor binding protein-3; IL-6, interleukin-6; LDL, low-density lipoprotein; LGL, low-glycemic-load diet; NAFLD, nonalcoholic fatty liver disease; PAI-1, plasminogen activator inhibitor-1; REE, resting energy expenditure; TFEQ, Three-Factor Eating Questionnaire; TG, triglycerides; TNF-α, tumor necrosis factor α; TSH, thyroid-stimulating hormone; WBISI, Whole-Body Insulin Sensitivity Index; β-HCG, Human chorionic gonadotropin ♀, female; ♂, male; ↘, decrease(d); ↗, increase(d).

Study Methodology Characteristics

Dietary Intervention Approaches

The majority of studies were randomized controlled trials (58%), all of which had a parallel-group design, except for 1 study.⁵⁴ All studies subjected participants to 1 LC intervention, and 12 of them had 1 or more diet comparator arms. The weighted mean duration of the intervention was 3.5 months, ranging from 1 week⁵⁴ to 6 months.⁴⁸^,⁵¹^,⁵⁹^,⁶⁰ A follow-up was conducted in 5 studies, which included periods of 4 months,⁴⁵ 5.75 months,⁵⁸ and 9 months postintervention.⁴⁶^,⁴⁷^,⁵² Only 1 study included a control group without a dietary intervention,⁵⁰ while several studies included additional diet arms with an LF diet (n = 7),⁴⁴^,⁴⁹^,⁵⁰^,⁵²^,⁵³^,⁵⁶^,⁵⁸ a CR diet (n = 3),⁴⁶^,⁴⁷^,⁵⁵ or a standard diet (n = 2) (Table 2, Table S2).⁵²^,⁵³ Importantly, the caloric contents of LC interventions were limited in order to achieve either an energy deficit (n = 4)⁵⁰^,⁵²^,⁵³^,⁵⁷ or weight maintenance (n = 2),⁴⁴^,⁵⁴ or were unlimited (n = 13).⁴³^,^45–49^,⁵¹^,⁵⁵^,⁵⁶^,^58–61 Three studies restricted the daily caloric intake of both the LC and comparator arms in order to ensure an isocaloric content.⁵⁰^,⁵²^,⁵³ However, 5 studies restricted the caloric volume of the comparator but not the LC diet, 2 as LF diets⁴⁹^,⁵⁸ and 3 as CR diets.⁴⁶^,⁴⁷^,⁵⁵ Among eligible studies, varying degrees of carbohydrate restriction were explored with a weighted average of 70 g per day, ranging from lower than 20 g (∼10% of total caloric intake)⁴⁵^,⁴⁸^,⁴⁹^,⁵⁶^,⁵⁸ to ∼175 g (35% of total caloric intake)⁵⁰ of total caloric intake per day. Only 3 studies implemented structured exercise programs⁴⁹^,⁵⁸ or sessions led by a specialist,⁴⁷ while the remainder only recommended regular physical activity without a specific regimen.⁴⁸^,^50–53^,⁵⁹^,⁶⁰

Efficacy Endpoints and Assessment Methods

With regard to anthropometric parameters, the majority of the studies (n = 13)^43–45^,⁴⁸^,⁵⁰^,⁵¹^,^55–61 assessed weight and height with electronic scales and stadiometers before and after the intervention (Table 2). However, waist circumference and body composition were only evaluated in 4 and 10 studies using a tape measure and a range of methodologies, respectively (dual energy X-ray absorptiometry [n = 4],⁴⁴^,⁴⁷^,⁵⁷^,⁵⁸ bioelectrical impedance [n = 5],⁴⁸^,⁵⁰^,⁵²^,⁵³^,⁵⁷ creatinine excretion [n = 1],⁵⁷ or magnetic resonance imaging⁵⁴ [n = 1]). Biochemical analyses were carried out in 14 studies with assessments of lipid (n = 13; eg, TG, total cholesterol, HDL, LDL) and metabolic (n = 8; eg, insulin, leptin, adiponectin) profiles. Only 9 studies reported testing the level of ketone bodies, primarily via urine ketone sticks or reagent strips,^45–49^,⁵²^,⁵⁶^,⁵⁷^,⁶⁰ except for 1 study that measured β-hydroxybutyrate in the serum.⁵⁸ Diet adherence was confirmed verbally by the children and their parents, but in some cases, evaluated through 24-hour food diaries (n = 7).⁴³^,^46–49^,^51–53^,^56–58 While most studies provided only dietary guidelines to participants,⁴³^,^46–48^,⁵⁰^,⁵¹^,⁵⁵^,^58–61 recipes and menus were provided in 5 studies,⁴⁵^,⁴⁹^,⁵²^,⁵³^,⁵⁶ and food was given directly to families in 3 studies during at least part of the study.⁴⁴^,⁵⁴^,⁵⁷

Daily physical activity was not explicitly recorded in any study, but 2 studies did conduct an activity assessment at baseline by questionnaire. Others parameters included resting energy expenditure (REE) evaluated by indirect calorimetry in 4 studies,⁴⁴^,⁵⁰^,⁵⁴^,⁵⁷ general and eating-related psychological parameters including self-reported perceived general behavior,⁴⁵ self-esteem,⁵¹ eating behavior traits (eg, Three-Factor Eating Questionnaire [TFEQ], Children’s Eating Behaviour Questionnaire [CEBQ]),⁴⁶ subjective feelings of hunger and fullness,⁵⁸ and health-related quality of life (HRQOL)⁵³ were also evaluated throughout the intervention period in select studies and are described in Appendix S1. Ancillary outcomes outside the scope of this systematic review, such as heart characteristics through echocardiographic imaging,⁵⁹^,⁶⁰ sleep patterns via nocturnal polysomnography,⁵⁷ or menstrual cycles, were also reported and are described in Appendix S1.⁴⁹

Study Results

Anthropometrics

Low-carbohydrate arms only

A significant decrease in body weight⁴³^,⁴⁴^,^48–51^,^55–61 and BMI or BMI z-score⁴³^,⁴⁴^,⁴⁷^,⁴⁸^,^50–53^,^56–60 was observed among LC arms in 13 studies (Tables 2 and 3). Weight loss achieved during the intervention remained significant at the end of the follow-up in 3 of 5 studies.⁴⁷^,⁵²^,⁵⁸ Conversely, 1 study reported weight gain after the end of the LC intervention, but with a sample size too low to have sufficient statistical power.⁴⁵ Waist circumference was significantly lower after LC interventions in the 4 studies that assessed it.^47–50 Six out of 10 studies with available data reported a significant decrease in fat mass.⁴⁴^,⁴⁷^,⁴⁸^,⁵²^,⁵³^,⁵⁷

Table 3.

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Summary of Significant Results of the Different Arms of Selected Studies Detailing the Calorie-Restriction Status

Study (year)	LC-CR		LC, no CR		CD-CR		CD, no CR
Study (year)

Pauley et al (2021)⁴³			↓ Weight	↓TG
Pauley et al (2021)⁴³			↓BMI	↓ Insulin
Goss et al (2020)⁴⁴			↓ Weight ↓ BMI ↓ BMI z-score ↓ Fat mass weight maintained	↓ Hepatic lipid			Low-fat weight maintained
Felix et al (2020)⁴⁵			Sample number too low
Kirk et al (2017)⁴⁶			Protein unlimited		Hypocaloric diet TFEQ ↑ Cognitive restraint ↓ Hunger	↓ Disinhibition	Restricted-glycemic-load diet TFEQ ↑ Cognitive restraint ↓ Disinhibition ↓ Hunger Protein unlimited
Kirk et al (2017)⁴⁶			Protein unlimited		↓ 500 kilocalories daily 10% to 15% of their calories from protein
Kirk et al (2012)⁴⁷			↓ BMI z-score ↓ Body fat	↓ TG ↑ HDL ↓↓ Insulin	Hypocaloric diet ↓BMI z-score ↓ Body fat	↓ Insulin ↑ HDL	Restricted-glycemic-load diet ↓BMI z-score ↓ Insulin ↓ Body fat ↓ LDL ↓ Waist circumference Protein unlimited
			↓ Waist circumference		↓ Waist circumference
			Protein unlimited		↓ 500 kilocalories daily 10% to 15% of their calories from protein
Partsalaki et al (2012)⁴⁸			Ketogenic diet ↓↓ Weight ↓↓ Fat mass ↓↓ Waist circumference	↓ HOMA-IR ↓ Insulin ↑ Adiponectin	Hypocaloric diet ↓ Weight ↓ Fat mass	↓ HOMA-IR ↓ Insulin
			Protein unlimited		↓ Waist circumference
			Protein unlimited		↓ 500 kilocalories daily 12% to 22% of their calories from protein
Ornstein et al (2011)⁴⁹			↓ Weight ↓ Waist circumference Protein unlimited		Low-fat ↓ Weight ↓ Waist circumference
Ornstein et al (2011)⁴⁹			↓ Weight ↓ Waist circumference Protein unlimited		Protein unlimited
Truby et al (2016)⁵⁰	↓ Weight ↓ BMI z-score	↓ HOMA-IR ↓ Leptin ↑ Adiponectin			Low-fat ↓ Weight ↓ BMI z-score	↓ HOMA-IR ↓ Leptin ↑ Adiponectin	Control No intervention
	↓ Waist circumference ↓ 20% daily calorie intake compared with their energy expenditure				↓ Waist circumference
					↓ 20% daily calorie intake compared with their energy expenditure
Siegel et al (2009)⁵¹			↓BMI Protein unlimited
Demol et al (2009)⁵²	Low-carbohydrate, high-fat, low-protein				High-carbohydrate, low-fat, low-protein
	↓ BMI ↓ BMI z-score ↓ Fat mass	↓ Insulin ↓ HOMA-IR ↓ TG ↓ LDL ↓ Leptin			↓BMI ↓BMI z-score ↓ Fat mass isocaloric 20% protein	↓ TG ↓ LDL ↓ Leptin
	isocaloric 20% protein				Low-carbohydrate, low-fat, high-protein
	isocaloric 20% protein				↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric	↓ Insulin ↓ HOMA-IR ↓ TG ↓ LDL ↓ Leptin
Yackobovitch-Gavan et al (2008)⁵³	Low-carbohydrate, high-fat, low-protein				High-carbohydrate, low-fat, low-protein
	↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric 20% protein				↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric 20% protein
	↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric 20% protein				Low-carbohydrate, low-fat, high-protein ↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric
Sunehag et al (2005)⁵⁴ (crossover study)			↓ Total cholesterol isocaloric, weight maintained isonitrogenous				Standard diet isocaloric, weight maintained isonitrogenous
Bailes et al (2003)⁵⁵			Low-carbohydrate, high-protein		Calorie-restricted ↑ Weight ↑ BMI ↓ 20% of energy needs protein (15%-20%), fat (<30%)
Bailes et al (2003)⁵⁵			↓ Weight ↓ BMI Protein unlimited
Sondike et al (2003)⁵⁶			↓↓ Weight ↓↓ BMI	↓ TG			Low-fat ↓ Weight ↓ LDL ↓ BMI
Willi et al (1998)⁵⁷	Low-carbohydrate, low-fat, high-protein
	↓ Weight ↓ BMI ↓ Fat mass	↓ Cholesterol
	650 to 725 calories/d
Krebs et al (2010)⁵⁸			Low-carbohydrate, high-protein		Low-fat
Krebs et al (2010)⁵⁸			↓↓ BMI z-score	↓↓ TG ↓ LDL ↓ Insulin	↓ BMI z-score 70% of REE Protein unlimited	↓ TG ↓ LDL
Zeybek et al (2010)⁵⁹			↓ Weight ↓ BMI Protein unlimited	↓ HOMA-IR ↓ Insulin
Zeybek et al (2009)⁶⁰			↓ Weight ↓ BMI Protein unlimited
Dunlap and Bailes (2008)⁶¹			↓ TG Protein unlimited

Study (year)	LC-CR		LC, no CR		CD-CR		CD, no CR
Study (year)

Pauley et al (2021)⁴³			↓ Weight	↓TG
Pauley et al (2021)⁴³			↓BMI	↓ Insulin
Goss et al (2020)⁴⁴			↓ Weight ↓ BMI ↓ BMI z-score ↓ Fat mass weight maintained	↓ Hepatic lipid			Low-fat weight maintained
Felix et al (2020)⁴⁵			Sample number too low
Kirk et al (2017)⁴⁶			Protein unlimited		Hypocaloric diet TFEQ ↑ Cognitive restraint ↓ Hunger	↓ Disinhibition	Restricted-glycemic-load diet TFEQ ↑ Cognitive restraint ↓ Disinhibition ↓ Hunger Protein unlimited
Kirk et al (2017)⁴⁶			Protein unlimited		↓ 500 kilocalories daily 10% to 15% of their calories from protein
Kirk et al (2012)⁴⁷			↓ BMI z-score ↓ Body fat	↓ TG ↑ HDL ↓↓ Insulin	Hypocaloric diet ↓BMI z-score ↓ Body fat	↓ Insulin ↑ HDL	Restricted-glycemic-load diet ↓BMI z-score ↓ Insulin ↓ Body fat ↓ LDL ↓ Waist circumference Protein unlimited
			↓ Waist circumference		↓ Waist circumference
			Protein unlimited		↓ 500 kilocalories daily 10% to 15% of their calories from protein
Partsalaki et al (2012)⁴⁸			Ketogenic diet ↓↓ Weight ↓↓ Fat mass ↓↓ Waist circumference	↓ HOMA-IR ↓ Insulin ↑ Adiponectin	Hypocaloric diet ↓ Weight ↓ Fat mass	↓ HOMA-IR ↓ Insulin
			Protein unlimited		↓ Waist circumference
			Protein unlimited		↓ 500 kilocalories daily 12% to 22% of their calories from protein
Ornstein et al (2011)⁴⁹			↓ Weight ↓ Waist circumference Protein unlimited		Low-fat ↓ Weight ↓ Waist circumference
Ornstein et al (2011)⁴⁹			↓ Weight ↓ Waist circumference Protein unlimited		Protein unlimited
Truby et al (2016)⁵⁰	↓ Weight ↓ BMI z-score	↓ HOMA-IR ↓ Leptin ↑ Adiponectin			Low-fat ↓ Weight ↓ BMI z-score	↓ HOMA-IR ↓ Leptin ↑ Adiponectin	Control No intervention
	↓ Waist circumference ↓ 20% daily calorie intake compared with their energy expenditure				↓ Waist circumference
					↓ 20% daily calorie intake compared with their energy expenditure
Siegel et al (2009)⁵¹			↓BMI Protein unlimited
Demol et al (2009)⁵²	Low-carbohydrate, high-fat, low-protein				High-carbohydrate, low-fat, low-protein
	↓ BMI ↓ BMI z-score ↓ Fat mass	↓ Insulin ↓ HOMA-IR ↓ TG ↓ LDL ↓ Leptin			↓BMI ↓BMI z-score ↓ Fat mass isocaloric 20% protein	↓ TG ↓ LDL ↓ Leptin
	isocaloric 20% protein				Low-carbohydrate, low-fat, high-protein
	isocaloric 20% protein				↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric	↓ Insulin ↓ HOMA-IR ↓ TG ↓ LDL ↓ Leptin
Yackobovitch-Gavan et al (2008)⁵³	Low-carbohydrate, high-fat, low-protein				High-carbohydrate, low-fat, low-protein
	↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric 20% protein				↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric 20% protein
	↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric 20% protein				Low-carbohydrate, low-fat, high-protein ↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric
Sunehag et al (2005)⁵⁴ (crossover study)			↓ Total cholesterol isocaloric, weight maintained isonitrogenous				Standard diet isocaloric, weight maintained isonitrogenous
Bailes et al (2003)⁵⁵			Low-carbohydrate, high-protein		Calorie-restricted ↑ Weight ↑ BMI ↓ 20% of energy needs protein (15%-20%), fat (<30%)
Bailes et al (2003)⁵⁵			↓ Weight ↓ BMI Protein unlimited
Sondike et al (2003)⁵⁶			↓↓ Weight ↓↓ BMI	↓ TG			Low-fat ↓ Weight ↓ LDL ↓ BMI
Willi et al (1998)⁵⁷	Low-carbohydrate, low-fat, high-protein
	↓ Weight ↓ BMI ↓ Fat mass	↓ Cholesterol
	650 to 725 calories/d
Krebs et al (2010)⁵⁸			Low-carbohydrate, high-protein		Low-fat
Krebs et al (2010)⁵⁸			↓↓ BMI z-score	↓↓ TG ↓ LDL ↓ Insulin	↓ BMI z-score 70% of REE Protein unlimited	↓ TG ↓ LDL
Zeybek et al (2010)⁵⁹			↓ Weight ↓ BMI Protein unlimited	↓ HOMA-IR ↓ Insulin
Zeybek et al (2009)⁶⁰			↓ Weight ↓ BMI Protein unlimited
Dunlap and Bailes (2008)⁶¹			↓ TG Protein unlimited

Abbreviations: BMI, body mass index; CD, comparator diet; CR, caloric-restricted diet; HDL, high-density-lipoprotein cholesterol; HOMA-IR, homeostatic model assessment of insulin resistance; LC, low-carbohydrate diet; LDL, low-density-lipoprotein cholesterol; REE, resting energy expenditure; TFEQ, Three-Factor Eating Questionnaire; TG, Triglycerides; ↓, decrease; ↓↓, major decrease; ↑, increase.

Table 3.

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Summary of Significant Results of the Different Arms of Selected Studies Detailing the Calorie-Restriction Status

Study (year)	LC-CR		LC, no CR		CD-CR		CD, no CR
Study (year)

Pauley et al (2021)⁴³			↓ Weight	↓TG
Pauley et al (2021)⁴³			↓BMI	↓ Insulin
Goss et al (2020)⁴⁴			↓ Weight ↓ BMI ↓ BMI z-score ↓ Fat mass weight maintained	↓ Hepatic lipid			Low-fat weight maintained
Felix et al (2020)⁴⁵			Sample number too low
Kirk et al (2017)⁴⁶			Protein unlimited		Hypocaloric diet TFEQ ↑ Cognitive restraint ↓ Hunger	↓ Disinhibition	Restricted-glycemic-load diet TFEQ ↑ Cognitive restraint ↓ Disinhibition ↓ Hunger Protein unlimited
Kirk et al (2017)⁴⁶			Protein unlimited		↓ 500 kilocalories daily 10% to 15% of their calories from protein
Kirk et al (2012)⁴⁷			↓ BMI z-score ↓ Body fat	↓ TG ↑ HDL ↓↓ Insulin	Hypocaloric diet ↓BMI z-score ↓ Body fat	↓ Insulin ↑ HDL	Restricted-glycemic-load diet ↓BMI z-score ↓ Insulin ↓ Body fat ↓ LDL ↓ Waist circumference Protein unlimited
			↓ Waist circumference		↓ Waist circumference
			Protein unlimited		↓ 500 kilocalories daily 10% to 15% of their calories from protein
Partsalaki et al (2012)⁴⁸			Ketogenic diet ↓↓ Weight ↓↓ Fat mass ↓↓ Waist circumference	↓ HOMA-IR ↓ Insulin ↑ Adiponectin	Hypocaloric diet ↓ Weight ↓ Fat mass	↓ HOMA-IR ↓ Insulin
			Protein unlimited		↓ Waist circumference
			Protein unlimited		↓ 500 kilocalories daily 12% to 22% of their calories from protein
Ornstein et al (2011)⁴⁹			↓ Weight ↓ Waist circumference Protein unlimited		Low-fat ↓ Weight ↓ Waist circumference
Ornstein et al (2011)⁴⁹			↓ Weight ↓ Waist circumference Protein unlimited		Protein unlimited
Truby et al (2016)⁵⁰	↓ Weight ↓ BMI z-score	↓ HOMA-IR ↓ Leptin ↑ Adiponectin			Low-fat ↓ Weight ↓ BMI z-score	↓ HOMA-IR ↓ Leptin ↑ Adiponectin	Control No intervention
	↓ Waist circumference ↓ 20% daily calorie intake compared with their energy expenditure				↓ Waist circumference
					↓ 20% daily calorie intake compared with their energy expenditure
Siegel et al (2009)⁵¹			↓BMI Protein unlimited
Demol et al (2009)⁵²	Low-carbohydrate, high-fat, low-protein				High-carbohydrate, low-fat, low-protein
	↓ BMI ↓ BMI z-score ↓ Fat mass	↓ Insulin ↓ HOMA-IR ↓ TG ↓ LDL ↓ Leptin			↓BMI ↓BMI z-score ↓ Fat mass isocaloric 20% protein	↓ TG ↓ LDL ↓ Leptin
	isocaloric 20% protein				Low-carbohydrate, low-fat, high-protein
	isocaloric 20% protein				↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric	↓ Insulin ↓ HOMA-IR ↓ TG ↓ LDL ↓ Leptin
Yackobovitch-Gavan et al (2008)⁵³	Low-carbohydrate, high-fat, low-protein				High-carbohydrate, low-fat, low-protein
	↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric 20% protein				↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric 20% protein
	↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric 20% protein				Low-carbohydrate, low-fat, high-protein ↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric
Sunehag et al (2005)⁵⁴ (crossover study)			↓ Total cholesterol isocaloric, weight maintained isonitrogenous				Standard diet isocaloric, weight maintained isonitrogenous
Bailes et al (2003)⁵⁵			Low-carbohydrate, high-protein		Calorie-restricted ↑ Weight ↑ BMI ↓ 20% of energy needs protein (15%-20%), fat (<30%)
Bailes et al (2003)⁵⁵			↓ Weight ↓ BMI Protein unlimited
Sondike et al (2003)⁵⁶			↓↓ Weight ↓↓ BMI	↓ TG			Low-fat ↓ Weight ↓ LDL ↓ BMI
Willi et al (1998)⁵⁷	Low-carbohydrate, low-fat, high-protein
	↓ Weight ↓ BMI ↓ Fat mass	↓ Cholesterol
	650 to 725 calories/d
Krebs et al (2010)⁵⁸			Low-carbohydrate, high-protein		Low-fat
Krebs et al (2010)⁵⁸			↓↓ BMI z-score	↓↓ TG ↓ LDL ↓ Insulin	↓ BMI z-score 70% of REE Protein unlimited	↓ TG ↓ LDL
Zeybek et al (2010)⁵⁹			↓ Weight ↓ BMI Protein unlimited	↓ HOMA-IR ↓ Insulin
Zeybek et al (2009)⁶⁰			↓ Weight ↓ BMI Protein unlimited
Dunlap and Bailes (2008)⁶¹			↓ TG Protein unlimited

Study (year)	LC-CR		LC, no CR		CD-CR		CD, no CR
Study (year)

Pauley et al (2021)⁴³			↓ Weight	↓TG
Pauley et al (2021)⁴³			↓BMI	↓ Insulin
Goss et al (2020)⁴⁴			↓ Weight ↓ BMI ↓ BMI z-score ↓ Fat mass weight maintained	↓ Hepatic lipid			Low-fat weight maintained
Felix et al (2020)⁴⁵			Sample number too low
Kirk et al (2017)⁴⁶			Protein unlimited		Hypocaloric diet TFEQ ↑ Cognitive restraint ↓ Hunger	↓ Disinhibition	Restricted-glycemic-load diet TFEQ ↑ Cognitive restraint ↓ Disinhibition ↓ Hunger Protein unlimited
Kirk et al (2017)⁴⁶			Protein unlimited		↓ 500 kilocalories daily 10% to 15% of their calories from protein
Kirk et al (2012)⁴⁷			↓ BMI z-score ↓ Body fat	↓ TG ↑ HDL ↓↓ Insulin	Hypocaloric diet ↓BMI z-score ↓ Body fat	↓ Insulin ↑ HDL	Restricted-glycemic-load diet ↓BMI z-score ↓ Insulin ↓ Body fat ↓ LDL ↓ Waist circumference Protein unlimited
			↓ Waist circumference		↓ Waist circumference
			Protein unlimited		↓ 500 kilocalories daily 10% to 15% of their calories from protein
Partsalaki et al (2012)⁴⁸			Ketogenic diet ↓↓ Weight ↓↓ Fat mass ↓↓ Waist circumference	↓ HOMA-IR ↓ Insulin ↑ Adiponectin	Hypocaloric diet ↓ Weight ↓ Fat mass	↓ HOMA-IR ↓ Insulin
			Protein unlimited		↓ Waist circumference
			Protein unlimited		↓ 500 kilocalories daily 12% to 22% of their calories from protein
Ornstein et al (2011)⁴⁹			↓ Weight ↓ Waist circumference Protein unlimited		Low-fat ↓ Weight ↓ Waist circumference
Ornstein et al (2011)⁴⁹			↓ Weight ↓ Waist circumference Protein unlimited		Protein unlimited
Truby et al (2016)⁵⁰	↓ Weight ↓ BMI z-score	↓ HOMA-IR ↓ Leptin ↑ Adiponectin			Low-fat ↓ Weight ↓ BMI z-score	↓ HOMA-IR ↓ Leptin ↑ Adiponectin	Control No intervention
	↓ Waist circumference ↓ 20% daily calorie intake compared with their energy expenditure				↓ Waist circumference
					↓ 20% daily calorie intake compared with their energy expenditure
Siegel et al (2009)⁵¹			↓BMI Protein unlimited
Demol et al (2009)⁵²	Low-carbohydrate, high-fat, low-protein				High-carbohydrate, low-fat, low-protein
	↓ BMI ↓ BMI z-score ↓ Fat mass	↓ Insulin ↓ HOMA-IR ↓ TG ↓ LDL ↓ Leptin			↓BMI ↓BMI z-score ↓ Fat mass isocaloric 20% protein	↓ TG ↓ LDL ↓ Leptin
	isocaloric 20% protein				Low-carbohydrate, low-fat, high-protein
	isocaloric 20% protein				↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric	↓ Insulin ↓ HOMA-IR ↓ TG ↓ LDL ↓ Leptin
Yackobovitch-Gavan et al (2008)⁵³	Low-carbohydrate, high-fat, low-protein				High-carbohydrate, low-fat, low-protein
	↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric 20% protein				↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric 20% protein
	↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric 20% protein				Low-carbohydrate, low-fat, high-protein ↓ BMI ↓ BMI z-score ↓ Fat mass isocaloric
Sunehag et al (2005)⁵⁴ (crossover study)			↓ Total cholesterol isocaloric, weight maintained isonitrogenous				Standard diet isocaloric, weight maintained isonitrogenous
Bailes et al (2003)⁵⁵			Low-carbohydrate, high-protein		Calorie-restricted ↑ Weight ↑ BMI ↓ 20% of energy needs protein (15%-20%), fat (<30%)
Bailes et al (2003)⁵⁵			↓ Weight ↓ BMI Protein unlimited
Sondike et al (2003)⁵⁶			↓↓ Weight ↓↓ BMI	↓ TG			Low-fat ↓ Weight ↓ LDL ↓ BMI
Willi et al (1998)⁵⁷	Low-carbohydrate, low-fat, high-protein
	↓ Weight ↓ BMI ↓ Fat mass	↓ Cholesterol
	650 to 725 calories/d
Krebs et al (2010)⁵⁸			Low-carbohydrate, high-protein		Low-fat
Krebs et al (2010)⁵⁸			↓↓ BMI z-score	↓↓ TG ↓ LDL ↓ Insulin	↓ BMI z-score 70% of REE Protein unlimited	↓ TG ↓ LDL
Zeybek et al (2010)⁵⁹			↓ Weight ↓ BMI Protein unlimited	↓ HOMA-IR ↓ Insulin
Zeybek et al (2009)⁶⁰			↓ Weight ↓ BMI Protein unlimited
Dunlap and Bailes (2008)⁶¹			↓ TG Protein unlimited

Abbreviations: BMI, body mass index; CD, comparator diet; CR, caloric-restricted diet; HDL, high-density-lipoprotein cholesterol; HOMA-IR, homeostatic model assessment of insulin resistance; LC, low-carbohydrate diet; LDL, low-density-lipoprotein cholesterol; REE, resting energy expenditure; TFEQ, Three-Factor Eating Questionnaire; TG, Triglycerides; ↓, decrease; ↓↓, major decrease; ↑, increase.

Low-carbohydrate versus control diets

Two studies compared an LC diet with an LF comparator arm without CR in both arms (Tables 2 and 3).⁴⁴^,⁵⁶ A significant decrease in weight, BMI,⁵⁶ and BMI z-score⁴⁴ after both LC and LF interventions was reported in both, but with a significant decrease in fat mass observed only in the LC group.⁴⁴ Similarly, when both the LC and LF diets had CR but were isocaloric, studies⁵⁰^,⁵²^,⁵³ reported a similar decrease in weight,⁵⁰ BMI,⁵²^,⁵³ BMI z-score,⁵⁰^,⁵²^,⁵³ waist circumference,⁵⁰ and fat mass⁵²^,⁵³ in both groups. Of interest, Demol et al⁵² and Yackobovitch-Gavan et al⁵³ both included 2 LC groups, with either an LF or high-fat (HF) content, and observed similar effects on anthropometric parameters relative to the control diet. No studies included both an LC group with CR and a CR control group without macronutrient-ratio modification.

Three studies compared a nonrestricted LC diet with a CR diet and assessed anthropometric parameters.⁴⁷^,⁴⁸^,⁵⁵ Partsalaki et al⁴⁸ observed a greater weight, fat mass, and waist circumference decrease in the LC group compared with the CR group. Conversely, similar reductions between LC and control groups in weight, BMI z-score, waist circumference, and fat mass were reported in the 2 other studies.⁴⁷^,⁵⁵ Of interest, Bailes et al⁵⁵ revealed a decrease in weight and BMI after an LC, high-protein diet, but an increase following the CR diet. Two studies included a nonrestricted LC group and a restricted LF group.⁴⁹^,⁵⁸ The sample size of Ornstein et al⁴⁹ did not have adequate power to compare both diets, but they reported a decrease in weight⁴⁹ and waist circumference⁴⁹ after both diets. Krebs et al⁵⁸ reported that BMI z-score decreased after both LC and control diets, but with a greater reduction after the LC, high-protein diet.⁵⁸

Lipid and Metabolic Profiles

Low-carbohydrate arms only

Levels of major hormones involved in energy metabolism and satiety were generally modified by an LC diet in a beneficial manner (Tables 2 and 3). Fasting serum insulin⁴⁴^,⁴⁷^,⁴⁸^,⁵²^,⁵⁸ and homeostasis model assessment of insulin resistance (HOMA-IR)⁴⁴^,⁴⁸^,⁵⁰^,⁵²^,⁵⁸ decreased after an LC intervention in 5 studies, while leptin⁵⁰^,⁵² and adiponectin⁴⁸^,⁵⁰ decreased and increased in 2 studies, respectively (Table 2). Lipid profiles were also significantly improved as demonstrated by a reduction in serum TG⁴⁷^,⁵²^,⁵⁶^,⁵⁸^,⁶¹ and total cholesterol (including LDL)⁵²^,⁵⁷^,⁵⁸^,⁶¹ in most single-arm studies. However, Sunehag et al⁵⁴ found total cholesterol and LDL to increase after restriction of carbohydrate (CHO) to 30% of daily caloric intake.

Low-carbohydrate versus control diets

The 2 studies comparing an LC diet with an LF comparator arm without CR in either reported a significant decrease in hepatic lipids and TG only in the LC group, but in LDL only in the LF group (Tables 2 and 3).⁴⁴^,⁵⁶ Only 2 of 3 studies incorporating isocaloric, but energy-restricted LC and LF diets investigated biochemical parameters.⁵⁰^,⁵² In both studies, leptin was decreased (n = 2) in both groups while a decrease in HOMA-IR was either observed in both groups⁵⁰ or only in the LC group postintervention.⁵² Additionally, LDL and TG decreased in both groups in 1 study,⁵² while favorable changes in fasting insulin⁵² and adiponectin⁵⁰ were observed only in the LC group in both studies. Demol et al⁵² incorporated a second LC group, which was also LF and isocaloric. Interestingly, the decreases in insulin and HOMA-IR were observed in both LC groups independently of fat restriction.

Two studies compared a nonrestricted LC diet with a CR diet and assessed biochemical parameters.⁴⁷^,⁴⁸ Partsalaki et al⁴⁸ found a greater fasting insulin and HOMA-IR reduction in the LC group compared with the CR group, and an increase in adiponectin only in the LC group. Although Kirk et al⁴⁷ observed a greater reduction in fasting insulin in the LC group relative to CR and low-glycemic-diet groups, the reduction was only maintained at follow-up (ie, 9 months) within the low-glycemic and CR groups. However, the converse was evident for changes in TG. With regard to lipids, while both the LC and control diets induced an increase in HDL by the end of the follow-up period, a concomitant decrease in LDL was only observed in the low-glycemic-diet group.⁵⁸ Two studies⁴⁹^,⁵⁸ included a nonrestricted LC group and a restricted LF group, but only 1 study investigated biochemical parameters.⁵⁸ Krebs et al⁵⁸ reported a decrease in TG and LDL after both diets, but with a 3-fold difference in magnitude for TG favoring the LC, high-protein diet. Moreover, fasting insulin was only significantly reduced in the LC, high-protein group.⁵⁸

Importantly, out of 9 studies^45–49^,⁵²^,⁵⁶^,⁵⁷^,⁶⁰ that measured serum ketone bodies, only 4 detected them reliably in participants throughout the trial,⁵⁴^,^56–58 with 1 study showing no significant difference in urinary ketone bodies between groups.⁵² Among the 4 studies assessing ketosis, only 2 reported the ketone body concentration, with 2.28 ± 0.34 without indicated a unit in the study of Krebs et al⁵⁸ and 0.20 ± 0.03 mM in the study of Sunehag et al,⁵⁴ which seems low for a ketosis state.

Meta-analysis Results

Phase 1: Mean Change Within LC Arms

In meta-analyses of changes in anthropometrics, 12, 14, and 6 studies included data on weight, BMI, and BMI z-score, respectively, pre- and postintervention. The random-effects meta-analyses yielded a significant decrease in weight (mean change [MC] = -7.09 [95% CI: -9.60, -4.58] kg; P < .001), BMI (MC = -3.01 [-3.71, -2.30] kg/m²; P < .001), and BMI z-score (MC = -0.27 [-0.48, -0.06] z-score; P = .020), on average, after an LC diet (Figure 3). However, between-study heterogeneity was high in meta-analyses of all 3 parameters (I² range: 91.1%–96.1%; Table 4). Indeed, as noted by the prediction intervals (PIs), only the decrease in weight remained significant after accounting for this heterogeneity (95% PI: -5.61, -0.41 kg). Meta-regressions with intervention duration as a covariate revealed that duration did not significantly moderate these anthropometric changes (P values > .30). Moreover, the degree of carbohydrate restriction also did not significantly moderate intervention-induced anthropometric changes, although it trended towards significance in the meta-regression of weight (P = .068, R² = 0.231), indicating that fewer carbohydrates consumed was associated with greater weight loss during the intervention.

Figure 3.

Forest Plots Representing Results From the First Phase of the Meta-analysis Indicating Changes in Parameters During an LC intervention. Plots are sorted in columns by anthropometric (left; ie, weight [A], BMI [B], and BMI-Z [C]) and biological outcomes (TG [D], LDL [E], HDL [F], insulin [G], and HOMA-IR [H]). Effect sizes are within-subject weighted mean changes from baseline to postintervention, and pooled in a random-effects meta-analysis. Effect sizes are sorted by carbohydrate intake per day and include the corresponding intervention duration and completion rate. Abbreviations: BMI, body mass index; BMI-Z, BMI z-score; CHO, carbohydrates; HDL, high-density-lipoprotein cholesterol; HK, one-way random effects model by Hoffman and Kringle; HOMA-IR, homeostasis model assessment of insulin resistance; LC, low-carbohydrate; LDL, low-density-lipoprotein cholesterol; MC, mean change; TG, triglycerides

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Table 4.

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Results of Phase 1 of the Meta-analysis on the Effect of an LC Diet on Anthropometric, Lipid, and Metabolic Parameters in Overweight Youth or Those With Obesity

Parameters	k	n	MC	95% CI	P	Heterogeneity
Parameters	k	n	MC	95% CI	P	I² (%) [95% CI]	τ² [95% CI]	P
Anthropometric parameters
Weight (kg)	12	139	− 7.09	−9.60; -4.58	<.0001	96.1 [94.5, 97.2]	14.57 [6.71, 43.40]	<.0001
BMI	14	168	− 3.01	−3.71; -2.30	<.0001	94.0 [91.5, 95.8]	1.32 [0.59, 3.56]	<.0001
BMI z-score	6	104	− 0.27	−0.48; -0.06	.0204	91.1 [83.3, 95.2]	0.03 [0.01, 0.29]	<.0001
Biological parameters
TG (mg/dL)	11	199	− 29.16	−45.06; -13.26	.0022	85.0 [74.8, 91.0]	444.46 [169.71, 1676.94]	<.0001
LDL (mg/dL)	10	199	− 3.66	−9.26; 1.93	.1723	53.1 [3.9, 77.1]	22.10 [0.26, 221.04]	.0237
HDL (mg/dL)	9	199	− 0.29	−1.78; 1.20	.6629	61.3 [19.8, 81.3]	1.78 [0.17, 15.57]	.0081
Insulin (ng/mL)	6	122	− 7.13	−9.27; -4.99	.0004	0.0 [0.0, 74.6]	0.00 [0.00, >100.00]	.5686
HOMA-IR	7	113	− 1.19	−1.81; -0.58	.0032	83.1 [66.6, 91.5]	0.42 [0.06, 1.22]	<.0001

Parameters	k	n	MC	95% CI	P	Heterogeneity
Parameters	k	n	MC	95% CI	P	I² (%) [95% CI]	τ² [95% CI]	P
Anthropometric parameters
Weight (kg)	12	139	− 7.09	−9.60; -4.58	<.0001	96.1 [94.5, 97.2]	14.57 [6.71, 43.40]	<.0001
BMI	14	168	− 3.01	−3.71; -2.30	<.0001	94.0 [91.5, 95.8]	1.32 [0.59, 3.56]	<.0001
BMI z-score	6	104	− 0.27	−0.48; -0.06	.0204	91.1 [83.3, 95.2]	0.03 [0.01, 0.29]	<.0001
Biological parameters
TG (mg/dL)	11	199	− 29.16	−45.06; -13.26	.0022	85.0 [74.8, 91.0]	444.46 [169.71, 1676.94]	<.0001
LDL (mg/dL)	10	199	− 3.66	−9.26; 1.93	.1723	53.1 [3.9, 77.1]	22.10 [0.26, 221.04]	.0237
HDL (mg/dL)	9	199	− 0.29	−1.78; 1.20	.6629	61.3 [19.8, 81.3]	1.78 [0.17, 15.57]	.0081
Insulin (ng/mL)	6	122	− 7.13	−9.27; -4.99	.0004	0.0 [0.0, 74.6]	0.00 [0.00, >100.00]	.5686
HOMA-IR	7	113	− 1.19	−1.81; -0.58	.0032	83.1 [66.6, 91.5]	0.42 [0.06, 1.22]	<.0001

Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; k, number of studies involved in the analysis; LC, low-carbohydrate; LDL, low-density lipoprotein; MC, mean change; TG, triglycerides.

Table 4.

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Results of Phase 1 of the Meta-analysis on the Effect of an LC Diet on Anthropometric, Lipid, and Metabolic Parameters in Overweight Youth or Those With Obesity

Parameters	k	n	MC	95% CI	P	Heterogeneity
Parameters	k	n	MC	95% CI	P	I² (%) [95% CI]	τ² [95% CI]	P
Anthropometric parameters
Weight (kg)	12	139	− 7.09	−9.60; -4.58	<.0001	96.1 [94.5, 97.2]	14.57 [6.71, 43.40]	<.0001
BMI	14	168	− 3.01	−3.71; -2.30	<.0001	94.0 [91.5, 95.8]	1.32 [0.59, 3.56]	<.0001
BMI z-score	6	104	− 0.27	−0.48; -0.06	.0204	91.1 [83.3, 95.2]	0.03 [0.01, 0.29]	<.0001
Biological parameters
TG (mg/dL)	11	199	− 29.16	−45.06; -13.26	.0022	85.0 [74.8, 91.0]	444.46 [169.71, 1676.94]	<.0001
LDL (mg/dL)	10	199	− 3.66	−9.26; 1.93	.1723	53.1 [3.9, 77.1]	22.10 [0.26, 221.04]	.0237
HDL (mg/dL)	9	199	− 0.29	−1.78; 1.20	.6629	61.3 [19.8, 81.3]	1.78 [0.17, 15.57]	.0081
Insulin (ng/mL)	6	122	− 7.13	−9.27; -4.99	.0004	0.0 [0.0, 74.6]	0.00 [0.00, >100.00]	.5686
HOMA-IR	7	113	− 1.19	−1.81; -0.58	.0032	83.1 [66.6, 91.5]	0.42 [0.06, 1.22]	<.0001

Parameters	k	n	MC	95% CI	P	Heterogeneity
Parameters	k	n	MC	95% CI	P	I² (%) [95% CI]	τ² [95% CI]	P
Anthropometric parameters
Weight (kg)	12	139	− 7.09	−9.60; -4.58	<.0001	96.1 [94.5, 97.2]	14.57 [6.71, 43.40]	<.0001
BMI	14	168	− 3.01	−3.71; -2.30	<.0001	94.0 [91.5, 95.8]	1.32 [0.59, 3.56]	<.0001
BMI z-score	6	104	− 0.27	−0.48; -0.06	.0204	91.1 [83.3, 95.2]	0.03 [0.01, 0.29]	<.0001
Biological parameters
TG (mg/dL)	11	199	− 29.16	−45.06; -13.26	.0022	85.0 [74.8, 91.0]	444.46 [169.71, 1676.94]	<.0001
LDL (mg/dL)	10	199	− 3.66	−9.26; 1.93	.1723	53.1 [3.9, 77.1]	22.10 [0.26, 221.04]	.0237
HDL (mg/dL)	9	199	− 0.29	−1.78; 1.20	.6629	61.3 [19.8, 81.3]	1.78 [0.17, 15.57]	.0081
Insulin (ng/mL)	6	122	− 7.13	−9.27; -4.99	.0004	0.0 [0.0, 74.6]	0.00 [0.00, >100.00]	.5686
HOMA-IR	7	113	− 1.19	−1.81; -0.58	.0032	83.1 [66.6, 91.5]	0.42 [0.06, 1.22]	<.0001

Abbreviations: BMI, body mass index; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; k, number of studies involved in the analysis; LC, low-carbohydrate; LDL, low-density lipoprotein; MC, mean change; TG, triglycerides.

With regard to lipid and metabolic parameters, a significant decrease in TG (MC = -29.16 [95% CI: -45.06, -13.26] mg/dL; P = .002), serum insulin (MC = -7.13 [-9.27, -4.99] µU/mL; P < .001), and HOMA-IR (MC = -1.19 [-1.81, -0.58] units; P = .003) was observed after an LC diet (Figure 3D, G, H). However, no significant changes in cholesterol-related outcomes (LDL and HDL) were detected (P values > .10) (Figure 3E, F). Heterogeneity between studies varied by parameter from low (ie, insulin) to high (ie, TG, HOMA-IR), but the relatively small number of studies with available data meant a wider range of confidence estimates for variance in effect sizes (see Table 4). As a consequence, the PIs for TG (95% PI: -79.51, 21.19 mg/dL) and HOMA-IR (95% PI: -2.98, 0.59 units) indicated that increases could be observed in future studies. Intervention duration was not a consequential factor in effect size determination, but it did appear that increases in LDL were marginally greater within longer LC interventions (P = .076, R² = 0.160). The degree of carbohydrate restriction only significantly moderated changes in HOMA-IR, suggesting that greater improvements in HOMA-IR during LC trials occurred with less carbohydrate intake (P < .001, R² = 1.00).

Visual inspection of funnel plots indicated the presence of asymmetry in meta-analyses of BMI and HOMA-IR, which was confirmed by Egger’s test for the former (intercept = 6.45, SE = 1.88, P = .005). With regard to BMI, the trim-and-fill analysis indicated that the bias trended towards the null, with 4 missing studies to the left after removal of outliers (adjusted MC = -3.52 [95% CI: -3.90, -2.60] kg/m²; P < .001), although the pooled effect size was not materially different. Conversely, the meta-analyses of HOMA-IR change appeared to suggest a bias towards the left, and the adjusted pooled effect size was nonsignificant (adjusted MC = -0.32 [-1.20, -0.56] units; P = .439). Funnel plots for the first meta-analytic phase can be found in Figure S1. Sensitivity analyses revealed that the reduction in LDL became statistically significant upon removal of an outlying effect size (adjusted MC = -4.69 [-7.58, -1.80] mg/dL; P = .006). Removal of outliers and/or influential cases did not significantly alter the results of any other outcomes.

Phase 2: Mean Differences Between LC and Control Diets

A total of 6, 8, and 5 studies reported weight, BMI, and BMI z-score variation, respectively, against a comparator diet (Table 5, Figure 4). Decreases in weight (MD = -4.15 [95% CI: -6.66, -1.65] kg; P = .008) and BMI (MD = -1.07 [-1.94, -0.19] kg/m²; P = .023) were statistically greater in favor of the LC diet (Figure 4A, B), but only marginally greater in terms of BMI z-score (MD = -0.12 [-0.27, 0.02] z-score; P = .071) (Figure 4C). Between-study heterogeneity remained high in this phase for anthropometric parameters (I² range: 69.9%–84.6%; Table 5), thus the PI did not corroborate the significant effects found for weight (95% PI: -10.70, 2.39 kg) and BMI (95% PI: -3.60, 1.46 kg/m²). Neither duration nor the level of carbohydrate restriction had a significant impact on effect sizes (P values > .09).

Figure 4.

Forest Plots Representing Results From the Second Phase of the Meta-analysis Indicating the Difference in Changes Between LC and Control Interventions. Plots are sorted in columns by anthropometric (left; ie, weight [A], BMI [B], and BMI-Z [C]) and biological outcomes (TG [D], LDL [E], HDL [F], insulin [G], and HOMA-IR [H]). Effect sizes are weighted mean differences between postintervention LC and control values regressed against baseline values, which are sorted by carbohydrate intake per day, and include the corresponding intervention duration, completion rate for the LC arm, and the type of diet used for the control arm. Abbreviations: BMI, body mass index; BMI-Z, BMI z-score; CHO, carbohydrates; HDL, high-density-lipoprotein cholesterol; HK, one-way random effects model by Hoffman and Kringle; HOMA-IR, homeostasis model assessment of insulin resistance; LC, low-carbohydrate diet; LDL, low-density-lipoprotein cholesterol; MD, mean difference; TG, triglycerides

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Table 5.

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Results of Phase 2 of the Meta-analysis Comparing the Efficacity of LC Diets With Other Diets to Improve Anthropometric, Lipid, and Metabolic Parameters in Overweight Youth or Those With Obesity

Parameters	k	LC,^a n	CG,^b n	MD	95% CI	P	Heterogeneity
Parameters	k	LC,^a n	CG,^b n	MD	95% CI	P	I² (%) [95% CI]	τ² [95% CI]	P
Anthropometric parameters
Weight (kg)	6	139	88	− 4.15	−6.66; -1.65	.0080	84.6 [68.2, 92.5]	4.61 [0.87, 28.46]	<.0001
BMI	8	168	155	− 1.07	−1.94; -0.19	.0234	82.1 [65.9, 90.6]	0.93 [0.20, 3.29]	<.0001
BMI z-score	5	104	114	− 0.12	−0.27; 0.02	.0713	69.9 [23.0, 88.2]	0.01 [0.00, 0.13]	.0100
Biological parameters
TG (mg/dL)	8	199	187	− 16.11	−28.36; -3.86	.0171	48.8 [0.0, 77.2]	80.78 [0.00, 807.87]	.0574
LDL (mg/dL)	8	199	186	3.39	−2.36; 9.13	.2057	29.4 [0.0, 68.4]	0.00 [0.00, >100.00]	.1937
HDL (mg/dL)	8	199	186	2.59	0.53; 4.64	.0206	57.0 [5.5, 80.4]	3.25 [0.04, 23.77]	.0226
Insulin (ng/mL)	5	122	115	− 3.41	−11.35; 4.53	.2990	78.6 [49.0, 91.1]	10.26 [5.78, 102.56]	.0009
HOMA-IR	5	113	106	− 0.06	−0.61; 0.49	.7792	63.8 [4.5, 86.3]	0.00 [0.00, 60.84]	.0261

Parameters	k	LC,^a n	CG,^b n	MD	95% CI	P	Heterogeneity
Parameters	k	LC,^a n	CG,^b n	MD	95% CI	P	I² (%) [95% CI]	τ² [95% CI]	P
Anthropometric parameters
Weight (kg)	6	139	88	− 4.15	−6.66; -1.65	.0080	84.6 [68.2, 92.5]	4.61 [0.87, 28.46]	<.0001
BMI	8	168	155	− 1.07	−1.94; -0.19	.0234	82.1 [65.9, 90.6]	0.93 [0.20, 3.29]	<.0001
BMI z-score	5	104	114	− 0.12	−0.27; 0.02	.0713	69.9 [23.0, 88.2]	0.01 [0.00, 0.13]	.0100
Biological parameters
TG (mg/dL)	8	199	187	− 16.11	−28.36; -3.86	.0171	48.8 [0.0, 77.2]	80.78 [0.00, 807.87]	.0574
LDL (mg/dL)	8	199	186	3.39	−2.36; 9.13	.2057	29.4 [0.0, 68.4]	0.00 [0.00, >100.00]	.1937
HDL (mg/dL)	8	199	186	2.59	0.53; 4.64	.0206	57.0 [5.5, 80.4]	3.25 [0.04, 23.77]	.0226
Insulin (ng/mL)	5	122	115	− 3.41	−11.35; 4.53	.2990	78.6 [49.0, 91.1]	10.26 [5.78, 102.56]	.0009
HOMA-IR	5	113	106	− 0.06	−0.61; 0.49	.7792	63.8 [4.5, 86.3]	0.00 [0.00, 60.84]	.0261

Abbreviations: BMI, body mass index; CG, comparator group; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; k, number of studies involved in the analysis; LC, low-carbohydrate; LDL, low-density lipoprotein; MD, mean difference; TG, triglycerides.

a

Number of participants involved at baseline in the low-carbohydrate group.

b

Number of participants involved at baseline in the comparator group.

Table 5.

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Results of Phase 2 of the Meta-analysis Comparing the Efficacity of LC Diets With Other Diets to Improve Anthropometric, Lipid, and Metabolic Parameters in Overweight Youth or Those With Obesity

Parameters	k	LC,^a n	CG,^b n	MD	95% CI	P	Heterogeneity
Parameters	k	LC,^a n	CG,^b n	MD	95% CI	P	I² (%) [95% CI]	τ² [95% CI]	P
Anthropometric parameters
Weight (kg)	6	139	88	− 4.15	−6.66; -1.65	.0080	84.6 [68.2, 92.5]	4.61 [0.87, 28.46]	<.0001
BMI	8	168	155	− 1.07	−1.94; -0.19	.0234	82.1 [65.9, 90.6]	0.93 [0.20, 3.29]	<.0001
BMI z-score	5	104	114	− 0.12	−0.27; 0.02	.0713	69.9 [23.0, 88.2]	0.01 [0.00, 0.13]	.0100
Biological parameters
TG (mg/dL)	8	199	187	− 16.11	−28.36; -3.86	.0171	48.8 [0.0, 77.2]	80.78 [0.00, 807.87]	.0574
LDL (mg/dL)	8	199	186	3.39	−2.36; 9.13	.2057	29.4 [0.0, 68.4]	0.00 [0.00, >100.00]	.1937
HDL (mg/dL)	8	199	186	2.59	0.53; 4.64	.0206	57.0 [5.5, 80.4]	3.25 [0.04, 23.77]	.0226
Insulin (ng/mL)	5	122	115	− 3.41	−11.35; 4.53	.2990	78.6 [49.0, 91.1]	10.26 [5.78, 102.56]	.0009
HOMA-IR	5	113	106	− 0.06	−0.61; 0.49	.7792	63.8 [4.5, 86.3]	0.00 [0.00, 60.84]	.0261

Parameters	k	LC,^a n	CG,^b n	MD	95% CI	P	Heterogeneity
Parameters	k	LC,^a n	CG,^b n	MD	95% CI	P	I² (%) [95% CI]	τ² [95% CI]	P
Anthropometric parameters
Weight (kg)	6	139	88	− 4.15	−6.66; -1.65	.0080	84.6 [68.2, 92.5]	4.61 [0.87, 28.46]	<.0001
BMI	8	168	155	− 1.07	−1.94; -0.19	.0234	82.1 [65.9, 90.6]	0.93 [0.20, 3.29]	<.0001
BMI z-score	5	104	114	− 0.12	−0.27; 0.02	.0713	69.9 [23.0, 88.2]	0.01 [0.00, 0.13]	.0100
Biological parameters
TG (mg/dL)	8	199	187	− 16.11	−28.36; -3.86	.0171	48.8 [0.0, 77.2]	80.78 [0.00, 807.87]	.0574
LDL (mg/dL)	8	199	186	3.39	−2.36; 9.13	.2057	29.4 [0.0, 68.4]	0.00 [0.00, >100.00]	.1937
HDL (mg/dL)	8	199	186	2.59	0.53; 4.64	.0206	57.0 [5.5, 80.4]	3.25 [0.04, 23.77]	.0226
Insulin (ng/mL)	5	122	115	− 3.41	−11.35; 4.53	.2990	78.6 [49.0, 91.1]	10.26 [5.78, 102.56]	.0009
HOMA-IR	5	113	106	− 0.06	−0.61; 0.49	.7792	63.8 [4.5, 86.3]	0.00 [0.00, 60.84]	.0261

Abbreviations: BMI, body mass index; CG, comparator group; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; k, number of studies involved in the analysis; LC, low-carbohydrate; LDL, low-density lipoprotein; MD, mean difference; TG, triglycerides.

a

Number of participants involved at baseline in the low-carbohydrate group.

b

Number of participants involved at baseline in the comparator group.

A total of 8 and 5 controlled studies had data available on lipid- and metabolic-related outcomes, respectively (Table 5, Figure 4). Improvements in TG (MD = -16.11 [-28.36, -3.86] mg/dL; P = .017) and HDL (MD = 2.59 [0.53, 4.64] mg/dL; P = .021) were statistically greater in the LC diet group relative to a comparator diet (Figure 4D, F). However, an LC diet did not lead to more favorable outcomes in LDL, insulin, or HOMA-IR (Table 5; Figure 4E, G, H). Effect size heterogeneity varied notably among these parameters from low (ie, LDL) to moderate (ie, TG, HDL, HOMA-IR) and high (ie, insulin) (Table 5), although reliably lower than anthropometric measures. Even with moderate heterogeneity, the PI in meta-analyses of TG (95% PI: -41.49, 9.27 mg/dL) and HDL (95% PI: -2.31, 7.49 mg/dL) extended beyond the bounds of statistical significance. Similar to anthropometric outcomes, effect sizes did not significantly vary as a function of intervention duration or level of carbohydrate intake.

Among anthropometric measures, notable funnel plot asymmetry was evident in the meta-analysis of BMI, with the trim-and-fill analysis suggesting 5 missing studies to the left (adjusted MD = -2.47 [95% CI: -3.73, -1.20] kg/m²; P = .001). Within biological parameters, potential bias towards the left was indicated by visual inspection of funnel plots for insulin (adjusted MD = -0.28 [-12.30, 11.74] µU/mL; P = .958) and HOMA-IR (adjusted MD = -0.001 [-0.54, 0.54] units; P = .997), with adjustments trending towards a null difference between groups. Funnel plots for the second meta-analytic stage are displayed in the Figure S2. In sensitivity analyses of mean differences, removal of outliers and/or influential cases identified using the leave-one-out method did not materially change the pooled results for all outcomes.

DISCUSSION

Summary of Evidence

The present systematic review and meta-analysis is the first to synthesize evidence pertaining to the efficacy of LC diets to improve anthropometric and metabolic outcomes in children and adolescents with overweight/obesity. The pooled evidence suggests that consuming an LC diet, limiting the daily carbohydrate intake to 30 g per day or 17% of the total caloric intake, with or without CR for a duration of at least 3 months can significantly decrease weight, BMI, and BMI z-score with concomitant improvements in different metabolic biomarkers, such as serum TG and insulin. Intervention duration and the degree of carbohydrate restriction did not significantly moderate intervention-induced anthropometric, lipid, and metabolic parameters according to the meta-regression results, except for HOMA-IR, suggesting that greater improvements in HOMA-IR during LC trials occurred with less carbohydrate intake. Although fewer in number, evidence from controlled trials suggests that LC diets with or without CR, at least initially, may lead to similar, or sometimes greater, improvements in anthropometric and lipid-related outcomes than standard dietary strategies for weight loss, such as CR or LF diets with or without CR.

Taken together, these results present a preliminary challenge to the general assumption that deliberate restriction of energy is the only viable strategy for weight loss, and by extension, improvements in metabolic health, which remains a contentious issue in the literature.

Low-Carbohydrate Diets and Weight Loss

Other reviews⁶³^,⁶⁴ have also highlighted the efficacy and safety of LC diets under medical supervision in adolescents with obesity to improve weight status, insulin resistance, lipid profile, and cardiovascular risk. Conversely, Southcombe et al⁶⁵ reported in their systematic review and meta-analysis that only dietary interventions involving some degree of CR may be effective to induce weight loss in children and adolescents with obesity, while interventions with no energy target were ineffective and even resulted in a BMI gain. However, their meta-analysis results also showed a similar BMI reduction for pooled studies targeting macronutrient distribution (LC and LF diets) with an energy restriction or a eucaloric content.

According to the present review, studies comparing LC diets with or without energy restriction with LF or CR diets generally reported enhanced improvements in anthropometric parameters after LC diets. Gow et al²³ also suggested a greater clinical benefit of an LC diet (15–60 g carbohydrates/d) on both BMI and BMI z-score compared with an LF diet (≤33% of energy from fat) over interventions of 2 to 6 months in duration, but they included both studies with or without an energy restriction and similarly demonstrated high clinical heterogeneity between studies, which limits firm conclusions.

However, the 3 studies⁵⁰^,⁵²^,⁵³ comparing energy-restricted and isocaloric LC diets with a standard CR diet, adjusted for protein content,⁵²^,⁵³ demonstrated similar benefits in anthropometric changes, reinforcing the efficacy of CR for weight loss. Therefore, the greater improvements in anthropometric parameters observed in trials comparing nonrestricted LC groups with CR, restricted-LF, or nonrestricted LF groups may be due, in part, to potential effects on energy intake and appetite. However, results were mixed. While Krebs et al⁵⁸ reported similar daily energy intake in both nonrestricted LC and restricted-LF groups with no subjective hunger or fullness modification, Sondike et al⁵⁶ reported greater energy intake in the nonrestricted LC arm compared with the nonrestricted LF arm, but with a greater weight and BMI loss in the former. Low-carbohydrate diets without CR were at least as effective as CR diets; thus, benefits in health outcomes can be achieved without some of the negative consequences associated with chronic CR.

Low-Carbohydrate Diets and Metabolic Health

Similarly, studies included in the present review comparing LC diets with or without energy restriction with LF or CR diets generally reported enhanced improvements in metabolic parameters after LC diets. Our results were in accordance with other reviews,⁶³^,⁶⁴ which also highlighted the efficacy and safety of LC diets under medical supervision in adolescents with obesity to improve insulin resistance, lipid profile, and cardiovascular risk.

Low-carbohydrate diets seem to induce greater improvements in TG and HDL, on average, even when the calorie content is not restricted. Generally, analyses suggested that the degree of carbohydrate restriction does not have to be severe to elicit metabolic-related improvements, although insulin resistance may decrease to a greater degree initially with more severe restriction. However, these findings must be interpreted with caution due to high between-study heterogeneity in effect size and the limited number of existing studies in children and adolescents with overweight/obesity.

Likewise, an umbrella review⁶⁶ in adults with obesity found beneficial effects of LC diets on several cardiometabolic parameters, such as a reduction in TG, an increase in HDL, and a reduction in insulin resistance with a very-low-calorie ketogenic diet. However, they also observed a clinically meaningful increase in LDL. In the present analysis conducted in youth, no significant modification of the LDL concentration was observed, but even tends to be reduced. Thus, while similar beneficial effects seem to be observed in both adults and youth following an LC diet, the increase in LDL seems to be an adult-specific issue or observed only with a high degree of carbohydrate restriction. However, more studies are needed and especially studies evaluating the serum concentration of small LDL particles, which have been associated with increased cardiovascular risk contrary to large LDL particles.⁶⁷

Low-Carbohydrate Diets: Biological and Psychological Mechanisms

The proposed clinical effectiveness of LC or ketogenic diets for weight loss is based on the carbohydrate-insulin model proposed by Ludwig et al⁶⁸^,⁶⁹ in 2002. This model postulates that a diet high in carbohydrates is associated with chronic hyperinsulinemia and cellular insulin resistance from excess serum glucose, therefore leading to excess weight gain and hyperphagia. In contrast, a state of ketosis that may be induced by a certain degree of carbohydrate (or calorie) restriction, depending on the individual,⁷⁰ involves ketone bodies as the main energy substrates. Ketone bodies are made during lipolysis, which takes place in the hepatic mitochondria, by transforming free fatty acids, or ethanol, into acetoacetate and β-hydroxybutyrate. Ketolysis subsequently occurs in the mitochondria of extrahepatic tissues, such as the heart, brain, and muscles, to convert ketones into energy.²⁰

Numerous benefits seem to arise from the state of ketosis. For example, ketosis typically leads to a transient and small increase in resting energy expenditure (REE) due to the stimulation of fat oxidation, gluconeogenesis, and metabolic adaptations in the brain (ie, switching from glucose to ketone energy sources), which is not observed with an LF diet.⁷¹ However, the included studies⁴⁴^,⁵⁰^,⁵⁴^,⁵⁷ assessing REE in our review either did not report it after the intervention or showed no difference during weight loss compared with other diets. Importantly, a ketogenic diet is often higher in dietary protein, which elevates the thermic food effect and tends to promote satiety.⁷² Among the interventions with unlimited protein intake, Kirk et al⁴⁷ reported a higher protein intake in the LC group compared with the restricted-glycemic-load group. In their study, Demol et al⁵² limited the protein intake to 20% of the daily energy intake in both the isocaloric LC/HF and high-carbohydrate/LF groups and observed the same effects on the anthropometric and biochemical parameters that followed. Moreover, a state of ketosis induced by LC diets has been clinically shown to reduce hunger,¹⁹ inflammation, oxidative stress, and serum glucose and insulin concentrations, and stimulate the formation and regeneration of mitochondria and autophagy in adults.¹³^,²⁰^,²¹ An LC diet (15% of carbohydrates) intervention in children with Prader-Willi syndrome induced an increase in glucagon-like peptide 1 (GLP-1) and a reduction in the ratio of ghrelin to GLP-1, suggesting a reduction in appetite.⁷³ However, more studies are needed to make conclusions on the impact of an LC diet on appetite.

A ketogenic diet may also have potential positive effects on obesity-induced cognitive damage and mood in adults.¹³ Several psychological disorders, such as anxiety disorders and depression, are characterized by neurotransmitter metabolism impairments with, notably, reduced inhibitory γ-aminobutyric acid (GABA) neurotransmission. Due to the decrease in the glucose and glycolysis pathway in the brain, the central nervous system energy supplier switches from glucose to ketone bodies, enhancing the synthesis and transmission of GABA while decreasing aspartic acid concentration and the excitability of neurons.¹³ However, based on 2 systematic reviews, the short- and long-term psychosocial improvements in obese adults following either an LF or an LC weight-loss plan appear to be independent of the macronutrient composition of the diet⁶² and no significant associations have been reported between an LC ketogenic diet and the risk of depression and anxiety in adults.⁷⁴ A randomized controlled trial reported less anxiety and mood problems as well as an improvement in cognitive function during a ketogenic diet compared with a standard diet in children with epilepsy.⁷⁵ However, a systematic review from 2022 evaluating the effects of a ketogenic diet in children and adults with pharmaco-resistant epilepsy on cognitive function reported conflicting results.⁷⁶

Beyond the heterogeneity in the degree of carbohydrate restriction, biological variability within a population, related to genes, perinatal factors, health status, or other exposures, may affect how a specific individual responds to LC diets.⁶⁹ For example, individuals with a genetic disposition for a high insulin response to carbohydrates may stand to benefit the most from an LC diet, whereas others with a predisposition to high cholesterol may better respond to an LF diet. Six studies reported a decrease in insulin after an LC diet⁴⁷^,⁴⁸^,⁵⁰^,⁵²^,⁵⁸^,⁵⁹ associated with a decreased in HOMA-IR⁴⁸^,⁵⁰^,⁵² but with a higher decrease after an LC diet compared with a high-carbohydrate, CR, or low-glycemic-index diet.⁴⁷^,⁵² However, further studies comparing individuals based on the presence of relevant polymorphisms are needed to confirm this observation. Interestingly, the only included study with a low-glycemic-diet group⁴⁷ without energy restriction reported no additional benefit in weight loss and improvements in metabolic parameters over an LC diet without restriction or CR alone, suggesting the potential importance of insulin responses on weight and metabolism.

Adverse and Long-term Effects of LC Diets

While short-term LC diet interventions (ie, 2 to 6 months) seem to be effective for the management of pediatric obesity, their long-term safety remains controversial. Most studies in this review lasted less than 6 months and did not include a follow-up; thus, long-term effects and implications remain difficult to determine. While short-term effects of LC diets on weight management and cardiometabolic markers seem effective, medium- and long-term effects need to be better characterized.

For example, an LC diet is associated with a reduction in intake of foods rich in specific micronutrients, such as fiber, the consequences of which may not manifest in shorter term trials.⁷⁷ Therefore, carbohydrate restriction may make it difficult to reach the daily nutritional requirements of fiber and other micronutrients needed for proper growth and health.⁷⁷ Relatedly, the gut microbiota and its diversity, another important factor involved in overall health, which is altered in obesity,⁷⁸ may be affected by such dietary changes via modification of the substrate types available in the diet.¹² In adults, several studies have investigated the effect of a ketogenic diet on the gut microbiota, with mixed results.⁷⁹ However, no study has yet evaluated the effect of LC diets on the gut microbiota of youth with obesity during weight loss. Despite the report of numerous benefits of a gut microbiota–mediated ketogenic effect in a growing number of disease states, Tagliabue et al⁸⁰ reported potential gut dysbiosis in a cohort of children and adults subjected to a ketogenic diet for 3 months. An LC and HF diet seems to be associated with a lower microbiota diversity, primarily due to the reduction in undigested carbohydrate intake, the main energy source of the microbiome.⁸¹ Consequently, treatment with prebiotics or probiotics could be relevant during the short- or long-term ketogenic therapy to reduce impacts on the gut microbiota and maintain intestinal homeostasis.⁸⁰ More follow-up studies are required to monitor the longer-term changes in gut microbiota profiles during LC diets, and how they associate with other pertinent metabolic outcomes.⁸²

Finally, the short- and long-term adherence and barriers to LC diets need to be more closely examined with both qualitative and quantitative studies. Felix et al⁴⁵ reported on the challenges for families to implement an LC diet, due to the necessity to carefully plan all meals, increased financial costs, and the acceptance of peers. However, Pauley et al⁴³ reported a higher completion rate with the LC diet with children under 12 years old and in girls compared with adolescents and boys, suggesting an age- and gender-specific appeal of an LC diet. While the completion rate was higher for the LC group compared with the LF group in the study of Ibarra-Reynoso et al,⁸³ the opposite trend was reported in the study of Kirk et al⁴⁷ with CR and low-glycemic-load groups. Furthermore, while Bailes et al⁵⁵ allowed the participants to choose their diet, only 10 out of 37 participants chose the LC diet. In 1 study with adults, the initial adherence to a ketogenic diet was higher than with an LF diet, but the difference did not persist beyond 5 to 6 months of intervention during the maintenance phase.⁸⁴ Therefore, some of the conflicting results reported in the literature may be attributable to discrepancies in diet adherence rather than elevated benefits of a particular diet per se.

Of clinical interest, few studies reported adverse outcomes following an LC diet. Demol et al⁵² indicated some side effects, such as headache, gastrointestinal discomfort, and bad mood, but occurrences were not significantly different between the LC, the LF, and the LC/LF groups. In the 12-week intervention by Sondike et al,⁵⁶ some participants complained about constipation or diarrhea (3 of 16) and headache (2 of 16) in the LC group only, while restricting their carbohydrate intake to 20 g per day. A high level of ketosis may also induce hypoglycemia, lactic acidosis, and hyperammonemia, causing nausea, vomiting, stomach pain, or flu-like symptoms, and may predispose to kidney stone formation.¹⁵^,²² However, overall, following an LC diet from 2 to 6 months does not seem to induce significant side effects in children and adolescents with obesity, but further studies are needed to provide more a more detailed characterization of potential adverse effects based on diet duration.

Limitations of Evidence and Future Directions

One of the most prominent challenges in this area is achieving a consensus as to what constitutes an LC diet. As illustrated by the high heterogeneity demonstrated in the present review, no official definition has been currently established concerning what constitutes an LC diet. Among eligible studies, a wide range of carbohydrate restriction was observed, ranging from less than 10%⁴⁵ per day to 50%⁸³ of the total caloric intake per day (not included), and was rarely justified in a scientific manner. The high heterogeneity in the degree of carbohydrate restriction may be related to other critical differences in dietary approaches that influenced the outcome of meta-analyses, such as protein content. Facing a lack of consensus, our eligibility criteria were limited to an upper limit of 40% of carbohydrates per day according to the PNNS,²⁷ with a view of creating a broader scope from which to conduct the review. However, a limitation of this approach is a lack of certainty concerning the putative mechanism underpinning the benefits of carbohydrate restriction specifically—namely, ketogenesis. Thus, salient aspects to address may include the need for simultaneous energy restriction, protein content, degree of carbohydrate restriction, and personalization based on cultural background.

Levels of serum ketone bodies could be used as a criterion for LC diets, but there is likely to be individual variability in the level of carbohydrate restriction needed to elicit a threshold of ketogenesis. The detection of ketosis, especially in the serum as the gold standard, is rarely evaluated due to logistical challenges, as was observed in the present review. Among the 19 included studies, only 9 assessed levels of ketone bodies,^45–49^,⁵²^,^56–58^,⁶⁰ primarily through urine samples, with only 1 study measuring β-hydroxybutyrate in the blood. Although the most common, less invasive techniques are detection through urine and breath, such approaches may often lead to false-negative results as they are limited to the detection of acetoacetate and acetone, but not β-hydroxybutyrate, the predominant ketone body produced in humans.²⁰ Therefore, future studies ought to consider inclusion of blood concentrations of all relevant ketone bodies to provide a comprehensive view of total ketone production, and test for associations with key outcomes. Altogether, a lack of standardization toward measurement of ketones may have contributed to the substantial heterogeneity observed in the present review. Importantly, without such an assessment, it can only be assumed that the observed changes are attributable to the putative metabolic adaptation underpinning the rationale for an LC diet (ie, ketosis). Indeed, it cannot be ruled out that other simultaneous dietary changes (eg, less sugar, less processed foods, more protein, more fruits and vegetables, less energy intake, reduced snacking) could be underlying the observed weight loss during LC diet trials, in full or in part.

Since very few included studies reported adherence, specific attention should be paid to evaluate the adherence and acceptability of LC diets for children and families. The evaluation of the acceptability of this dietary approach in different cultural contexts might be of interest as most of the studies included in the present review were conducted in the United States. This may be an interesting avenue for mixed-methods research to identify facilitators and barriers to dietary adherence encompassing psychosocial factors. Relatedly, individual variation may be explored further in order to identify conditions and characteristics that promote adherence to carbohydrate restriction over other conventional approaches and vice versa (eg, sex differences).

Additional parameters indicative of diet efficacy and sustainability may deserve attention in future studies. While most studies in this review assessed weight and BMI change during the intervention, the measurement of waist circumference (n = 4) and body composition (n = 10) was less common. Among the studies assessing body composition, changes in fat mass were primarily examined, with changes in fat-free mass seldomly reported. The preservation of lean mass, such as skeletal muscle and bone density, represent important indicators of overall health, and may contribute to more sustainable weight loss.⁸⁵^,⁸⁶ Therefore, it may be of interest to investigate qualitatively the components of weight loss during different dietary interventions (ie, fat mass to fat-free mass ratio).

In the present review, specific attention was paid to the evolution of lipid (eg, TG, total cholesterol, HDL, and LDL) and, less frequently, hormonal (eg, insulin, leptin, adiponectin) profiles. However, others parameters related to metabolic health should be considered in future studies, such as glucose concentrations and other hormones involved in appetite regulation⁸⁷ (eg, ghrelin, cholecystokinin, GLP-1, or polypeptide YY). It has been shown that LC diets may reduce appetite,¹⁹^,⁷² but the lack of pertinent data from this review does provide any corroboration on this point. Thyroid hormones⁸⁸ (eg, thyrotropin-releasing hormone, free T3 and T4) and steroid hormones⁸⁹ (eg, glucocorticoids, androgens, testosterone, estrogen), based on their central role in many bodily functions including basal metabolic rate and growth, could be critical in characterizing a comprehensive response to LC diets. Indeed, previous studies have reported an improvement in the androgen profile,⁹⁰ but no modification of ghrelin secretion,⁹¹ which is known to be lower in youth with obesity, after an LF diet intervention. Therefore, it may be of interest to compare such observations with those after an LC diet. In addition, a state of ketosis appears to induce a greater beneficial effect on GLP-1 in females compared with males, which may exemplify a potential gender-dependent effect of LC diets, and should be investigated in youth as well.⁹² Finally, as low-grade inflammation is associated with pediatric obesity, biomarkers of inflammation (eg, C-reactive protein, plasma viscosity, and erythrocyte sedimentation rate) could also be a relevant outcome to test.⁹³

Another critical factor that may be involved in demonstrable metabolic changes is engagement in physical activity. In the present review, most studies provided general recommendations to engage in regular physical activity but did not assess adherence during the intervention. Still other studies, although in the minority, utilized a multidisciplinary approach by also including a supervised exercise program for the duration of the intervention. Such differences clearly represent a prominent bias within the results related to weight loss and cardiometabolic parameters, which can be influenced by exercise independently.⁹⁴ Therefore, it is difficult to fully attribute the results of these studies to the LC dietary intervention alone without recorded physical activity. It may be clinically useful to explore the synergistic effects of LC diets in combination with physical activity relative to traditional multidisciplinary approaches, with particular emphasis on preservation of lean mass. The main study limitations are summarized in Table 6.

Table 6.

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Main Limitations of the Current Research and Directions for the Future

Limitations of the current studies	Directions for future research
No official definition has been currently established concerning what constitutes an LC diet. However, the challenge lies in the lack of certainty concerning the putative mechanism and the degree of carbohydrate restriction needed to induce the benefits of carbohydrate restriction specifically, namely, ketogenesis.	Achieving a consensus as to what constitutes an LC diet, which will help facilitate standardization of methods across labs and clinicians interested in implementing this approach for obesity management.
High heterogeneity in the intervention methodologies	Standardize simultaneously degree of energy restriction (if applicable), protein content, degree of carbohydrate restriction, and personalization based on cultural background Evaluate individual variation in responses to LC diets to identify conditions and characteristics promoting favorable responses to carbohydrate restriction over other conventional approaches and vice versa (eg, sex differences)
Lack of diet adherence assessment and recipes/meal planning	Provide meal or recipes plan and assess the diet adherence through food diaries
Detection of ketosis, especially in the serum as the gold standard, which is rarely evaluated. Studies may rely on a single assessment of ketone bodies over all the intervention.	More meticulous examination of ketone bodies production using reliable methodology as ketone bodies (β-hydroxybutyrate, acetoacetate, acetone assessment in the serum) Evaluation of ketosis at least once per day
Physical activity assessment rarely monitored	Assess physical activity level, which may influence metabolism and all the anthropometric and biochemical parameters evaluated Explore synergistic effects of LC diets in combination with physical activity relative to traditional multidisciplinary approaches, with particular emphasis on preservation of lean mass
Most of the studies conducted in the United States	Acceptability and efficacy of this dietary approach in different cultural contexts might be of interest.
Lack of waist circumference and body-composition evaluation, especially of fat-free mass and bone density	Investigate qualitatively the components of weight loss during different dietary interventions (ie, fat mass to fat-free mass ratio) and bone density
Lack of biochemical evaluation	Assess the effect of such diets on others biochemical parameters, such as: Glucose concentrations, insulin, leptin, adiponectin Other hormones involved in appetite regulation (eg, ghrelin, cholecystokinin, glucagon-like peptide-1 or polypeptide YY) Hormones presenting a central role in many bodily functions including basal metabolic rate and growth thyroid (eg, thyrotropin-releasing hormone, free T3 and T4) and steroid hormones (eg, glucocorticoids, androgens, testosterone, estrogen) Biomarkers of inflammation (eg, C-reactive protein, plasma viscosity, and erythrocyte sedimentation rate) as low-grade inflammation is associated with pediatric obesity

Limitations of the current studies	Directions for future research
No official definition has been currently established concerning what constitutes an LC diet. However, the challenge lies in the lack of certainty concerning the putative mechanism and the degree of carbohydrate restriction needed to induce the benefits of carbohydrate restriction specifically, namely, ketogenesis.	Achieving a consensus as to what constitutes an LC diet, which will help facilitate standardization of methods across labs and clinicians interested in implementing this approach for obesity management.
High heterogeneity in the intervention methodologies	Standardize simultaneously degree of energy restriction (if applicable), protein content, degree of carbohydrate restriction, and personalization based on cultural background Evaluate individual variation in responses to LC diets to identify conditions and characteristics promoting favorable responses to carbohydrate restriction over other conventional approaches and vice versa (eg, sex differences)
Lack of diet adherence assessment and recipes/meal planning	Provide meal or recipes plan and assess the diet adherence through food diaries
Detection of ketosis, especially in the serum as the gold standard, which is rarely evaluated. Studies may rely on a single assessment of ketone bodies over all the intervention.	More meticulous examination of ketone bodies production using reliable methodology as ketone bodies (β-hydroxybutyrate, acetoacetate, acetone assessment in the serum) Evaluation of ketosis at least once per day
Physical activity assessment rarely monitored	Assess physical activity level, which may influence metabolism and all the anthropometric and biochemical parameters evaluated Explore synergistic effects of LC diets in combination with physical activity relative to traditional multidisciplinary approaches, with particular emphasis on preservation of lean mass
Most of the studies conducted in the United States	Acceptability and efficacy of this dietary approach in different cultural contexts might be of interest.
Lack of waist circumference and body-composition evaluation, especially of fat-free mass and bone density	Investigate qualitatively the components of weight loss during different dietary interventions (ie, fat mass to fat-free mass ratio) and bone density
Lack of biochemical evaluation	Assess the effect of such diets on others biochemical parameters, such as: Glucose concentrations, insulin, leptin, adiponectin Other hormones involved in appetite regulation (eg, ghrelin, cholecystokinin, glucagon-like peptide-1 or polypeptide YY) Hormones presenting a central role in many bodily functions including basal metabolic rate and growth thyroid (eg, thyrotropin-releasing hormone, free T3 and T4) and steroid hormones (eg, glucocorticoids, androgens, testosterone, estrogen) Biomarkers of inflammation (eg, C-reactive protein, plasma viscosity, and erythrocyte sedimentation rate) as low-grade inflammation is associated with pediatric obesity

Abbreviation: LC, low-carbohydrate.

Table 6.

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Main Limitations of the Current Research and Directions for the Future

Limitations of the current studies	Directions for future research
No official definition has been currently established concerning what constitutes an LC diet. However, the challenge lies in the lack of certainty concerning the putative mechanism and the degree of carbohydrate restriction needed to induce the benefits of carbohydrate restriction specifically, namely, ketogenesis.	Achieving a consensus as to what constitutes an LC diet, which will help facilitate standardization of methods across labs and clinicians interested in implementing this approach for obesity management.
High heterogeneity in the intervention methodologies	Standardize simultaneously degree of energy restriction (if applicable), protein content, degree of carbohydrate restriction, and personalization based on cultural background Evaluate individual variation in responses to LC diets to identify conditions and characteristics promoting favorable responses to carbohydrate restriction over other conventional approaches and vice versa (eg, sex differences)
Lack of diet adherence assessment and recipes/meal planning	Provide meal or recipes plan and assess the diet adherence through food diaries
Detection of ketosis, especially in the serum as the gold standard, which is rarely evaluated. Studies may rely on a single assessment of ketone bodies over all the intervention.	More meticulous examination of ketone bodies production using reliable methodology as ketone bodies (β-hydroxybutyrate, acetoacetate, acetone assessment in the serum) Evaluation of ketosis at least once per day
Physical activity assessment rarely monitored	Assess physical activity level, which may influence metabolism and all the anthropometric and biochemical parameters evaluated Explore synergistic effects of LC diets in combination with physical activity relative to traditional multidisciplinary approaches, with particular emphasis on preservation of lean mass
Most of the studies conducted in the United States	Acceptability and efficacy of this dietary approach in different cultural contexts might be of interest.
Lack of waist circumference and body-composition evaluation, especially of fat-free mass and bone density	Investigate qualitatively the components of weight loss during different dietary interventions (ie, fat mass to fat-free mass ratio) and bone density
Lack of biochemical evaluation	Assess the effect of such diets on others biochemical parameters, such as: Glucose concentrations, insulin, leptin, adiponectin Other hormones involved in appetite regulation (eg, ghrelin, cholecystokinin, glucagon-like peptide-1 or polypeptide YY) Hormones presenting a central role in many bodily functions including basal metabolic rate and growth thyroid (eg, thyrotropin-releasing hormone, free T3 and T4) and steroid hormones (eg, glucocorticoids, androgens, testosterone, estrogen) Biomarkers of inflammation (eg, C-reactive protein, plasma viscosity, and erythrocyte sedimentation rate) as low-grade inflammation is associated with pediatric obesity

Limitations of the current studies	Directions for future research
No official definition has been currently established concerning what constitutes an LC diet. However, the challenge lies in the lack of certainty concerning the putative mechanism and the degree of carbohydrate restriction needed to induce the benefits of carbohydrate restriction specifically, namely, ketogenesis.	Achieving a consensus as to what constitutes an LC diet, which will help facilitate standardization of methods across labs and clinicians interested in implementing this approach for obesity management.
High heterogeneity in the intervention methodologies	Standardize simultaneously degree of energy restriction (if applicable), protein content, degree of carbohydrate restriction, and personalization based on cultural background Evaluate individual variation in responses to LC diets to identify conditions and characteristics promoting favorable responses to carbohydrate restriction over other conventional approaches and vice versa (eg, sex differences)
Lack of diet adherence assessment and recipes/meal planning	Provide meal or recipes plan and assess the diet adherence through food diaries
Detection of ketosis, especially in the serum as the gold standard, which is rarely evaluated. Studies may rely on a single assessment of ketone bodies over all the intervention.	More meticulous examination of ketone bodies production using reliable methodology as ketone bodies (β-hydroxybutyrate, acetoacetate, acetone assessment in the serum) Evaluation of ketosis at least once per day
Physical activity assessment rarely monitored	Assess physical activity level, which may influence metabolism and all the anthropometric and biochemical parameters evaluated Explore synergistic effects of LC diets in combination with physical activity relative to traditional multidisciplinary approaches, with particular emphasis on preservation of lean mass
Most of the studies conducted in the United States	Acceptability and efficacy of this dietary approach in different cultural contexts might be of interest.
Lack of waist circumference and body-composition evaluation, especially of fat-free mass and bone density	Investigate qualitatively the components of weight loss during different dietary interventions (ie, fat mass to fat-free mass ratio) and bone density
Lack of biochemical evaluation	Assess the effect of such diets on others biochemical parameters, such as: Glucose concentrations, insulin, leptin, adiponectin Other hormones involved in appetite regulation (eg, ghrelin, cholecystokinin, glucagon-like peptide-1 or polypeptide YY) Hormones presenting a central role in many bodily functions including basal metabolic rate and growth thyroid (eg, thyrotropin-releasing hormone, free T3 and T4) and steroid hormones (eg, glucocorticoids, androgens, testosterone, estrogen) Biomarkers of inflammation (eg, C-reactive protein, plasma viscosity, and erythrocyte sedimentation rate) as low-grade inflammation is associated with pediatric obesity

Abbreviation: LC, low-carbohydrate.

Implications for Clinical Practice and Policy

Low-carbohydrate diets may represent a viable short-term alternative when young patients with obesity do not respond to conventional dietary and lifestyle changes, as described and proposed in the Staged Transitional Eating Plan.⁹⁵ Based on our results, an LC diet with less than 35% of total caloric intake from carbohydrates (<175 g/d) for 2 to 6 months could be efficacious in improving anthropometric, lipid, and metabolic parameters in children and adolescents with obesity, even without CR, but interventions should be conducted under the supervision of a medical team due to the potential for adverse events associated with the initial transition to ketosis—in particular, water and electrolyte loss—with an emphasis on monitoring serum ketones. The degree of carbohydrate restriction may need to be adjusted under this upper threshold in accordance with child acceptance, presentation of adverse events, and level of serum ketone bodies present. No strong evidence supports any differences in efficacy or adherence based on age or sex, but additional research is needed to explore this. Importantly, the implementation of such a restrictive diet may introduce psychosocial burdens on children and their families, including financial cost and social exclusion; thus, support from peers, families, and/or guardians is essential.⁴⁵ Low-carbohydrate diet adherence, poorly investigated in youth, does not seem to be high and may decrease with time, but may be greater than with CR diets over the long term. Clinicians will likely need to account for individual variability in dietary acceptance and efficacy, thus, for example, adequately profiling patients as suitable candidates for LC diets based on their responses to certain foods, their cardiometabolic profile (eg, insulin resistance), and psychological vulnerabilities (ie, eating disorders).

Pediatricians and healthcare teams should carefully plan ketogenic meals with families. Carbohydrate reduction may begin by a complete elimination of sugary beverages and a decrease in carbohydrates from ultra-processed food sources while increasing healthy fat sources, such as nuts, seeds, vegetables, and whole low-sugar fruits like berries. In addition, the production of ketones should be checked at least every week in the serum and every day through urine ketone sticks, at least initially, in order to confirm metabolic adaptation associated with LC diets. When possible and for LC interventions of more than 6 months, serum concentrations of LDL should be monitored, especially small LDL particles, which are associated with increased cardiovascular risk as opposed to large LDL particles.⁶⁷ If the LC diet does not include enough nuts, seeds, and low-carbohydrate vegetables and fruits, clinicians may consider supplementing with fiber to maintain gastrointestinal health. An additional treatment with prebiotics or probiotics in some cases could be relevant during the short- or long-term ketogenic therapy to reduce the impact of a low-fiber diet on the gut microbiota to maintain intestinal homeostasis.⁸⁰ Finally, it could be interesting to investigate how the addition of physical activity affects the efficacy and adherence to LC diets relative to other interventions to enhance outcomes related to anthropometric, metabolic, and psychological parameters. Nevertheless, particular care should be taken when re-introducing carbohydrates to favor carbohydrate sources with a low glycemic index, ideally from natural sources (ie, certain fruits and vegetables).

Importantly, as LC diets without CR were at least as effective as CR diets, metabolic changes and weight loss can be achieved without the negative consequences associated with CR diets, such as loss of lean mass and increased hunger. However, in regard to the potential drawbacks associated with LC diets, it may also be interesting to explore other strategies without carbohydrate restriction that may lead to increased short-term ketone production, such as fasting, time-restricted feeding, or intense physical exercise.⁸² It is important to note that these recommendations apply to children with obesity, but without juvenile (type 1) diabetes, a minority demographic that requires more specific and meticulously monitored dietary regimens. Furthermore, with regard to the small number of studies eligible for review, firm clinical recommendations cannot be made from such a small number of studies with high methodological heterogeneity.

CONCLUSION

In response to the obesity epidemic affecting pediatric populations of all backgrounds, numerous dietary strategies have been tested to elicit beneficial and enduring metabolic changes, including weight loss. While restriction of calorie and/or fat intake has long been accepted as the standard dietary intervention for weight loss, alternative approaches, such as carbohydrate restriction, have gained in popularity of late due to prevailing limitations of prolonged CR, such as loss of lean mass and poor adherence. Overall, the present systematic review found LC diets, with or without CR, to be effective for weight loss and improvements in metabolic biomarkers, but meta-analyses were characterized by substantial between-study heterogeneity in intervention design and execution. Future studies may consider direct comparisons of LC interventions with varying degrees of carbohydrate restriction and caloric assessment to determine if the beneficial effects of LC diets are primarily due to the decrease in energy intake per se or unique metabolic adaptations induced by carbohydrate restriction. In parallel, they should also better monitor daily physical activity, serum ketone bodies using more valid and reliable methods, and daily food intake in order to ensure diet adherence and ketosis. The efficacy of LC diets to modify supplementary outcomes, such as adrenal hormones, thyroid function, inflammation, appetite, metabolic rate, and body composition (ie, fat and fat-free mass), should also be further explored. Especially within the context of younger individuals, a specific focus should be on short- and long-term safety and prevention of the development of eating disorders. An LC diet of at least 2 months and with carbohydrate restriction of no more than 35% of daily caloric intake, under the supervision of a medical team, may be a relatively effective strategy in the short-term management of pediatric obesity to quickly improve anthropometric and biological parameters, especially for patients who do not respond to conventional dietary and lifestyle changes. However, implementation strategies need to be considered, including proper meal planning, regular ketosis assessment, and coordination with families and peers. The long-term efficacy of LC diets, and ketogenic states, is currently not well characterized, thus requiring further investigation with more adequately powered controlled trials before firm conclusions can be made.

Author Contributions

E.F. wrote the article and contributed to the work’s conception, design, and data collection, interpretation, and analysis. H.M. conducted the meta-analysis, contributed to the data interpretation and analysis, and participated in the writing and critical revision of the article. D.T. and Z.S.A. contributed to the work’s conception and design and in the critical revision of the article.

Supplementary Material

Supplementary Material is available at Nutrition Reviews online.

Funding

The authors declare no specific funding or sponsorship for this work.

Conflicts of Interest

None declared.

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Article Contents

Low-Carbohydrate Diets for the Management of Pediatric Obesity: A Systematic Review and Meta-analysis

Abstract

INTRODUCTION

METHODS

Search Strategy and Screening Process

Inclusion and Exclusion Criteria

Data Extraction, Synthesis, and Meta-analysis Procedure

Quality Assessment

Ethical Considerations

RESULTS

Quality Assessment

Participant Characteristics

Study Methodology Characteristics

Dietary Intervention Approaches

Efficacy Endpoints and Assessment Methods

Study Results

Anthropometrics

Low-carbohydrate arms only

Low-carbohydrate versus control diets

Lipid and Metabolic Profiles

Low-carbohydrate arms only

Low-carbohydrate versus control diets

Meta-analysis Results

Phase 1: Mean Change Within LC Arms

Phase 2: Mean Differences Between LC and Control Diets

DISCUSSION

Summary of Evidence

Low-Carbohydrate Diets and Weight Loss

Low-Carbohydrate Diets and Metabolic Health

Low-Carbohydrate Diets: Biological and Psychological Mechanisms

Adverse and Long-term Effects of LC Diets

Limitations of Evidence and Future Directions

Implications for Clinical Practice and Policy

CONCLUSION

Author Contributions

Supplementary Material

Funding

Conflicts of Interest

REFERENCES

Supplementary data

Citations

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