Journal Pre-proof

Effect of early time-restricted feeding on the metabolic profile of adults with excess
weight: a systematic review with meta-analysis

Isabele Rejane de Oliveira Maranhão Pureza, Mateus de Lima Macena, André

Eduardo da Silva Junior, Dafiny Rodrigues Silva Praxedes, Laís Gomes Lessa
Vasconcelos, Nassib Bezerra Bueno
PII: S0261-5614(20)30574-4
DOI: https://doi.org/10.1016/j.clnu.2020.10.031
Reference: YCLNU 4528

To appear in: Clinical Nutrition

Received Date: 20 August 2020

Revised Date: 12 October 2020
Accepted Date: 17 October 2020

Please cite this article as: Rejane de Oliveira Maranhão Pureza I, de Lima Macena M, Eduardo da Silva
Junior A, Silva Praxedes DR, Lessa Vasconcelos LG, Bueno NB, Effect of early time-restricted feeding
on the metabolic profile of adults with excess weight: a systematic review with meta-analysis, Clinical
Nutrition, https://doi.org/10.1016/j.clnu.2020.10.031.

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© 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
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Effect of early time-restricted feeding on the metabolic profile of adults

with excess weight: a systematic review with meta-analysis

AUTHORS: Isabele Rejane de Oliveira Maranhão Purezab, Mateus de Lima Macenaa,

André Eduardo da Silva Juniora, Dafiny Rodrigues Silva Praxedesa, Laís Gomes Lessa

Vasconcelosa, Nassib Bezerra Buenoa*.

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AFILLIATION:

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a
Faculdade de Nutrição (FANUT) - Universidade Federal de Alagoas (UFAL), Campus
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AC Simões, 57072-900, Cidade Universitária, Maceió, Alagoas
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Programa de Pós-Graduação em Nutrição, Universidade Federal de São Paulo, São

Paulo, Brasil
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* Corresponding author: Faculdade de Nutrição, Universidade Federal de Alagoas,

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Campus AC Simões, 57072-900, Cidade Universitária, Maceió, Alagoas, Brazil.

E-mail address: nassib.bueno@fanut.ufal.br

ABBREVIATIONS: BMI: Body mass index; CRP: C-reactive protein; eTRF: TRF:

early time-restricted feeding; dTRF: delayed time-restricted feeding; GLP-1: glucagon-

like peptide; HDL-C: HDL-cholesterol; LDL-C: LDL cholesterol; IL-6: Interleukin-6;

PYY: Peptide YY; RMR: resting metabolic rate; TRF: Time-restricted feeding; TAG:

triacylglycerol.
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ABSTRACT

Background & Aims: Time-restricted feeding (TRF) studies have been summarized in

previous systematic reviews, but these were not specific for individuals with excess

weight and studies involving early time-restricted feeding (eTRF). This meta-analysis

aimed to evaluate the effect of eTRF on the metabolic profile of adults with excess

weight.

Methods: Data were extracted from MEDLINE, CENTRAL, LILACS, Web of

Science, ClinicalTrials.gov, OpenGrey.eu, Greylit, and by manual search. Randomized

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controlled trials in which the participants were older than 18 years, with a body mass

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index greater than 25 kg/m² and that were allocated in an intervention with eTRF were
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included. The studies should have assessed any of the following outcomes from the
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metabolic profile: resting metabolic rate, triacylglycerol, total cholesterol, HDL-
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cholesterol, and LDL-cholesterol, fasting blood glucose, insulin, HOMA-IR, C-reactive

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protein, Interleukin-6, cortisol, leptin, Ghrelin, Peptide YY and glucagon-like peptide,

hemodynamic parameters, and appetite. The risk of bias was assessed using the
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Cochrane collaboration tool. Publication bias was examined with a funnel plot and
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Egger’s test. GRADE was used to assess the overall quality of evidence.

Results: Ten articles from nine randomized clinical trials, with 264 individuals, were

included in qualitative analysis and eight articles with 184 individuals were included in

the meta-analysis. There were significant effects on the fasting blood glucose (WMD: -

2.75; 95% CI [-4.59; -0.90] mg/dL; p < 0.01; I² = 88.7%; 7 studies) and HOMA-IR

(WMD: -0.50; 95% CI [-0.82; -0.19]; p <0.01; I² = 50.8%; 4 studies). The other

outcomes were not significant. Three studies showed a high risk of bias. Seven

outcomes were classified as very low quality and one as low quality. There was

evidence of publication bias for fasting blood glucose.

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Conclusions: Although the eTRF regimen seems to have a beneficial effect on the

fasting blood glucose and HOMA-IR of individuals with excess weight, the results of

this meta-analysis should be analyzed with caution due to the low-quality evidence.

Keywords: obesity; overweight; metabolism; intermittent fasting

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Introduction

In 2016, world data indicated that 39% of adults over 18 years old (39% of men

and 40% of women) had excess weight, and in general, about 13% of the adult

population (11% of men and 15% of women) had obesity [1]. The incidence of obesity

is ascending and although the causes are multifactorial, the nutritional imbalance is the

major contributor [2]. Considered an epidemic and, consequently, a public health

problem, obesity has negative impacts on the country's active economy because it is

directly associated with chronic diseases and non-communicable diseases, such as

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diabetes mellitus, systemic arterial hypertension, coronary artery disease, brain stroke,

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some types of cancer, obstructive sleep apnea and osteoarthritis. These situations
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generate early retirement due to disability and temporary absenteeism, especially due to
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cardiovascular diseases [3].
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Lifestyle interventions, including qualitative and quantitative dietary

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modifications, and increased exercise, have been the first line of therapy to combat

obesity and metabolic diseases. However, their success has been limited to a small
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percentage of individuals [4,5]. The fact that obesity reaches epidemic proportions
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worldwide demands new approaches [6]. Among the emerging strategies, intermittent

fasting seems to assist not only in the treatment of obesity but also of the metabolic

diseases associated with excess weight [7,8].

The regulation of the period of food intake, a type of intermittent fasting called

time-restricted feeding (TRF), consists of following the same routine of eating every

day, with a certain number of hours designated as the fasting window and the remaining

hours as the feeding window. This is the most commonly used method for daily energy

restriction in laboratory studies of rodents (limited daily feeding) [9]. The use of

strategies such as TRF, as well as other types of intermittent fasting or diets with low

energy content, can induce reflex effects on the circadian clock in several organs (liver,
 5

pancreas, cardiomyocytes, among others) [10,11,12]. As suggested by the early TRF

(eTRF) proposal, when the food intake period is aligned with the central circadian

“clock” it can cause changes in the regulation of the metabolism of lipids, proteins, and

carbohydrates [13].

In humans, there has been an increasing number of studies involving TRF in

general [14-30] which led, to our knowledge, to the development of four reviews on this

theme [31-34]. Lote-oke et al. [34] used a non-systematic method, which included

observational studies, randomized, and non-randomized clinical trials, with individuals

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with or without excess weight. Marianna et al. [33] performed a meta-analysis of

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randomized studies with TRF, with interventions longer than 4 weeks of duration, but
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the studies included individuals with normal weight. Although Rynders et al. [32] and
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Moon et al. [31] conducted a meta-analysis that included studies with excess weight
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individuals, they did not limit the interventions only to the eTRF regimen. Furthermore,
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Rynders et al. [32], included other intermittent fasting regimens, such as alternate-day

fasting, and compared it with continuous energy restriction. Furthermore, Moon et al.
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[31] included single-arm, non-randomized studies, which does not allow determining
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whether the effects found in the selected studies are specifically due to the TRF

intervention. Therefore, despite addressing the metabolic profile, these reviews, even

with meta-analyses, were not specific for individuals with excess weight and did not

standardize the inclusion of specific eTRF studies. Thus, the objective of the present

systematic review with meta-analysis is to evaluate the effect of eTRF on the metabolic

profile of adults with excess weight.

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Methods

Protocol and registration

This systematic review is reported according to the Preferred Reporting Items

for Systematic Reviews and MetaAnalyses (PRISMA) Statement [35]. The protocol was

previously published in the PROSPERO database (http://www.crd.york.

ac.uk/PROSPERO), under record number CRD42018109601

Eligibility Criteria

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Only randomized clinical trials that met the following criteria were included:

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study participants over 18 years of age, with a body mass index (BMI) greater than
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25kg/m² and who were assigned to an intervention with eTRF (that is, submitted to a
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daily regimen with a limited number of hours as a feeding window and a fasting
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window, usually of 12 to 21 hours a day, associated or not with energy restriction) and
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eating in alignment with circadian rhythms. This combined intervention was defined as

eTRF, a subtype of TRF in which dinner is eaten in the mid-afternoon [26]. Studies that
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presented interventions with characteristics of eTRF but did not specifically refer to the
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intervention as eTRF were also included.

There were no restrictions based on sex, race, or comorbidities. At a minimum,

studies should have assessed any of the following outcomes from the metabolic profile:

resting metabolic rate (RMR), triacylglycerol (TAG), total cholesterol, HDL-cholesterol

(HDL-C) and LDL-cholesterol (LDL-C), fasting blood glucose, insulin, HOMA-IR, C-

reactive protein (CRP), Interleukin-6 (IL-6), cortisol, leptin, Ghrelin, Peptide YY

(PYY), glucagon-like peptide (GLP-1), and appetite by visual analog scale (in mm).

The exclusion criteria involved studies with a concomitant pharmacological

intervention; individuals working in shifts and duplicate publications of the included

studies.
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Information sources

The following databases were searched until October 1, 2020: MEDLINE,

CENTRAL, LILACS, Web of Science, and ClinicalTrials.gov. Also, the following gray

literature databases were searched: OpenGrey.eu and Greylit. There was a manual

search of the reference list of the articles included and of the reviews found.

Search strategy

The search strategy included terms related to participants (individuals with

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excess weight), intervention (time-restricted feeding) and outcomes (metabolic profile -

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inflammatory markers and glycemic, lipidic, and hormonal profile, and appetite), as
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well as the Cochrane strategy terms for searching randomized clinical trials [36].
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The search was not restricted to specific years of publication or languages. The
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following example shows the specific keywords (or MeSH terms) used for the search at
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MEDLINE:

("time-restricted feeding" OR "time-restricted eating" OR "intermittent fasting" OR

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fasting[MeSH Terms]) AND (blood glucose OR appetite OR resting metabolic rate OR

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energy expenditure OR insulin OR leptin OR inflammatory markers OR hormones OR

hormones profile OR body weight OR body composition OR weight loss) AND

(randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab]

OR clinical trials as topic[mesh: noexp] OR randomly[tiab] OR trial[ti] OR

placebo[tiab]) NOT ((animals [mh]) NOT humans [mh]))

Data extraction

The titles and abstracts of the retrieved articles were independently assessed by

two researchers, who were not blind to the authors or the titles of the journals. Full-text

versions of potentially eligible articles have been retrieved for further evaluation. The
 8

extracted outcomes were the mean changes between baseline and final values (with the

associated dispersion measures) for: RMR (in kilocalories), TAG (mg/dL), total

cholesterol (mg/dL), HDL-C and LDL-C (mg/dL), fasting blood glucose (mg/dL),

insulin (mU/ml), HOMA-IR, inflammatory markers (CRP (in mg/L), IL-6 (pg/ml),

cortisol (μg/dL), leptin (ng/dL), Ghrelin (pg/ml), PYY (pg/ml) and GLP-1 (pmol/l), and

appetite by visual analog scale (in mm).

All necessary information was extracted from published articles, protocols, and

commentaries related to each study, and, in studies with more than two experimental

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groups, the most appropriate one was chosen, and any disagreements were resolved by

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consensus. Contact was made with the authors of the articles that lacked relevant data.
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When it was not possible to obtain adequate data, due to communication failure,
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imputations were made for the missing data [37]. In the study by Jamshed et al. [23],
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triacylglycerol data were extracted from graphical representations using the software
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GetData Graph Digitizer, version 2.2.0.20.

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Risk of bias assessment

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The risk of bias was independently assessed by two authors using the “Risk of

bias” tool, developed by Cochrane Collaboration for randomized controlled trials. Three

domains were included: Random sequence generation; Allocation concealment, and 3)

handling of missing data (intention-to-treat or per-protocol analysis) [38]. Grading of

Recommendations Assessment, Development, and Evaluation (GRADE) assessment

(www.gradeworkinggroup.org/) [39] was used to assess the overall quality of evidence.

Assessment of the overall quality was based on the following domains: risk of bias,

consistency of results across studies, directness, and precision of results, and the

likelihood of publication bias. GRADE assessments were conducted for all the
 9

outcomes included in the meta-analysis. Two independent researchers performed the

risk of bias and GRADE assessments.

Data analysis

Groups with eTRF and groups with skipping dinner were used as the

“intervention group”, as they correspond to a similar fasting period, with a feeding

window during the beginning of the day. The changes for each outcome were analyzed,

reported as the differences between the final and baseline mean values for each group.

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The effect size was calculated from the weighted mean difference (WMD) between

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these differences. The random-effects model of Dersimonian and Laird was used.
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Heterogeneity was measured using the I² statistic and Cochran's Q test. Analyses with I²
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values greater than 50% were explored using sensitivity analyses excluding one study at
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a time, to verify whether any study was responsible for heterogeneity. Subgroup
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analyses were performed considering the different regimens of weight management

(weight loss induction or weight maintenance) of the included studies. Publication bias
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was examined with a funnel plot and Egger’s test [40]. An alpha value equal to 5% was
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adopted for all analyses. The analyses were conducted with the aid of the metan

package of the Software Stata v 13.0 (StataCorp, College Station, TX, USA).
 10

Results

Search results

Of the 3699 unique records identified in the database search, 51 full-text

publications were retrieved for later evaluation. Of these, 41 were excluded after full-

text analysis, as they did not meet the inclusion criteria, and ten articles from nine

studies, involving 264 individuals were included in the qualitative analysis. In the

quantitative analysis, eight studies were included, involving 184 individuals, as shown

in the flowchart (Figure 1). Studies follow-up ranged from a minimum of 1 day and a

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maximum of 12 weeks.

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Characteristics of the included studies
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The articles by Ravussin et al. [24] and Jamshed et al. [23] are from the same
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study, but the former reported the fasting blood glucose, insulin, HOMA-IR, LDL-C,
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HDL-C, and TAG as outcomes, and the latter reported RMR, leptin levels, active
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ghrelin, PYY, GLP-1, and appetite as outcomes. Seven of the studies presented two

intervention groups [12, 17, 22-24, 26, 30], three studies [23, 24, 26] compared the 12-
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hour TRF regimen and the eTRF. Only one study [22] compared a later restriction of
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the feeding period, called delayed TRF (dTRF), with the eTRF. Cienfuegos et al. [14]

compared 4-h and 6-h TRF regimens versus the control group. Another study [41]

compared three interventions, being a group with usual dietary intake, a group with

skipping breakfast, and another group with skipping dinner. Kahleova et al. [30]

compared the effect of six versus two meals a day, including only breakfast and lunch.

Parr et al. [17] compared the effects of TRF versus extended feeding. The study

conducted by Singh et al [12] included individuals to ingest most of the daily calories as

a single daily meal either in the evening (4 weeks) or in the morning (4 weeks). The

characteristics of the included studies can be seen in Table 1.

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Risk of bias assessment

The risk of bias in the studies is shown in Table 2. The nine studies presented an

adequate random sequence generation; however, three studies [15, 22, 30] did not report

the method adopted for allocation concealment. Two studies [15, 41] did not report the

handling of its missing data, and two studies [23, 24, 26] were categorized as having a

high risk of bias due to the use of per-protocol analysis or to the dropouts rate >10%.

Qualitative analysis

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Regarding stress markers, Sutton et al. [26] and Jamshed et al. [23] found a

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decrease in cortisol levels in the intervention group compared to the control group,
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while Parr et al. [17] did not show differences between groups (Table 3). Sutton et al.
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[26] found decreased CRP levels and increased levels of IL-6 in the intervention group
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compared to the control group, while Cienfuegos et al. [14] did not find a significant
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effect on 8-isoprostane, TNF-alpha, and IL-6. Only three studies included [12, 14, 26]

analyzed hemodynamic parameters, in which it were observed decreases in systolic

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blood pressure levels in the studies conducted by Sutton et al. [26] and Singh et al [12].
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Only Sutton et al. [26] collected measures of arterial stiffness, but changes with eTRF

intervention were not observed.

Data analysis

Pooled data and subgroup analyses for fasting blood glucose, insulin, HOMA-

IR, and ghrelin values are shown in Figure 2 (a, b, c, d; respectively) and

triacylglycerol, total cholesterol, LDL-cholesterol, and HDL-cholesterol values are

shown in Figure 3 (a, b, c, d; respectively).

Fasting Blood Glucose

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Seven studies (167 individuals) analyzed fasting blood glucose as an outcome.

Individuals assigned to an eTRF intervention showed a significant reduction in fasting

blood glucose levels compared to the control group (WMD -2.75; 95% CI [-4.59; -0.90]

mg/dL; p < 0.01; I² = 88.7%, p < 0.01). Removing the study by Parr et al. [17] reversed

the heterogeneity and maintained the significant reduction (WMD -3.27; 95% CI [-4.11;

-2.41] mg/dL; p < 0.01; I² = 0%, p = 0.61). There was a similar result in both subgroups

according to weight management regimen (weight loss: WMD -3.76; 95% CI [-4.99; -

2.52] mg/dL; p < 0.01; I² = 0%, p = 0.39; 2 studies [22, 30]; and weight maintenance:

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WMD -2.09; 95% CI [-4.00; -0.19] mg/dL; p = 0.03; I² = 82.3%, p < 0.01; 5 studies [12,

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14, 17, 23, 26]). The funnel plot was asymmetric (Figure 4) and there was evidence of
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publication bias by the Egger’s test (p = 0.01).
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Insulin
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Six studies (145 individuals) were included. Individuals submitted to eTRF did

not show differences in insulin levels compared to the control group (WMD -1.54; 95%
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CI [-3.35; 0.26] mUI/L; p = 0.09; I² = 76.8%, p <0.01). Heterogeneity was not reversed
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with removal of any single study. The findings were similar in both subgroups

according to weight management regimen (weight loss: WMD -1.03; 95% CI [-3.39;

1.32] mUI/L; p = 0.39; I² = 84%, p = 0.01; 2 studies [22, 30]; and weight maintenance:

WMD -1.25; 95% CI [-4.94; 2.43] mUI/L; p = 0.50; I² = 77.2%, p = 0.01; 4 studies [14,

17, 23, 26]).

HOMA-IR

In four studies included, with 79 individuals, it was observed that those

designated for an intervention with eTRF achieved a decrease in the values of HOMA-

IR, compared to the control group (WMD -0.50; 95% CI [-0.82; -0.19]; p < 0.01; I² =
 13

50.8%, p = 0.10). In sensitivity analyses, a reversion in the heterogeneity without

changes in statistical significance was observed when removing the study by Jamshed et

al. [23] (WMD -0.35; 95% CI [-0.69; -0.02]; p = 0.03; I² = 15.1%, p = 0.30). The four

included studies applied a weight maintenance regimen.

Ghrelin

Three studies were included, with 38 individuals evaluated. There was no

difference in ghrelin levels between groups (WMD -18.45; 95% CI [-45.94; 9.03]

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pg/ml, p = 0.18; I² = 91.8%, p < 0.01). When removing the article by Ravussin et al.

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[24], the heterogeneity was reversed but the outcome remained without statistical
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significance (WMD -5.40; 95% CI [-16.41; 5.60] pg/ml, p = 0.33; I² = 0%, p =0.95).
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This result was also found in the subgroup analysis according to weight management
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(weight loss: WMD -5.0; 95% CI [-21.96; 11.96] pg/ml; p = 0.56; 1 study [22]; and
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weight maintenance: WMD -24.72; 95% CI [-61.27; 11.81] pg/ml; p = 0.18; I² = 94.2%,

p < 0.01; 2 studies [24, 26]).

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Triacylglycerol

Six studies were included, with 145 individuals evaluated. There was no

difference in triacylglycerol levels between groups (WMD 1.61; 95% CI [-7.82; 11.05]

mg/dL, p = 0.73; I² = 80.0%, p < 0.01). In sensitivity analyses, when removing the study

by Sutton et al. [26] the heterogeneity decreased but the outcome remained without

statistical significance (WMD -2.76; 95% CI [-8.64; 3.11]; p = 0.35; I² = 54.0%, p =

0.06). Results were similar in the subgroups according to weight management regimen

(weight loss: WMD 0.20; 95% CI [-18.01; 18.41] mg/dL; p = 0.98; I² = 85.3%, p <

0.01; 2 studies [22, 30]; and weight management: WMD 5.22; 95% CI [-11.67; 22.13]

mg/dL; p = 0.54; I² = 83.5%, p < 0.01; 4 studies [14, 17, 23, 26]).
 14

Total cholesterol

Three studies were included, with 77 individuals. There was no difference in

total cholesterol levels between groups (WMD 6.33; 95% CI [-3.45; 16.12] mg/dL, p =

0.20; I² = 82.6%, p < 0.01). In the subgroup analysis according to weight management,

only one study [30] composed the weight loss induction subgroup and it did not show

significant changes (WMD –0.77; 95% CI [-1.61; 0.07] mg/dL; p = 0.07). In the

subgroup with participants in weight maintenance [23, 26] there was a significant

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increase of the total cholesterol levels in the eTRF group compared to the control group

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(WMD 11.18; 95% CI [4.26; 18.11] mg/dL; p < 0.01; I² = 0%, p = 0.67).
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LDL cholesterol
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Four studies were included, with 116 individuals evaluated. There was no
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difference in LDL cholesterol levels between groups (WMD 0.37; 95% CI [-2.97; 3.72]

mg/dL, p = 0.82; I² = 73.8%, p < 0.01). In sensitivity analyses, when removing the study
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by Cienfuegos et al. [14] the heterogeneity was reversed but the outcome remained
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without statistical significance (WMD 2.65; 95% CI [-2.26; 7.57]; p = 0.29; I² = 39.1%,

p = 0.19). These results were also found in the subgroup analysis according to weight

management (weight loss: WMD 0.77; 95% CI [-0.70; 1.61] mg/dL; p = 0.07; 1 study

[30] and weight maintenance: WMD 1.91; 95% CI [-6.28; 10.10] mg/dL; p = 0.64; I² =

69.9%, p = 0.03; 3 studies [14, 23, 26]).

HDL cholesterol

Four studies were included, with 116 individuals evaluated. There was no

difference in HDL cholesterol levels between groups (WMD 0.52; 95% CI [-0.71; 0.59]

mg/dL, p = 0.85; I² = 69.4%, p = 0.02). Removing the study by Jamshed et al. [23] did
 15

not alter statistical significance, but reversed heterogeneity (WMD -0.15; 95% CI [-

0.35; 0.04] mg/dL; p = 0.13; I² = 13.3%, p = 0.31). Results were similar in the subgroup

analysis according to weight management (weight loss: WMD -0.50; 95% CI [-1.04;

0.04] mg/dL; p = 0.07; 1 study [30]; and weight maintenance: WMD 0.55; 95% CI [-

1.13; 2.24] mg/dL; p = 0.52; I² = 74%, p = 0.02; 3 studies [14, 23, 26]).

GRADE assessment

Results from the GRADE assessment are in Table 5. Among the eight outcomes

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analyzed, seven outcomes (fasting blood glucose, insulin, ghrelin, triacylglycerol, total

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cholesterol, HDL cholesterol, and LDL cholesterol) were classified as very low quality

and one (HOMA-IR) as low quality.

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Future Studies
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During the search on clinicaltrials.gov, 22 registries of clinical trials were

identified, with eTRF as an intervention in individuals with excess weight; these trials
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are ongoing or expected to be completed between 2019 and 2023. Among these studies,
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different outcomes are being analyzed: RMR (n = 5), lipid profile (n = 14), glycemic

profile (n = 20), stress markers (n = 7), appetite hormones (n = 5) and appetite by visual

analog scale (n = 4), as can be seen in Table 4.

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Discussion

The present review included ten articles from nine studies, with 264 individuals

in total. The meta-analysis, which included eight articles and 184 individuals, found a

significant decrease in the fasting blood glucose levels and HOMA-IR in the eTRF

group compared to the control group. However, no changes in insulin, ghrelin, and lipid

profile levels (triacylglycerol, total cholesterol, HDL-cholesterol, and LDL-cholesterol)

were observed. Regarding total cholesterol levels, a significant increase in the eTRF

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group compared to the control group was found in the subgroup of studies including

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only participants in weight maintenance regimens. Three studies showed a high risk of
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bias. Seven outcomes were classified as very low quality and one as low quality. There
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was evidence of publication bias in the outcome with more included studies, fasting
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blood glucose.
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Our results for the glycemic profile are following a meta-analysis published by

Marianna et al. [33], in which there were no differences in the insulin levels between
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groups, with a WMD of -0.34 mUI/mL, compared to our result of -1.54 mUI/mL. The
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fasting blood glucose findings are also similar, in which we found an effect of -2.75

mg/dL compared to an effect of -2.45 mg/dL reported by Marianna et al. [33], both with

statistical significance. Likewise, it was reported by Moon et al. [31] a significant

change of fasting blood glucose levels of -2.29 mg/dL in the subgroup analysis

composed by studies including participants with any metabolic abnormality.

Furthermore, we observed evidence of publication bias when analyzing the fasting

blood glucose outcome. This indicates that small studies with null findings were not

retrieved by our database searches, and hence, the significant findings in fasting blood

glucose levels must be seen with caution.

 17

Regarding HOMA-IR, we found a significant decrease of 0.50 and Marianna et

al. (2019) found a decrease of 0.05, without statistical significance. Nevertheless, both

effects may not be clinically important. It is worth mentioning that Marianna et al. [33]

included studies with individuals who practiced resistance exercises, who were pre-

diabetic, and who did not present excess weight. Also, the intervention with TRF was

not restricted to eTRF, which highlights the methodological differences between both

meta-analyses.

The impacts on the glucose metabolism of rodents under the TRF regimen are

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extensively discussed, but still controversial [42-44]. Human studies, mainly

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randomized clinical trials, are even scarcer, as can be seen from the number of studies
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included in this meta-analysis. Usually, periods of fasting or energy deficits alter the
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proportions of cellular levels of adenosine monophosphate (AMP) and adenosine
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triphosphate (ATP), this, in turn, activates the enzyme AMP-activated 5'protein kinase
na

(AMPK), which among others effects, promotes glucose uptake in muscle and alters

glycolysis and lipolysis rates [45]. Jamshed et al. [23] found lower glycemic and insulin
ur

levels in the morning, and greater expression in the AKT2 gene, which lead them to
Jo

formulate the hypothesis that, as the AKT2 protein participates in insulin signaling via

the enzyme phosphatidylinositol-3 kinase, insulin signaling at the beginning of the day

would be improved, corroborating with the effects presented by the eTRF. Such

mechanisms may be an answer to understand the favorable results for fasting blood

glucose and HOMA-IR found in the eTRF group in our meta-analysis.

As for ghrelin, the intervention adopted in the included studies did not affect its

serum levels, and, to our knowledge, no meta-analysis involving eTRF analyzed ghrelin

levels as an outcome. However, all included studies showed a decrease in ghrelin levels,

and the study by Ravussin et al. [24] showed the highest decrease, accompanied by a

deficit in the desire to eat on the visual scale. However, both the hormonal evaluation of
 18

orexigenic and anorexigenic hormones are rarely addressed among studies with TRF, as

the effect of TRF on these hormones is still unclear.

The findings on the lipid profile are still not very consistent. Our findings are

similar to those reported in a meta-analysis conducted by Moon et al. [31], which did

not report significant changes in LDL-C and HDL-C levels. Although Moon et al. [31]

have reported that the triglycerides levels significantly decreased; there were no

significant results in subgroup analysis with studies including participants with a

metabolic abnormality. Even so, it is worth mentioning that Moon et al. [31] included

of
studies with various designs and heterogeneous samples, as mentioned earlier. In the

ro
qualitative analysis, Jamshed et al. [23] observed a significant increase in the total
-p
cholesterol, LDL-cholesterol, and HDL-cholesterol levels, while Sutton et al. [26]
re
observed a significant increase in the triacylglycerol and total cholesterol levels, both in
lP

the eTRF group. Possibly, the increase in circulating lipids levels is associated with the
na

longer duration of fasting performed by participants before the test, which can

contribute to the re-esterification of triacylglycerol after lipolysis and in the hepatic and
ur

intramuscular storage of triacylglycerol [46]. On the other hand, a review that assessed
Jo

the impact of other types of intermittent fasting found favorable effects on serum

cholesterol and triacylglycerol levels. The authors showed that trials with alternating

days fasting, lasting three to 12 weeks were able to decrease approximately 10-21% of

cholesterol and 14-42% of triacylglycerol in non-obese and in individuals with excess

weight, similarly in studies that conducted complete days fasting, lasting 12 to 24 weeks

[47].

Only the study by Ravussin et al. [24] and Kahleova et al. [30] evaluated RMR

and showed no significant differences between groups for this outcome. Ravussin et al.

[24] had also evaluated total energy expenditure (TEE) and showed that eTRF increased

TEE during the daytime and it was offset by a decrease in TEE at nighttime and during
 19

sleep. The authors also analyzed the thermic effect of food (TEF), in which eTRF

increased TEF at lunch, at dinner, and when averaged across the three meals, but not at

breakfast. Similarly, in a randomized clinical trial, Pureza et al [18] also evaluated RMR

in women with obesity who underwent the TRF regimen of 12h combined with a

hypoenergetic diet and found no differences compared to controls that performed only

the hypoenergetic diet. RMR is known to decrease with prolonged fasting and this may

be a counter-regulatory way to decrease energy loss [48]. It would be expected an

increase in RMR mediated by the AMPK pathway in eTRF patients since the circadian

of
system orchestrates the metabolism in a 24-hour cycle giving rise to rhythms in energy

ro
expenditure; however, it is not what has been seen in recent studies [45, 49].
-p
The studies by Sutton et al. [26] and Jamshed et al. [23] are similar regarding the
re
fasting time applied in the intervention and the time of feeding window in the control
lP

groups, but the effects found in the serum cortisol levels were discrepant, which turns
na

the effect of the eTRF controversial in this metabolic and circadian hormone [50].

However, in a meta-analysis developed to clarify the effects of energy restriction on

ur

plasma cortisol and to evaluate cortisol as an indicator of stress during energy

Jo

restriction, it was observed that energy restriction significantly increased the cortisol

serum level in 13 studies (357 participants in total), with fasting being the energy

restriction with the greatest effect [51]. Other stress markers, such as TNF-alpha, CRP,

IL-6, appear to be unaffected by the performance of intermittent fasting models [26, 29,

52-57].

Both studies in which the participants were submitted to weight loss induction or

weight maintenance were included in our analysis. Considering the effects of weight

change in the metabolic profile, subgroup analysis was conducted for all metabolic

outcomes. However, only total cholesterol showed a different behavior between

subgroups, with a significant increase in the eTRF group for the subgroup of studies
 20

with participants in weight maintenance. As previously discussed, this subgroup

included two studies [23, 26] with a longer fasting duration (18h) which may contribute

to an increase in the circulating lipids levels [46].

Future studies, presented in our search results, include 22 trials investigating

eTRF that are in progress or completed. Although publications of these studies have not

yet been identified, we believe that they can assist in elucidating the effects discussed in

this section and possibly contribute to updating the data of this meta-analysis. It is

noteworthy that eTRF may be less feasible to be practiced by the community due to

of
several factors such as workday schedules (impairing the consumption of a home-

ro
cooked dinner before 6 or 7 pm), social meetings in the evening, and the lowest ghrelin
-p
levels in the morning, which reduces the drive to eat. Thus, delaying the initiation of
re
TRF (dTRF) would be an option. However, despite the low number of studies
lP

investigating eTRF, some promising results have been observed in the metabolic profile
na

of animal models and humans following this regimen, unlike studies with dTRF, which

are even scarcer. Furthermore, the metabolic consequences of dTRF are unclear [47].
ur

Therefore, future intervention studies comparing eTRF and dTRF must be conducted to
Jo

assess the metabolic impacts of delaying the initiation of TRF as well as to assess its

social acceptability and long-term adherence [58].

The main limitation of our review lies in the fact that few studies met our

inclusion criteria, which may have contributed to the lack of robustness and the

impossibility of conducting meta-analyses for some of our outcomes, as in the RMR,

stress markers, and other hormones related to appetite. However, we believe that the

fact of evaluating only studies with individuals with excess weight brings an advance to

the existing literature since there are no reviews with this purpose. It is also noteworthy

that, possibly, the public most benefited and interested in this dietary strategy are

individuals who wish to lose weight and to improve metabolic profile, to avoid the
 21

development of diseases. We believe that with the forecast of increasing publications

about the effects of eTRF on excess weight, this review may contribute to the direction

of future analyses on this type of intermittent fasting. Furthermore, the evidence of

publication bias in our meta-analysis cannot completely rule out the possibility that this

diminishes the significance of our results. Also, the low-quality evidence should be

considered when applying the eTRF in clinical practice.

Thus, although the eTRF regimen seems to have a beneficial effect on the

fasting blood glucose and HOMA-IR of individuals with excess weight, the results of

of
this meta-analysis should be analyzed with caution due to the low-quality evidence.

ro
eTRF is an emergent practice, with few randomized controlled clinical trials, and future

studies may change our estimates.

-p
re
lP
na

Acknowledgments

Declaration of interest statement

ur

“The authors declare no conflicts of interests”

Jo
 22

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 30

1 FIGURE LEGENDS

2 Figure 1. Flowchart of study selection

3 Figure 2. Meta-analysis of the effects of early time-restricted feeding versus controls on

4 blood fasting glucose (a), insulin (b), HOMA-IR (c) and ghrelin (d)

5 Figure 3. Meta-analysis of the effects of early time-restricted feeding versus controls on

6 triacylglycerol (a), total cholesterol (b), LDL-cholesterol (c), and HDL-cholesterol (d)

of
7 Figure 4. Funnel plots for Fasting blood glucose levels

ro
-p
re
lP
na
ur
Jo
 31

Age
Author, year Sample Study Study Weight
Sex range Control group Intervention group
[ref] size duration design management
(years)

of
ro
-p
re
lP
na
ur
Jo

Table 1. Characteristics of included studies

 32

F: 25 Two meals a day (14

Kahleova et al., 2014 [30] 54 30 - 70 12 weeks Cross-over Weight loss Six meals a day
M: 29 hours fasting)
F: 8 Skipping dinner (18
Nas et al., 2017 [41] 17 20 - 31 1 day Cross-over Maintenance Usual diet
M: 9 hours fasting)
12
Sutton et al., 2018 [26] M: 12 35 - 70 5 weeks Cross-over Maintenance 12 h fasting 18 h fasting

Ravussin et al., 2019 [24] and 11 F: 4

20 - 45 4 days Cross-over Maintenance 12 h fasting 18 h fasting

f
Jamshed et al., 2019 [23] M: 7

o
15 h fasting

ro
15
Hutchison et al., 2019 [22] M: 15 35 - 70 7 days Cross-over Weight loss (eating window between 12 pm 15 h fasting
and 9 pm)

-p
F: 2 TRF in the TRF in the morning
Singh et al., 2019 [12] 22 18 - 42 4 weeks Cross-over Maintenance
M: 20 evening (8.00–9:30 PM) (8.00 to 9.30 AM)

re
Extended feeding (9 hours
Parr et al., 2020 [17] 14 M: 14 30 – 45 5 days Cross-over Maintenance 16 h fasting

lP
fasting)
F: 36
Cienfuegos et al. 2020 [14] 39 18 -65 8 weeks Parallel-arm Maintenance Usual diet 18 h fasting
M:3

na
Zeb et al., 2020 [15] 80 M: 80 18-38 25 days Parallel-arm Maintenance Usual diet 16 h fasting
M: Male; F: Female; TRF: Time-restricted feeding
ur
Jo

Table 2. Risk of bias assessment in the included articles

Sequence Allocation Missing

Fonte Overall
generation concealment data
 33

Kahleova et al., 2014

Low Low Low Low
[30]
Nas et al., 2017
Low Low Unclear Low
[41]

f
Sutton et al., 2018

o
Low Unclear High High
[26]

ro
Ravussin et al., 2019 [24]and
Low Low High High

-p
Jamshed et al., 2019 [23]
Hutchison et al., 2019

re
Low Unclear Low High
[22]

lP
Singh et al., 2019
Low Low Low Low
[12]

na
Parr et al., 2020
Low Low Low Low
[17]
Cienfuegos et al. 2020
[14]
Low ur Low Low Low
Jo
Zeb et al., 2020
Low Low Unclear Low
[15]

Table 3. Changes in resting metabolic rate, hemodynamic parameters, stress markers, glycemic and lipid profile, appetite hormones, and appetite

in randomized clinical trials of early time-restricted feeding

 34

Resting
Author, year Hemodynamic
Weight metabolic Stress markers Lipid profile Glycemic profile Appetite hormones Appetite (VAS)
(ref) parameters
rate
The intervention group
There was a showed an increase of 0.11 The intervention group
higher mmol/L in triacylglycerol showed a reduction of
There was no
reduction with levels and of 0,02 mmol/L in 0.31+ mmol/L in blood
difference
Kahleova et al., two meals a LDL-cholesterol levels, and glucose levels and a
between N/A N/A N/A N/A
2014 [30] day (-3.7 kg; a reduction of 0,02mmol/L in decrease of 0.06 pmol/L
groups (p =
95% CI −4.1, total cholesterol levels and of in insulin levels but did

f
0.3)
−3.4 kg) than 0,013 mmol/L in HDL- not show statistical

o
six meals+ cholesterol levels, but did not significance

ro
show significance.
There was no difference
Nas et al., 2017 in HOMA-IR between

-p
N/A N/A N/A N/A N/A N/A N/A
[41] the intervention and
control groups.

re
eTRF lowered
The intervention
morning levels of
group showed a

lP
systolic and
reduction of 0.1 The intervention group
diastolic blood
(SEM 3.67) μg/dL showed an increase of 57
pressure by 11 ± 4 The intervention group
in the levels of (SEM 36.76) mg/dL+ in The intervention group
mm Hg* reduced 23 (SEM 7) pg/mL+

na
cortisol and of -0.3 triacylglycerol levels, of 13 showed a reduction of 2 The intervention
and 10 ± 4 mm Hg*, in the levels of PYY and
(SEM 2.82) mg/L (SEM 14.14) mg/dL* in total (SEM 5.65) mg/dL in showed a reduction of
Sutton et al., respectively. despite presenting a reduction
N/A N/A in the levels of cholesterol levels, of 0.6 blood glucose levels, 3.4 22 (SEM 7) mm+
2018 [26] However, eTRF did of 5.7 (SEM 6.6) pg/ml in the
not affect the
augmentation ur
PCR-US, however,
it presented an
increase of 0.45
(SEM 0.9) mg/dL of HDL-
cholesterol and an increase
of 2 (SEM 6) mg/dL of
(SEM 4.52), and an
increase of 0.84 (SEM
3.33) in HOMA-IR.
levels of ghrelin and 1.2
(SEM 1) of GLP- 1, did not
compared to the control
group.
Jo
index (p = 0.53) or show significance.
(SEM 0.27) pg/mL LDL-cholesterol compared
pulse wave velocity
at IL-6 levels, to the control group.
(p = 0.23), which
compared to the
are measures of
control group.
arterial stiffness.
The intervention group
The intervention did
showed a reduction of 43 (SD
RMR: there not affect appetite at
15) pg/ml* in ghrelin levels: 4
was no breakfast or in the
Ravussin et al., (DP 1) ng/ml * in leptin
N/A difference N/A N/A N/A N/A middle of the night.
2019 [24] levels and 0.8 (SD 0.3)
between Reduced the average
pmol/mL* in levels of GLP-1,
groups. desire to eat by 5 (SD
but did not affect PYY levels
2) mm.
(p = 0.25)
 35

The intervention group The intervention group

The intervention
increased LDL-cholesterol reduced fasting glycemia
group showed a
and HDL-cholesterol levels by 2 (SD 1) mg/dl*,
reduction of 1.4
Jamshed et al., by 9 (SD 4) mg/dl* and 3 insulin by 2.9 (SD 0.4)
N/A N/A N/A (SD 0.6) μg/dL* in N/A N/A
2019 [23] (DP 1) mg/dl *, respectively. mU/l+, and HOMA-IR by
cortisol levels
However, it did not affect 0.73 (SD 0.11)+
compared to the
triacylglycerol levels (p = concerning the control
control group.
0.29). group.
The intervention group
showed a reduction in
blood glucose of 3.6 The intervention group The intervention
The intervention reduced

f
Hutchison et al., [95% CI -4.89; -2.31] mg reduced -4 pg/mL in GLP-1 showed a reduction of 5

o
0.5 kg N/A N/A N/A triacylglycerol levels by 8.85
2019 [22] / dL and an increase of levels, -6 pg/mL PYY and -5 (7.51) mm compared to
[-17.8; 0.1] mg/dL+

ro
2.45 [95% CI 0.54; 4.36] pg/mL in ghrelin levels. the control group.
mIU/L in insulin levels.

-p
The intervention Fasting blood glucose is
reduced SBP levels lower after AM feeding

re
Singh et al., by 1.50 mmHg [- than after PM feeding
2019 0.80 N/A 2.92; -0.17]*. N/A N/A (74.86 versus 77.95; N/A N/A
[12] However, it did not difference

lP
affect the DBP and = 3.09 mg/dl, paired t =
PP levels. 4.22, P < .001).

na
Fasting insulin and
For cortisol, there Fasting triacylglycerol levels Fasting leptin, GLP-1, and For hunger, there were
Parr et al., 2020 glucose levels there were
[17]
N/A N/A N/A
ur
were no differences
between groups.
there were no differences
between groups.
no differences between
groups.
PYY levels there were no
differences between groups.
no differences between
groups.
Jo
The intervention The intervention group
The did not affect SBP There were no did not show significant
intervention and DBP levels significant effects changes in fasting
Cienfuegos et The intervention did not
group lost on inflammatory glucose. However, the
al. 2020 N/A affect any effect on plasma N/A N/A
more weight markers (8- experimental group
[14] lipid levels.
than the isoprostane, TNF- showed greater decreases
control. + alpha and IL-6) in fasting insulin than
controls
 36

The intervention group

reduced serum TC+ and TG+
Zeb et al., 2020 levels and increased HDL-c+
N/A N/A N/A N/A N/A N/A N/A
[15] levels compared to the non-
TRF group, while LDL-c
levels remained constant.

*(p < 0.05); + (p < 0.01)

N/A: Not available; TC: Total cholesterol; TG: triglycerides; SBP: systolic blood pressure; DPB: diastolic blood pressure; SEM: Standard error mean.

o f
ro
-p
re
lP
na
ur
Jo
 37

Table 4. Studies registered at clinictrials.gov in overweight individuals submitted to time-restricted eating and presence of resting metabolic rate, glucose profile, lipid profile, stress

markers, appetite and appetite hormones as analyzed outcomes

Study beginning Completion

Register forecast (year) RMR Lipid Profile Glycemic Profile Stress Markers Appetite hormones Appetite
(year)

f
Yes Yes

o
NCT04000516 2017 2019 No No No No

ro
2019 2022 No Yes Yes No No No
NCT03802253

-p
2018 2022 No Yes Yes No No No
NCT03745612
Yes

re
NCT03792282 2019 2021 No Yes Yes No No
2019 2020 No Yes Yes No No No

lP
NCT03786523
2013 2017 No No Yes Yes No No
NCT01895179

na
2018 2019 No Yes Yes No No Yes
NCT03459703
No
NCT03848390 2019

2019
2020

2023
ur No
Yes

Yes
Yes

Yes
No

Yes
No

No
No

No
Jo
NCT03504683
2017 2019 Yes No Yes No No No
NCT03969745
2018 2020 Yes Yes Yes Yes Yes No
NCT03574103
2019 2021 No Yes Yes Yes No No
NCT03792282
2019 2019 No No Yes Yes Yes No
NCT04062773
2020 2023 No Yes Yes No No Yes
NCT04351672
2019 2021 No No Yes No No No
NCT04009239
2019 2020 No Yes Yes No Yes Yes
NCT03854656
 38

2020 2020 No Yes No No No No

NCT04348019
2020 2021 No Yes Yes No No No
NCT04243746
2018 2019 Yes Yes Yes Yes Yes No
NCT03590158
2018 2021 No No Yes No Yes No
NCT03533023
2019 2021 Yes No Yes No No No
NCT03809299

f
No No

o
NCT03527368 2018 2020 No Yes No No

ro
NCT04155619 2020 2023 No No Yes Yes No No

-p
re
lP
na
ur
Jo
 39

Table 5. Summary of findings for assessment quality of evidence

Question: Early Time-restricted feeding compared to usual diet or delay time-restricted feeding for the treatment of overweight and obesity in adults

Quality assessment № of patients Effect

Usual Quality Importance

№ of Risk of Other Absolute
Study design Inconsistency Indirectness Imprecision eTRF diet or

f
studies bias considerations (95% CI)
dTRF

o
ro
-p
Fasting blood glucose

◯
◯
◯

re
7 randomised seriousa seriousj seriousb not serious 148 147 MD -2.75 ⨁ IMPORTANT
trials N/A mg/dL VERY

lP
(-4.59; -0.90) LOW

Insulin

na
6 randomised seriousd seriousj seriousb not serious 126 125 MD -1.54 ⨁ ◯
◯
◯ CRITIC
trials
ur N/A mU/ml
(-3.35; 0.26)
VERY
LOW
Jo
HOMA-IR
4 randomised
trials
seriouse not serious seriousb not serious
N/A
60 59 MD -0.50
(-0.82; - 0.19)
⨁⨁
LOW
◯
◯ CRITIC

Ghrelin
3 randomised
trials
seriousf seriousj seriousb seriousc 38 38 MD -18.45
pg/ml
⨁ ◯
◯
◯
VERY
IMPORTANT
N/A
(-45.94; - LOW
9.03)
 40

Question: Early Time-restricted feeding compared to usual diet or delay time-restricted feeding for the treatment of overweight and obesity in adults

Quality assessment № of patients Effect

Usual Quality Importance

№ of Risk of Other Absolute
Study design Inconsistency Indirectness Imprecision eTRF diet or
studies bias considerations (95% CI)
dTRF

o f
ro
Triacylglycerol

◯
◯
◯

-p
6 randomised seriousg seriousj serious b seriousc 126 125 MD 1.61 ⨁ CRITIC

re
trials N/A mg/dL VERY
(-7.82;11.05) LOW

lP
Total cholesterol
serioush seriousj seriousb seriousc ◯
◯
◯

na
3 randomised 77 77 MD 6.33 ⨁ IMPORTANT
trials N/A mg/dL VERY
(-3.45; 16.12) LOW
HDL cholesterol ur
◯
◯
◯
Jo
4 randomised seriouse seriousj seriousi not serious 97 96 MD 0.52 ⨁ IMPORTANT
trials N/A mg/dL VERY
(-0.71; 0.59) LOW
LDL cholesterol
4 randomised
trials
seriouse seriousj seriousi not serious
N/A
97 96 MD 0.37
mg/dL
⨁◯
◯
◯
VERY
IMPORTANT

(-2.97; 3.72) LOW

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
 41

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

CI: Confidence interval; MD: Mean difference

a. Two (Sutton et al., 2018 and Jameshed et al., 2019) out of the seven included studies present a high risk of bias for attrition.
b. There was a serious risk of indirectness due to the imbalanced gender distribution
c. There was serious imprecision considering the small number of studies and a wide confidence interval.
d. Two (Sutton et al., 2018 and Jameshed et al., 2019) out of the six included studies present a high risk of bias for attrition.

f
e. Two (Sutton et al., 2018 and Jameshed et al., 2019) out of the four included studies present a high risk of bias for attrition.

o
f. Two (Sutton et al., 2018 and Ravussin et al., 2019) out of the three included studies present a high risk of bias for attrition.

ro
g. One (Sutton et al., 2018) out of the five included studies present a high risk of bias for attrition.
h. Two (Sutton et al., 2018 and Jameshed et al., 2019) out of the three included studies present a high risk of bias for attrition.

-p
i. There was a serious risk of indirectness due to the imbalanced gender distribution (Cienfuegos et al. 2020).
j. There was heterogeneity with I² value of > 75%.

re
lP
na
ur
Jo
Identification

Records identified through Additional records identified

database searching through other sources
(n = 6204) (n = 14)

Records after duplicates removed

(n = 3699)
Screening

of
Records screened Records excluded

ro
(n = 3699) (n = 3437)

-p
re
Full-text articles excluded,
Full-text articles assessed with reasons (n = 41)
lP

for eligibility
Eligibility

n = 9 non-randomized
(n = 51)
clinical trial
na

n = 8 with
athletes/physically active
ur

Articles included in n = 7 with lean individuals

qualitative synthesis
Jo

(n = 10) n = 3 did not measure any

outcome of interest

n = 4 another type of
Included

intermittent fasting (ADF –

Articles included in Alternate Day Fasting)
quantitative synthesis n = 2 delay time-restricted
(meta-analysis) feeding
(n = 8)
n = 3 TRF with self-
selected fasting period

n = 1 TRF without fasting

period reported

n = 3 intermittent energy
restriction

n = 1 animal model
 Fasting blood glucose Insulin
a. Study % b. Study %
ID ES (95% CI) Weight ID ES (95% CI) Weight

Weight loss induction

Weight loss induction
Kahleova et al., 2014 -5.58 (-9.92, -1.23) 9.46
Kahleova et al., 2014 -0.01 (-0.08, 0.06) 30.32
Hutchinson et al., 2019 -3.60 (-4.89, -2.31) 18.16
Hutchinson et al., 2019 -2.45 (-4.36, -0.54) 22.29
Subtotal (I-squared = 0.0%, p = 0.392) -3.76 (-5.00, -2.52) 27.62
. Subtotal (I-squared = 84.0%, p = 0.012) -1.04 (-3.40, 1.32) 52.62

Weight maintenance .

Sutton et al., 2018 -2.00 (-6.39, 2.39) 9.36 Weight maintenance

Jamshed et al., 2019 -2.00 (-4.22, 0.22) 15.46 Sutton et al., 2018 -3.40 (-6.91, 0.11) 13.67
Singh et al., 2019 -3.09 (-4.56, -1.63) 17.70 Jamshed et al., 2019 -2.90 (-5.83, 0.03) 16.41
Cienfuegos et al. 2020 -4.90 (-9.02, -0.77) 9.98

f
Parr et al., 2020 2.26 (-0.50, 5.02) 17.30

o
Parr et al., 2020 -0.19 (-0.39, 0.01) 19.88
Subtotal (I-squared = 77.2%, p = 0.012) -1.26 (-4.95, 2.43) 47.38
Subtotal (I-squared = 82.3%, p = 0.000) -2.10 (-4.00, -0.19) 72.38

ro
.
.
Overall (I-squared = 75.3%, p = 0.003) -1.10 (-2.85, 0.65) 100.00
Overall (I-squared = 88.7%, p = 0.000) -2.75 (-4.60, -0.91) 100.00

-p
NOTE: Weights are from random effects analysis NOTE: Weights are from random effects analysis

re
-9.92 0 9.92 -6.91 0 6.91
decreased in eTRF increased in eTRF decreased in eTRF increased in eTRF

lP
na
HOMA-IR Ghrelin
c. d. Study %

Study
ur % ID ES (95% CI) Weight
Jo
ID ES (95% CI) Weight

Weight loss induction

Hutchinson et al., 2019 -5.00 (-21.96, 11.96) 32.05

Weight maintenance
Subtotal (I-squared = .%, p = .) -5.00 (-21.96, 11.96) 32.05
Nas et al., 2017 0.00 (-0.63, 0.63) 16.95
.
Sutton et al., 2018 -0.84 (-1.76, 0.08) 9.56
Weight maintenance
Jamshed et al., 2019 -0.73 (-0.97, -0.48) 40.29
Ravussin et al., 2019 -43.00 (-53.07, -32.92) 34.80

Cienfuegos et al. 2020 -0.40 (-0.73, -0.06) 33.20

Sutton et al., 2018 -5.70 (-20.18, 8.78) 33.15

Subtotal (I-squared = 50.8%, p = 0.107) -0.51 (-0.82, -0.19) 100.00 Subtotal (I-squared = 94.2%, p = 0.000) -24.73 (-61.27, 11.82) 67.95

. .

Overall (I-squared = 50.8%, p = 0.107) -0.51 (-0.82, -0.19) 100.00 Overall (I-squared = 91.8%, p = 0.000) -18.46 (-45.94, 9.03) 100.00

NOTE: Weights are from random effects analysis NOTE: Weights are from random effects analysis

-61.3 0 61.3
-1.76 0 1.76
decreased in eTRF increased in eTRF decreased in eTRF increased in eTRF
Triacylglycerol Total cholesterol
a. Study % b. Study %
ID ES (95% CI) Weight
ID ES (95% CI) Weight
Weight loss induction
Kahleova et al., 2014 9.74 (-0.99, 20.47) 19.95 Weight loss induction
Hutchinson et al., 2019 -8.85 (-17.80, 0.10) 21.64
Kahleova et al., 2014 -0.77 (-1.61, 0.07) 41.63
Subtotal (I-squared = 85.3%, p = 0.009) 0.20 (-18.01, 18.41) 41.59
Subtotal (I-squared = .%, p = .) -0.77 (-1.61, 0.07) 41.63
.
.
Weight maintenance
Sutton et al., 2018 57.00 (28.38, 85.61) 7.77 Weight maintenance
Parr et al., 2020 -8.86 (-19.70, 1.98) 19.84 Sutton et al., 2018 13.00 (1.99, 24.00)27.33
Cienfuegos et al. 2020 -1.90 (-3.49, -0.30) 26.63 Jamshed et al., 2019 10.00 (1.09, 18.90)31.03

f
Jamshed et al., 2019 -13.56 (-56.15, 29.03) 4.17

o
Subtotal (I-squared = 0.0%, p = 0.678) 11.19 (4.26, 18.11)58.37
Subtotal (I-squared = 83.5%, p = 0.000) 5.23 (-11.68, 22.13) 58.41

ro
.
.
Overall (I-squared = 82.6%, p = 0.003) 6.34 (-3.45, 16.12) 100.00
Overall (I-squared = 80.0%, p = 0.000) 1.63 (-7.84, 11.09) 100.00

-p
NOTE: Weights are from random effects analysis NOTE: Weights are from random effects analysis

re
-85.6 0 85.6 -24 0 24
decreased in eTRF increased in eTRF decreased in eTRF increased in eTRF

lP
na
LDL-cholesterol HDL-cholesterol
d. Study
c. Study
ID ur
ES (95% CI)
%

Weight
%
Jo
ID ES (95% CI) Weight

Weight loss induction

Weight loss induction
Kahleova et al., 2014 0.77 (-0.07, 1.61) 45.45
Kahleova et al., 2014 -0.50 (-1.04, 0.04) 36.14
Subtotal (I-squared = .%, p = .) 0.77 (-0.07, 1.61) 45.45
Subtotal (I-squared = .%, p = .) -0.50 (-1.04, 0.04) 36.14
.
.
Weight maintenance
Weight maintenance
Sutton et al., 2018 2.00 (-11.20, 15.20) 5.67
Sutton et al., 2018 -0.60 (-2.57, 1.37) 8.98
Jamshed et al., 2019 9.00 (0.09, 17.90) 10.87 Jamshed et al., 2019 3.00 (0.77, 5.22) 7.34
Cienfuegos et al. 2020 -2.80 (-5.15, -0.44) 38.01 Cienfuegos et al. 2020 -0.10 (-0.18, -0.01) 47.54
Subtotal (I-squared = 69.9%, p = 0.036) 1.91 (-6.29, 10.11) 54.55 Subtotal (I-squared = 74.0%, p = 0.021) 0.55 (-1.14, 2.24) 63.86
. .
Overall (I-squared = 73.8%, p = 0.009) 0.38 (-2.97, 3.73) 100.00 Overall (I-squared = 69.4%, p = 0.020) -0.06 (-0.72, 0.59) 100.00

NOTE: Weights are from random effects analysis NOTE: Weights are from random effects analysis

-17.9 0 17.9 -5.22 0 5.22

decreased in eTRF increased in eTRF decreased in eTRF increased in eTRF
 0
Studies

p < 1%

1% < p < 5%

.5 5% < p < 10%

p > 10%
Standard error

1.5

of
ro
2.5
-5 -p0
Effect estimate
5
re
lP
na
ur
Jo