Critical Reviews in Food Science and Nutrition

ISSN: 1040-8398 (Print) 1549-7852 (Online) Journal homepage: https://www.tandfonline.com/loi/bfsn20

Impact of intermittent energy restriction on

anthropometric outcomes and intermediate
disease markers in patients with overweight and
obesity: systematic review and meta-analyses

Lukas Schwingshackl, Jasmin Zähringer, Kai Nitschke, Gabriel Torbahn,

Szimonetta Lohner, Tilman Kühn, Luigi Fontana, Nicola Veronese, Christine
Schmucker & Joerg J Meerpohl

To cite this article: Lukas Schwingshackl, Jasmin Zähringer, Kai Nitschke, Gabriel Torbahn,
Szimonetta Lohner, Tilman Kühn, Luigi Fontana, Nicola Veronese, Christine Schmucker & Joerg
J Meerpohl (2020): Impact of intermittent energy restriction on anthropometric outcomes and
intermediate disease markers in patients with overweight and obesity: systematic review and meta-
analyses, Critical Reviews in Food Science and Nutrition

To link to this article: https://doi.org/10.1080/10408398.2020.1757616

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CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
https://doi.org/10.1080/10408398.2020.1757616

REVIEW

Impact of intermittent energy restriction on anthropometric outcomes and

intermediate disease markers in patients with overweight and obesity:
systematic review and meta-analyses
Lukas Schwingshackla, Jasmin Z€ahringera, Kai Nitschkea, Gabriel Torbahnb, Szimonetta Lohnerc, Tilman Ku
€hnd,
e,f g a a,h
Luigi Fontana , Nicola Veronese , Christine Schmucker , and Joerg J Meerpohl
a
Institute for Evidence in Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany;
b
Institute for Biomedicine of Aging, Friedrich-Alexander-Universit€at Erlangen-Nu€rnberg, Nuremberg, Germany; cCochrane Hungary, Clinical
Center of the University of Pecs, Medical School, University of Pecs, Pecs, Hungary; dGerman Cancer Research Center (DKFZ), Division of
Cancer Epidemiology, Heidelberg, Germany; eFaculty of Medicine and Health and Charles Perkins Centre, University of Sydney, Sydney, NSW,
Australia; fDepartment of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy; gPrimary Care Department, Azienda ULSS 3
Serenissima, Venice, Italy; hCochrane Germany, Cochrane Germany Foundation, Freiburg, Germany

ABSTRACT KEYWORDS
This systematic review aims to investigate the effects of intermittent energy restriction (IER) on Meta-analysis; intermittent
anthropometric outcomes and intermediate disease markers. A systematic literature search was energy restriction; alternate-
conducted in three electronic databases. Randomized controlled trials (RCTs) were included if the day fasting; continuous
energy restriction; obesity;
intervention lasted
12 weeks and IER was compared with either continuous energy restriction weight loss
(CER) or a usual diet. Random-effects meta-analysis was performed for eight outcomes. Certainty
of evidence was assessed using GRADE. Seventeen RCTs with 1328 participants were included. IER
in comparison to a usual diet may reduce body weight (mean difference [MD]: 4.83 kg, 95%-CI:
5.46, 4.21; n ¼ 6 RCTs), waist circumference (MD: 1.73 cm, 95%-CI: 3.69, 0.24; n ¼ 2), fat mass
(MD: 2.54 kg, 95%-CI: 3.78, 1.31; n ¼ 6), triacylglycerols (MD: 0.20 mmol/L, 95%-CI: 0.38,
0.03; n ¼ 5) and systolic blood pressure (MD: 6.11 mmHg, 95%-CI: 9.59, 2.64; n ¼ 5). No
effects were observed for LDL-cholesterol, fasting glucose, and glycosylated-hemoglobin. Both, IER
and CER have similar effect on body weight (MD: 0.55 kg, 95%-CI: 1.01, 0.09; n ¼ 13), and fat
mass (MD: 0.66 kg, 95%-CI: 1.14, 0.19; n ¼ 10), and all other outcomes. In conclusion, IER
improves anthropometric outcomes and intermediate disease markers when compared to a usual
diet. The effects of IER on weight loss are similar to weight loss achieved by CER.

Introduction
According to the World Health Organization (WHO), nearly
2 billion adults are overweight and more than 600 million
patients are obese (WHO 2017). High body-mass index
(BMI) is associated with increased risk of chronic diseases
such as cardiovascular disease, diabetes and cancer (Guh
et al. 2009). Continuous energy restriction (CER) is the most
common dietary strategy for weight loss, and involves
restricting energy intake by 15–30% (Yumuk et al. 2015;
Fontana and Klein 2007). Recently, intermittent fasting (IF)
regimens have gained considerable popularity, since many
overweight and patients with obesity find the rigidity of CER
very difficult to maintain (Varady 2011). IF comprises several
dietary approaches with alternating phases of fasting (very
low or zero energy intake) and normal or high energy intake
(alternate day fasting, ADF). Intermittent energy restriction
(IER) is a subclass of IF, with limited energy restriction to
20–25% (Patterson and Sears 2017). IER may alternate within
weeks, e.g. with two either consecutive or nonconsecutive
fasting days per week (so-called “5:2 diet”) or fasting every
other day (ADF) (Patterson and Sears 2017). Approaches
with periods of more than two consecutive fasting days fol-
lowed by non-fasting days are subsumed under the term
“periodic fasting”. Fasting periods alternating within days, e.g.
with 16 h of complete fasting during 24 h are called time
restricted feeding (TRF) (Patterson and Sears 2017). In animal
studies, CER showed positive effects on age-related and all-
cause survival and in the reduction of multiple chronic dis-
eases including the risk for cancer, while the role of IF is less
clear (Lv et al. 2014; Fontana and Partridge 2015).
Previous meta-analyses of randomized controlled trials
(RCTs) showed that IER was more effective in reducing
body weight compared to a usual diet (Harris, Hamilton,
et al. 2018), but showed little differences compared to CER
(Harris, McGarty, et al. 2018; Harris, Hamilton, et al. 2018;
Headland et al. 2016; Cioffi et al. 2018). However, these
meta-analyses were often limited by including also short-
term trials (12 weeks duration) (Alhamdan et al. 2016;
Cioffi et al. 2018; Cho et al. 2019), using trials with no

CONTACT Lukas Schwingshackl schwingshackl@ifem.uni-freiburg.de Breisacher Straße 153, 79110 Freiburg, Germany.
Supplemental data for this article can be accessed at https://doi.org/10.1080/10408398.2020.1757616.
ß 2020 Taylor & Francis Group, LLC
2 L. SCHWINGSHACKL ET AL.
comparison group (before and after meta-analysis)
(Alhamdan et al. 2016), using meal-replacement approaches
(Harris, McGarty, et al. 2018), including only a very limited
number of RCTs (n ¼ 4 for the meta-analysis of IER vs.
CER; and n ¼ 2 for the meta-analysis of IER vs. usual diet
on body weight (Harris, Hamilton, et al. 2018)), or they did
not evaluate the certainty of evidence (Alhamdan et al. 2016;
Cioffi et al. 2018; Headland et al. 2016; Cho et al. 2019). In
a previous meta-analysis (Tobias et al. 2015), meal replace-
ment drink interventions were not considered, probably
since meal replacement is not in the sense of a balanced
diet, and are often investigated an separate meta-analyses
(Astbury et al. 2019; Maston et al. 2019).
Moreover, to the best of our knowledge, none of the above
mentioned meta-analyses has conducted subgroup analyses
for the type of IER, sex, and study length or disease status
(overweight, obesity, type 2 diabetes). Therefore, the aim of
this research was to conduct a comprehensive, up-to date evi-
dence synthesis of RCTs investigating the impact of IER
versus CER or usual diet on anthropometric outcomes
and intermediate disease markers (low-density lipoprotein-
cholesterol, triacylglycerols, systolic blood pressure, fasting
glucose, and glycosylated hemoglobin: systematic reviews and
mendelian randomization studies have shown that these risk
factors were strongly related to cardiovascular disease (Holmes
et al. 2015; Ettehad et al. 2016; Di Angelantonio et al. 2014)
including the use of the Grading of Recommendations,
Assessment, Development, and Evaluation (GRADE) system.
Methods and design
This meta-analysis was registered in PROSPERO (International
Prospective Register of Systematic Reviews; www.crd.york.ac.uk/
prospero/index.asp, identifier CRD42019138577), and was
reported in adherence to PRISMA standards of quality for report-
ing systematic reviews and meta-analyses (Moher et al. 2009).
The present systematic review has been registered in
PROSPERO as a network meta-analysis. However we were
not able to conduct a network meta-analysis to compare
simultaneously all of the different fasting types (e.g. ADF,
restricted time feeding regimens) due to the scarcity of the
evidence. Therefore, the present systematic review is based
only on pairwise meta-analyses, and varies from the primary
planed project.
Search strategy
The systematic literature search was performed in the elec-
tronic databases Medline, Web of Science and the Cochrane
Central Register of Controlled Trials (CENTRAL) until 25th
March 2019 with no restriction of language and calendar
date using a pre-defined search strategy (Supplementary
material, Appendix S1).
The reference lists from eligible studies were screened to
identify additional relevant research. Screening and study selec-
tion was conducted by two authors independently (LS, JZ).
Selection of studies
Studies were included in the systematic review if they met
the following criteria:
i. Randomized controlled trials (RCTs; with a parallel or
cross-over design) comparing:
ii. IER as intervention:
i.e. ADF; Alternate-day fasting characterized by at least
one feast day (24 h) where participants are permitted to
eat ad libitum, and at least one fast day (24 h) per
week, where energy intake is rigorously reduced (to
about 25%) or withheld completely (Varady and
Hellerstein 2007). For instance, in an (5:2)-ADF regi-
men there are 5 feast and 2 fast days.
iii. versus at least one of the following comparisons:
a) CER: continuous energy restriction defined as
daily energy restriction by at least 15% (Varady
and Hellerstein 2007).
b) Usual diet (or minimal intervention: e.g. distribution
of a brochure with nutritional recommendations
at baseline).
iv. Minimum duration of the intervention:
12 weeks.
v. Participants with a mean age
18 years.
The following studies were excluded:
i. RCTs including patients with eating disorders; critically
ill and hospitalized patients; patients undergoing bariat-
ric surgery;
ii. RCTs based on liquid/formula diets, meal replacement
interventions or dietary supplements.
iii. Co-intervention (e.g. drug, diet, or physical activity)
not applied in all intervention arms.
iv. RCTs in which the various interventions were of
shorter duration (<12 weeks).
Data extraction
For included studies, two reviewers (LS, JZ) independently
extracted the following characteristics: name of first author,
year of publication, study origin (country), study design (RCT:
parallel or cross-over, including wash-out period), different
types of fasting methods, dietary adherence, sample size, disease
status (i.e. healthy, patients with obesity, overweight, diabetic,
hypercholesterolemia), mean age, mean BMI, type 2 diabetics
(%), female (%), study length (weeks), specification of the inter-
ventions arms (kcal/day), relevant outcome measures (primary
outcomes: body weight, waist circumference, fat mass; second-
ary outcomes: low-density lipoprotein-cholesterol (LDL-C), tria-
cylglycerols (TG), systolic blood pressure (SBP), fasting glucose
(FG), and glycosylated hemoglobin (HbA1c)), information on
potential conflict of interests, and major adverse events.
Risk of bias assessment
Risk of bias was assessed by two authors independently (SL,
GT) according to the method described in the Cochrane

Handbook for Systematic Reviews of Interventions (Higgins
et al. 2019). The following domains were considered: selec-
tion bias (random sequence generation and allocation con-
cealment), performance bias (blinding of participants and
personnel), detection bias (blinding of outcome assessment),
attrition bias (incomplete outcome data), reporting bias
(selective reporting), and other bias (carry over effect in
cross-over RCTs).
Data synthesis
Statistical analysis
The change scores reported as the differences between the
final and baseline mean values were pooled as mean differ-
ences (MDs) using a random effects model for each con-
tinuous outcome separately. Where RCTs did not report
results as change from baseline values, we calculated these
changes including the standard deviation differences follow-
ing the methods described in the Cochrane Handbook for
imputing data (Higgins et al. 2019). Furthermore, we
assumed a correlation coefficient of 0.5 between baseline
and follow-up measures in line with a recent Cochrane
Review which investigated the effects of a Mediterranean
dietary pattern on cardiovascular disease (Rees et al. 2019).
Heterogeneity in meta-analyses was tested with a standard
v2 test. The I2 parameter was used to quantify any inconsist-
ency: I2¼((Qdf))/Q  100%, where Q is the v2 statistic and
df is its degrees of freedom (Higgins et al. 2003). An I2-value
of greater than 50% was considered to represent considerable
heterogeneity (Higgins and Thompson 2002). Meta-analyses
were conducted using Review Manager (RevMan) Version 5.3
(“Review Manager (RevMan) [Computer program]. Version
5.3. Copenhagen: The Nordic Cochrane Centre, The
Cochrane Collaboration, 2014.”).
Subgroup analyses and sensitivity analyses
A-priori, we planned to conduct subgroup analyses for the
primary outcomes by considering: disease status (overweight
vs. patients with obesity), age (
65 years vs. <65 years), sex,
study length (
12 months vs. <12 months), and type of fast-
ing (IER5:2 and IER4:3; IERconsecutive days and IERnonconsecutive
days). Subgroup differences were assessed by interaction tests
available within RevMan Version 5.3 (“Review Manager
(RevMan) [Computer program]. Version 5.3. Copenhagen:
The Nordic Cochrane Centre, The Cochrane Collaboration,
2014.”). Moreover, we planned a-priori to conduct sensitiv-
ity analyses excluding high risk of bias studies.
Dissemination bias
To evaluate dissemination bias, a funnel plot was created for
each pairwise comparison, and Egger’s linear regression test
for funnel plot asymmetry was conducted to investigate
small study effects (Egger et al. 1997).
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 3
Grading of recommendations assessment,
development, and evaluation (certainty of
the evidence)
We followed the GRADE approach to rate the certainty of
evidence. For six prioritized outcomes (were rated according
to their importance following the GRADE approach: body
weight, waist circumference, fat mass, LDL-C, TG, and
SBP), two authors independently (LS, CS) rated the certainty
of evidence in each pooled estimate for the comparison IER
vs. usual diet, and IER vs. CER (Guyatt, Oxman, Akl, et al.
2011). Each outcome was evaluated with the following
GRADE criteria: risk of bias, indirectness, inconsistency,
imprecision (Guyatt, Oxman, Kunz, et al. 2011), and dissem-
ination bias (Balshem et al. 2011). GRADE specifies four
levels of certainty of evidence: high, moderate, low, and
very low.
Results
Out of 930 records identified through the literature search,
57 records were assessed as full texts in detail (Figure 1)
(references that have been excluded are listed in
Supplementary material, Appendix S2). Overall, 17 RCTs
(18 reports) (Bhutani et al. 2013; Carter, Clifton, and Keogh
2018, 2016; Conley et al. 2018; Harvie et al. 2013; Harvie
et al. 2011; Hill et al. 1989; Mraovic et al. 2018; Schubel
et al. 2018; Sundfor, Svendsen, and Tonstad 2018; Teng
et al. 2011; Teng et al. 2013; Todd 2015; Trepanowski et al.
2017; Gabel et al. 2019; Varady et al. 2013; Panizza et al.
2019; Viegener et al. 1990) with a total of 1328 participants
published between 1989 and 2019 were included in the sys-
tematic review and meta-analyses.
Six RCTs were conducted in the US (Bhutani et al. 2013;
Hill et al. 1989; Panizza et al. 2019; Trepanowski et al. 2017;
Varady et al. 2013; Viegener et al. 1990; Gabel et al. 2019),
three in the UK (Harvie et al. 2013; Harvie et al. 2011; Todd
2015) and Australia (Carter, Clifton, and Keogh 2016, 2018;
Conley et al. 2018), two studies in Malaysia (Teng et al.
2011; Teng et al. 2013), and one each in Serbia (Mraovic
et al. 2018), Germany (Schubel et al. 2018), and Norway
(Sundfor, Svendsen, and Tonstad 2018); the study length
ranged from 12 to 52 weeks; the mean age of the partici-
pants ranged from 31.7 to 67.6 years, their BMI from 26 to
35.3 kg/m2. In 15 RCTs, healthy patients with overweight or
obesity were included (Bhutani et al. 2013; Conley et al.
2018; Harvie et al. 2013; Harvie et al. 2011; Hill et al. 1989;
Mraovic et al. 2018; Schubel et al. 2018; Sundfor, Svendsen,
and Tonstad 2018; Teng et al. 2011; Teng et al. 2013; Todd
2015; Trepanowski et al. 2017; Gabel et al. 2019; Varady
et al. 2013; Panizza et al. 2019; Viegener et al. 1990), and
two RCTs included participants with type 2 diabetes (T2D)
(Carter, Clifton, and Keogh 2016, 2018). Eleven RCTs used
a IER5:2 design (Carter, Clifton, and Keogh 2018, 2016;
Conley et al. 2018; Harvie et al. 2013; Harvie et al. 2011;
Schubel et al. 2018; Sundfor, Svendsen, and Tonstad 2018;
Teng et al. 2011; Teng et al. 2013; Todd 2015; Panizza et al.
2019); fast days were mainly applied on nonconsecutive
days. The majority of the included RCTs reported no major
4 L. SCHWINGSHACKL ET AL.
Figure 1. Flow diagram showing study selection process.
adverse events. Only the two RCTs including patients with
T2D reported some major adverse events (hypoglycemia) in
a small number of patients, with no difference between IER
and CER (Carter, Clifton, and Keogh 2016, 2018). Study and
participant characteristics are summarized in Tables 1 and 2,
respectively.
Risk of bias
The results of the RoB assessment are provided in Figure S1
(Supplementary material). Four studies (24%) were judged
to have a low risk of selection bias (Bhutani et al. 2013;
Conley et al. 2018; Panizza et al. 2019; Sundfor, Svendsen,
and Tonstad 2018). No RCT adequately performed blinding
of participants and personnel (blinding of dietary interven-
tions impossible); however, one RCT (6%) was judged as
low risk of bias for blinding of outcome assessment (Conley
et al. 2018).Ten RCTs (59%) were judged as low risk of bias
for incomplete outcome data (Carter, Clifton, and Keogh
2018, 2016; Conley et al. 2018; Harvie et al. 2013; Schubel
et al. 2018; Sundfor, Svendsen, and Tonstad 2018; Teng
et al. 2013; Todd 2015; Varady et al. 2013; Panizza et al.
2019). Fifteen RCTs (88%) were judged to have a low risk of
bias for selective reporting (Bhutani et al. 2013; Carter,
Clifton, and Keogh 2018, 2016; Conley et al. 2018; Harvie
et al. 2013; Harvie et al. 2011; Mraovic et al. 2018; Schubel
et al. 2018; Sundfor, Svendsen, and Tonstad 2018; Teng
et al. 2011; Teng et al. 2013; Todd 2015; Trepanowski et al.
2017; Gabel et al. 2019; Panizza et al. 2019; Viegener et al.
1990), and twelve RCTs (71%) showed a low risk of other
bias (Bhutani et al. 2013; Carter, Clifton, and Keogh 2018;
Conley et al. 2018; Harvie et al. 2013; Harvie et al. 2011;
Hill et al. 1989; Schubel et al. 2018; Teng et al. 2011; Teng
et al. 2013; Trepanowski et al. 2017; Gabel et al. 2019;
Varady et al. 2013; Panizza et al. 2019) (Fig. S1). Overall,
eight RCTs (47%) were rated with a high risk of bias, due to
allocation concealment, blinding of outcomes assessment,
and incomplete outcome data.
The evidence profiles for the comparison IER vs. usual
diet and IER vs. CER on body weight, waist circumference,
fat mass, LDL-C, TG, and SBP are shown in Table 3 and 4.
Primary outcomes
IER vs usual diet. Compared to a usual diet, IER may
reduce body weight (MD: 4.83 kg, 95% CI: 5.46, 4.21;
I2 ¼ 3%, n ¼ 6 RCTs; low certainty of the evidence) and fat
mass (MD: 2.54 kg, 95% CI: 3.78, 1.31; I2 ¼ 64%, n ¼ 6
RCTs; low certainty of the evidence), and may slightly
reduce waist circumference (MD: 1.73 cm, 95% CI: 3.69,
Table 1. Study characteristics of the included randomized controlled trials.
Duration of
Sample size, Mean baseline Type 2 intervention, Conflict
References Country Study design Comparison Disease status Mean age BMI (k/m2) diabetes (%) Female (%) weeks Outcomes of interest
Bhutani et al. (2013) USA RCT, parallel IER vs. Control 83, Healthy patients 45.5 35 0 96 12 BW, WC, FM, LDL, TG, None
with obese SBP, FG
Carter, Clifton, and Australia RCT, parallel IER vs. CER 137, Patients with 62 35 100 77 52 BW, FM, FG, HbA1c None
Keogh (2018) obesity or
overweight, T2D
Carter, Clifton, and Australia RCT, parallel IER vs. CER 63, Patients with obesity 61.5 35.2 100 52 12 BW, FM, HbA1c None
Keogh (2016) or overweight, T2D
Conley et al. (2018) Australia RCT, parallel IER vs. CER 24, Healthy patients 67.6 34.9 0 0 12 BW, WC, LDL, TG, SBP, None
with obesity FG, HbA1c
Harvie et al. (2013) UK RCT, parallel IER vs. CER 77, Healthy patients with 46.8 31 0 100 16 BW, WC, FM, LDL, TG, None
obesity with increased SBP, FG, HbA1c
risk for breast cancer
Harvie et al. (2011) UK RCT, parallel IER vs. CER 107, Patients with 40.1 30.6 0 100 26 BW, WC, FM, LDL, TG, FG None
obesity with increased
risk for breast cancer
and/or metabolic
syndrome or healthy
Hill et al. (1989) USA RCT, parallel IER vs. CER 32, Healthy patients 38.5 30.8 0 100 12 BW, FM, SBP None
with obesity
Mraovic et al. (2018) Serbia RCT, parallel IER vs. CER 97, Healthy patients with 31.7 30.2 0 100 42 BW, WC, FM, LDL, TG, No statement
obesity or overweight FG, HbA1c
Panizza et al. (2019) USA RCT, parallel IER vs. CER 60, Healthy patients with 47.3 30.7 0 70 12 BW, WC, FM, LDL, TG, None
obesity or overweight SBP, FG
Schubel et al. (2018) Germany RCT, parallel IER vs. CER 150, Healthy patients 50.2 31.4 0 50 12 BW, WC, LDL, TG, FG None
vs. Control with obesity
or overweight
Sundfor, Svendsen, and Norway RCT, parallel IER vs. CER 112, Healthy patients 48.7 35.2 0 50 26 BW, WC, FM, LDL, TG, None
Tonstad (2018) with obesity with at SBP, FG, HbA1c
least 1 risk marker for
metabolic syndrome
Teng et al. (2011) Malaysia RCT, parallel IER vs. Control 28, Healthy overweight 58.8 26.7 0 0 12 BW, FM No statement
Teng et al. (2013) Malaysia RCT, parallel IER vs. Control 56, Healthy overweight 59.4 26.8 0 0 12 BW, FM, LDL, TG, None
SBP, FG
Todd (2015) UK RCT, parallel IER vs. CER 85, Healthy patients with 45.5 28.7 0 100 12 BW, WC, FM, SBP No statement
obesity with increased
risk for breast cancer
Trepanowski et al. USA RCT, parallel IER vs. CER 100, Healthy patients 44 34.3 0 86 24 BW, FM, LDL, TG, None
(2017); Gabel vs. Control with obesity SBP, FG
et al. (2019) or overweight
Varady et al. (2013) USA RCT, parallel IER vs. Control 32, Healthy normal 47.5 26 0 73 12 BW, FM, LDL, TG, SBP Dr. Varady
weight reported
and overweight receiving an
advance for
her book.
Otherwise
none
Viegener et al. (1990) USA RCT, parallel IER vs. CER 85, Healthy patients with 47.1 35.3 0 100 26 BW None
obesity or overweight
IER: intermittent energy restriction; BMI: body mass index; BW: body weight; CER: continuous energy restriction; FG: fasting glucose; FM: fat mass; HbA1c: glycosylated hemoglobin; LDL: low-density lipoprotein; RCT:
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION

randomized controlled trial; SBP: systolic blood pressure; TG: triacylglycerol; T2D: type 2 diabetes; WC: waist circumference; NA: not available.
5
6 L. SCHWINGSHACKL ET AL.

Table 2. Characteristics of the interventions of the included randomized controlled trials.

Specification of the
Specification of the Specification of the intervention/control
interventions arms (e.g. intervention/control arms (if applicable) (e.g.
Reference kcal per day) arms (e.g. kcal per day) kcal per day) Adherence Adverse events
Bhutani, 2013 (Bhutani IER (4:3): 25% of Control: Maintain NA 80% (IER) NA
et al. 2013) baseline requirement regular food habits
on fast days and were not
(consecutive). provided with any
food or
dietary counseling.
Carter, 2018 (Carter, IER (5:2): 500-600 kcal CER: 1200-1500 kcal/d. NA NA Eight T2D patients
Clifton, and on fast days (non- experienced
Keogh 2018) consecutive). hypoglycemia with
no difference
between IER
and CER.
Carter, 2016 (Carter, IER (5:2): 500-600 kcal CER: 1200-1500 kcal/d. NA NA Six T2D patients
Clifton, and on fast days experienced
Keogh 2016) (probably non- hypoglycemia with
consecutive; no difference
determined by between IER
participant). and CER.
Conley, 2018 (Conley IER (5:2): 600 kcal on CER: 500 kcal reduction NA 73% (IER) 75% No major adverse
et al. 2018) fast days (non- from baseline (CER) events
consecutive). requirement. were reported.
Harvie, 2013 (Harvie IER (5:2): 30% of CER: 25% energy NA 76% (IER) NA (CER) No major adverse
et al. 2013) baseline requirement restriction; events
and 40g carbohydrate Mediterranean- were reported.
on fast days type diet.
(consecutive);
Mediterranean-type
diet on feast days.
Harvie, 2011 (Harvie IER (5:2): 30% of CER: 25% energy NA 44% (IER) 32% (CER) No major adverse
et al. 2011) baseline requirement restriction from events
and 40g carbohydrate baseline requirement; were reported.
on fast days Mediterranean-
(consecutive); type diet.
Mediterranean-type
diet on feast days.
Hill, 1989 (Hill IER (4:3): consecutive CER: 1200 kcal/d. NA NA NA
et al. 1989) but weekly
alternating pattern;
average of <
1200 kcal/d.
Mraovic, 2018 (Mraovic IER (4:3), 30% and 70% CERa: 20% energy CERb: 50% energy NA NA
et al. 2018) of baseline restriction from restriction from
requirement (non- baseline requirement. baseline requirement.
consecutive).
Panizza, 2019 (Panizza IER (5:2): 30% of CER: 20% energy NA 91% (IER) NA (CER) No major adverse
et al. 2019) baseline requirement restriction from events
on fast days baseline were reported.
(consecutive); requirement þ DASH.
Mediterranean-type
diet on feast days.
Sch€ubel, 2018 (Schubel IER (5:2): 25% of CER: 20% energy Control: Guidelines of NA No major adverse
et al. 2018) baseline requirement restriction from the German Nutrition events
on fast days (non- baseline requirement. Society for a healthy were reported.
consecutive). balanced diet, and
support with
individual questions.
Sundfor, 2018(Sundfor, IER (5:2): 400/600 kcal CER: continuous NA NA No major adverse
Svendsen, and (female/male) on fast restriction (-400 to events
Tonstad 2018) days (non- -600 kcal/d), in total were reported.
consecutive). same energy intake
as IER group
per week.
Teng, 2011 (Teng IER (5:2) 300-500 kcal on Control: Maintain their NA NA NA
et al. 2011) fast days combined present lifestyle.
with Muslim Sunnah
fasting (meals at
sunrise and sunsets,
probably non-
consecutive).
NA NA NA
(continued)
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 7

Table 2. Continued.
Specification of the
Specification of the Specification of the intervention/control
interventions arms (e.g. intervention/control arms (if applicable) (e.g.
Reference kcal per day) arms (e.g. kcal per day) kcal per day) Adherence Adverse events
Teng, 2013 (Teng IER (5:2) 300-500 kcal on Control: Maintain their
et al. 2013) fast days combined present lifestyle.
with Muslim Sunnah
fasting (meals at
sunrise and sunsets,
probably non-
consecutive).
Todd, 2015 (Todd 2015) IER (5:2): 25% reduction CER: 25% energy NA NA NA
from baseline restriction from
requirement per baseline requirement;
week; Mediterranean- Mediterranean-
type diet on feast type diet.
days (consecutive).
Trepanowski, 2017 IER (4:3): 25% of CER: 20% energy Control: Maintain NA NA
Gabel, 2019 baseline requirement restriction from weight throughout
(Trepanowski et al. on fast days, 125% baseline requirement. the trial and not to
2017; Gabel on feast days (non- change their eating or
et al. 2019) consecutive). physical activity
habits. Controls
received no food or
dietary counseling but
visited the research
center at the same
frequency as the
intervention
participants (to
provide outcome
measurements).
Controls who
completed the 12-
month trial received 3
months of free
weight-loss counseling
and a 12-month gym
membership at the
end of the study.
Varady, 2013 (Varady IER (4:3): 25% of Control: Permitted to NA 98% (IER) NA No major adverse
et al. 2013) baseline requirement eat ad libitum every (Control) effects were reported.
on fast days (non- day, and were not
consecutive). provided with meals
from the
research center.
Viegener, 1990 IER (3:4): 1200 kcal on CER: 1200 kcal/d. NA 72% (IER) 78% No major adverse
(Viegener et al. 1990) fast days, low-fat, low (CER) effects were reported.
calorie diet (non-
consecutive).

0.24; I2 ¼ 0%, n ¼ 2 RCTs; moderate certainty of the evi-
dence) (Figures S2–4, Supplementary material).
IER vs CER. IER probably slightly reduces body weight (MD:
0.55 kg, 95% CI: 1.01, 0.09; I2 ¼ 0%, n ¼ 13 RCTs; moder-
ate certainty of the evidence), and fat mass (MD: 0.66 kg,
95% CI: 1.14, 0.19; I2 ¼ 0%, n ¼ 10 RCTs; moderate cer-
tainty of the evidence), and makes little to no difference to
waist circumference (MD: 0.57 cm, 95% CI: 1.56, 0.41;
I2 ¼ 0%, n ¼ 8 RCTs; high certainty of the evidence) when
compared to CER (Figures S5–7, Supplementary material).
Secondary outcomes
IER vs usual diet. Triacylglycerols may be slightly improved
by IER (MD: 0.20 mmol/L, 95% CI: 0.38, 0.03;
I2 ¼ 52%, n ¼ 5 RCTs; low certainty of the evidence), and
SBP is probably improved by IER (MD: 6.11 mmHg, 95%
CI: 9.59, 2.64; I2 ¼ 0%, n ¼ 5 RCTs; moderate certainty
of the evidence) as compared to a usual diet (Figures S8–9,
Supplementary material). No differences were observed for
LDL-C, FG, and HbA1c comparing IER vs. usual diet
(Figures S10–12 Supplementary material).
IER vs CER. Both, CER and IER have similar effects on
LDL-C, TG, SBP, FG and HbA1c (Figures S13–17
Supplementary material).
Subgroup and sensitivity analysis
In subgroup analyses, both IER4:3 and IER5:2 improved
anthropometric outcomes, such as body weight (MD4:3:
5.14 kg, 95% CI: 5.74, 4.54; MD5:2: 3.41 kg, 95% CI:
4.89, 1.93), and fat mass (MD4:3: 4.10 kg, 95% CI:
6.28, 1.92; MD5:2: 1.50 kg, 95% CI: 2.13, 0.87)
 8 L. SCHWINGSHACKL ET AL.

compared to a usual diet. The test for subgroup difference

IMPORTANT

IMPORTANT
Importance yielded a statistically significant (p < 0.05) more favorable
CRITICAL

CRITICAL

CRITICAL

CRITICAL
effect of IER4:3 (Table S1). In subgroup analyses, comparing
IER4:3 and IER5:2 with CER, IER5:2 (MD: 1.37 kg, 95% CI:
2.24, 0.49) performed slightly better than IER4:3 (MD:
MODERATE

MODERATE
Certainty

⨁⨁

⨁⨁

⨁⨁

⨁⨁
⨁⨁⨁

⨁⨁⨁
0.20 kg, 95% CI: 0.75, 0.35) for body weight. For the
LOW

LOW

LOW

LOW
comparison IERconsecutive days and IERnonconsecutive days a
slightly more pronounced beneficial effect on anthropomet-
(3.69 lower to 0.24 higher)

ric outcomes was observed favoring IERconsecutive days com-

(5.46 lower to 4.21 lower)

(3.78 lower to 1.31 lower)

(0.38 lower to 0.03 lower)

(9.59 lower to 2.64 lower)

(0.3 lower to 0.15 higher)
MD 0.08 mmol/L lower pared to CER (Table S2 Supplementary material). No

MD 6.11 mmHg lower

MD 0.2 mmol/L lower
subgroup differences were observed for disease status, sex,
Absolute
(95% CI)

MD 1.73 cm lower
MD 4.83 kg lower

MD 2.54 kg lower

and study length.

In sensitivity analyses, excluding high risk of bias (RoB)
RCTs, all findings of the main analysis were confirmed for
Effect

the comparison IER vs. usual diet. However, excluding high

RoB RCTs comparing IER vs. CER resulted in a slightly
more pronounced reduction in body weight (MD: 1.83 kg,
119-136 mmHg
2.9-3.6 mmol/L

1.1-1.9 mmol/L
99.0-104.2 cm
71.2- 93.3 kg

95% CI: 2.95, 0.72), and waist circumference (MD:

Comparator

18.2-42 kg
(Baseline)

1.35 cm, 95% CI: 2.58, 0.11) (Figures S18–19

Supplementary material).
Usual diet

Dietary adherence
No of patients

155

68

139

126

126

126

Adherence to IER was only reported in seven RCTs (41%),

and in three RCTs for CER. Average adherence for IER was
163

74

140

128

128

128

76% (range: 44% and 98%) and 62% (range 32% and 78%)
IER

for CER.
considerations
Other

Dissemination bias
none

none

none

none

none

none
Table 3. GRADE evidence profile – for the comparison intermittent energy restriction (IER) vs. usual diet.

Funnel plots for body weight and fat mass are shown in
Figures S20 and S21 (Supplementary material), and
Imprecision

appeared symmetric. The Egger’s test showed neither for

.downgraded since one RCT with weighting >50% judged as high risk of bias in two domains
seriousb,c
seriousb

seriousb

seriousb

seriousb

seriousb

body weight (p ¼ 0.32) nor for fat mass (p ¼ 0.77) a signifi-

cant asymmetry. Dissemination bias was mainly not assessed
.downgraded since 95% CI overlaps important benefit: -2 cm (de Koning et al. 2007)

based on funnel plots because all of the analyses (with the

Indirectness

not serious

not serious

not serious

not serious

not serious

not serious

exception of body weight and fat mass for the comparison

IER vs. CER) were based on <10 studies and the Cochrane
Systolic Blood Pressure (mmHg) (follow up: range 12 weeks to 24 weeks)

handbook recommends that
10 studies are necessary to

achieve clear conclusions regarding dissemination bias
.downgraded due to small sample size (<400) (Guyatt et al. 2011)
LDL-cholesterol (mmol/L) (follow up: range 12 weeks to 24 weeks)
Inconsistency

(Higgins et al. 2019).

not serious

not serious

not serious
seriousd

seriousd

seriousd
Body weight (kg) (follow up: range 12 weeks to 24 weeks)

Fat Mass (kg) (follow up: range 12 weeks to 24 weeks)

Discussion
TG (mmol/L) (follow up: range 12 weeks to 24 weeks)
Risk of bias

not serious

not serious

not serious

not serious

not serious

This systematic review synthesized direct evidence on the

Waist Circumference (cm) (follow up: 12 weeks)
seriousa

effects of IER vs. CER and usual diet on anthropometric

CI: Confidence interval; MD: Mean difference

.downgraded for inconsistency (I2
50%)

outcomes (body weight, waist circumference, fat mass) and

intermediate disease markers (LDL-C, TG, SBP, FG,
randomised trials

randomised trials

randomised trials

randomised trials

randomised trials

randomised trials

and HbA1c).
Study design

In summary, IER may reduce body weight, fat mass, TG

and probably improves waist circumference and SBP as
compared to a usual diet. Moreover, IER probably slightly
Certainty assessment

reduces body weight, and fat mass compared to CER. The

certainty of our findings was rated mainly low or moderate.
No of studies

In additional analyses, no important differences were

6

detected comparing different types of IER (4:3 vs. 5:2; con-

secutive vs. nonconsecutive days). Moreover, no subgroup
b

d
a

c
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 9

differences were observed for disease status, sex, and

IMPORTANT

IMPORTANT
Importance

CRITICAL

CRITICAL

CRITICAL

CRITICAL
study length.

Comparison with other systematic reviews

MODERATE

MODERATE

MODERATE

MODERATE
Certainty

⨁⨁⨁

⨁⨁⨁

⨁⨁⨁

⨁⨁⨁
⨁⨁⨁⨁

⨁⨁⨁⨁
Similarly to our systematic review, in a recent meta-analysis
HIGH

HIGH
of RCTs, IER was more effective than a usual diet to induce
weight loss (4 kg), and slightly more effective compared to
(1.56 lower to 0.41 higher)

(0.11 lower to 0.11 higher)

(0.13 lower to 0.06 higher)

(2.08 lower to 2.55 higher)

(1.01 lower to 0.09 lower)

(1.14 lower to 0.19 lower)

CER (Harris, Hamilton, et al. 2018). Moreover, IER was
more effective in reducing fat mass compared to a usual

MD 0.04 mmol/L lower

MD 0.24 mmHg higher

diet and CER, but these analyses were based on six RCTs
Absolute
(95% CI)

MD 0.57 cm lower
MD 0.55 kg lower

MD 0.66 kg lower

only, whereas we included 17 RCTs. On the contrary to our

MD 0 mmol/L

findings, in this meta-analysis no beneficial effects of IER

on SBP were reported, probably due to the low number of
Effect

included RCTs (Harris, Hamilton, et al. 2018).

Also in another meta-analysis of five RCTs, IER tended
Comparator (Baseline)

to be slightly more effective in reducing body weight as

116.8-140.8 mmHg
2.95-4.88 mmol/L

1.08-1.87 mmol/L
76.6- 107.5 kg

92.0-122.5 cm

compared to CER, although statistically not significant

26.4-42 kg

(Harris, McGarty, et al. 2018), whereas in two other meta-

analyses no differences were observed (Headland et al. 2016;
Cioffi et al. 2018). In line with our findings, in a meta-ana-
lysis investigating the effects of IER in comparison to CER
on intermediate disease markers (LDL, TG, FG and HbA1c),
No of patients

CER

519

345

396

303

323

295

no differences between the interventions were detected

Table 4. GRADE evidence profile – for the comparison intermittent energy restriction (IER) vs. continuous energy restriction (CER).

(Cioffi et al. 2018). In a before and after meta-analysis, IER

was equally effective in reducing body weight compared to a
472

296

347

276

264

277
IER

very low calorie diet, but was more effective in reducing fat
.downgraded since three out of eight RCTs with weighting >50% judged as high risk of bias in at least one domain

mass and showed lesser reduction of fat free mass

Other considerations

(Alhamdan et al. 2016). However, only one of the above

.downgraded since 95% CI overlaps important benefit (-2 mmHg) and harm (þ2 mmHg) (Ettehad et al. 2016)

mentioned meta-analyses evaluated the certainty of evidence

(Harris, Hamilton, et al. 2018), and all meta-analyses were
limited by a lower number of included RCTs (Harris,
none

none

none

none

none

none

.downgraded since a single RCT with weighting >50% judged as high risk of bias in two domains

Hamilton, et al. 2018; Headland et al. 2016; Alhamdan et al.

2016; Harris, McGarty, et al. 2018; Cioffi et al. 2018; Cho
Imprecision

not serious

not serious

not serious

not serious

et al. 2019), and were often limited by including also short-

seriousb

seriousd

term trials (12 weeks duration) (Alhamdan et al. 2016;

Cioffi et al. 2018; Cho et al. 2019).
The weight loss observed in our meta-analysis (4.83 kg),
Indirectness

not serious

not serious

not serious

not serious

not serious

not serious

following IER compared to a usual diet was comparable to

Systolic Blood Pressure (mmHg) (follow up: range 12 weeks to 26 weeks)

interventions with meal-replacement therapy (4 kg), but

were superior to interventions with orlistat (2.8 kg), or
Waist Circumference (cm) (follow up: range 12 weeks to 42 weeks)

LDL-cholesterol (mmol/L) (follow up: range 12 weeks to 42 weeks)

exercise alone (1.9 kg) (Franz et al. 2007). In a network

Inconsistency

not serious

randomised trials not serious not serious

randomised trials not serious not serious

not serious

randomised trials not serious not serious

randomised trials not serious not serious

.downgraded since 95% CI overlaps important benefit: -1 kg

meta-analysis, diet plus exercise was slightly (and signifi-

Body weight (kg) (follow up: range 12 weeks to 52 weeks)

cantly) more effective in reducing body weight (1.38 kg),

Fat Mass (kg) (follow up: range 12 weeks to 52 weeks)

TG (mmol/L) (follow up: range 12 weeks to 42 weeks)

waist circumference (1.68 cm) and fat mass (1.65 kg),

compared to diet alone, whereas diet was more effective
Risk of bias

CI: Confidence interval; MD: Mean difference

than exercise alone in reducing body weight (2.9 kg), and

randomised trials seriousa

randomised trials seriousc

fat mass (2.20 kg) (Schwingshackl, Dias, and Hoffmann

2014). Therefore, lifestyle interventions including both,
nutrition and exercise, seem to result in better results and
Study design

should be recommended since loss of muscle mass should

be preserved in weight loss interventions (Cava, Yeat, and
Mittendorfer 2017).
Certainty assessment

No of studies

Relevance of our findings

13

10

Clinical guidelines have concluded that in patients with

overweight and obesity, a reduction in body weight between
b

d
a

c
10 L. SCHWINGSHACKL ET AL.
5 and 10% of the initial body weight was inversely associ-
ated with risk of chronic diseases (Yumuk et al. 2015). In
our systematic review, weight loss (pre vs. post body weight)
was of sufficient magnitude to be associated with clinical
benefits following IER (range: 2.3 to 11.9 kg; mean:
5.8 kg) (Figures S2, S5, Supplementary material). This is an
important finding illustrating that most participants may
have lost equivalent or even greater than the 5% target
amount and thus provides evidence that IER regimens may
be clinically important approaches for weight management.
A recent meta-analysis of 54 RCTs with a study duration
of at least 12 months, provided high certainty of evidence
that weight loss interventions for patients with obesity
reduced the risk of overall mortality by nearly 20% (Ma
et al. 2017). Moreover, previous RCTs reported that a 5%
reduction of body weight is associated with a reduced risk
of type 2 diabetes. A 5-kg weight loss over time could
account for approximately 50% reduction in the risk of dia-
betes in a high-risk population (Hamman et al. 2006).
In a meta-analysis by Dattilo and Kris-Etherton (Dattilo
and Kris-Etherton 1992), each kilogram of weight loss was
associated with a 0.015 mmol/L decrease in TG. In our sys-
tematic review we observed a reduction of 0.2 mmol/L for
IER compared with a usual diet. Although reduction in TG
observed in our meta-analysis was clinically not relevant,
our findings underline the observations by Dattilo and
Kris-Etherton.
Regarding the influence of weight loss on SBP, our sys-
tematic review is in line with a meta-analysis of 25 RCTs,
showing that a weight reduction of 5 kg reduced SBP by
4.5 mmHg (Neter et al. 2003). The importance of blood
pressure reduction, as shown for IER is strengthened by a
large meta-analysis of epidemiological studies which have
shown that a decrease of approximately 10 mmHg reduction
in SBP was inversely associated with risk of cardiovascular
disease events by 20%, coronary heart disease by 17%, stroke
by 27%, heart failure by 28% and all-cause mortality by 13%
(Ettehad et al. 2016).
Strength & limitations
Our systematic review has several strengths and limitations
that need to be considered. Amongst the strengths are the a-
priori published protocol, the comprehensive search strategy,
risk of bias assessment, subgroup and sensitivity analyses,
evaluation of heterogeneity, assessment of possible dissemin-
ation bias, and the GRADE certainty of evidence judgment.
First, limitations of the current literature are the absence
of long-term IER trials (>12 months), therefore, we were
not able to provide data on the persistence of effects.
Second, the certainty of evidence was rated mainly low or
moderate for most outcomes. This was mostly driven by
risk of bias and imprecision (due to low sample size): over-
all, eight RCTs (47%) were rated with a high risk of bias,
due to issues with allocation concealment, blinding of out-
come assessments, and incomplete outcome data. Third, due
to the low number of RCTs addressing single outcomes, it
was not possible to investigate dissemination bias through
funnel plots for most outcomes, and to conduct several a-
priori planned subgroup analyses. Fourth, adherence to the
interventions is of major concern when interpreting inter-
vention studies but it was only reported in seven RCTs for
the IER groups and in three RCTs for the CER groups.
Therefore, effects of interventions may differ when adher-
ence would only be low. Fifth, we did not include restricted
time feeding regimens (where food is only consumed for a
certain number of consecutive hours per day and people fast
for the rest of the 24 h (Ganesan, Habboush, and Sultan
2018)) into our analysis due to the fact that only very few
trials exist and all of them last shorter than 12 weeks, or
were not randomized. Sixth, the statistically significant dif-
ferences in the effects of IER vs. CER on body weight and
fat mass should be interpreted with caution, as they were
marginal and because the majority of studies did not include
an objective assessment of actual energy intake. Thus, it can-
not be ruled out that slightly greater decreases in body
weight and fat mass were due to slightly lower net energy
intake under IER compared to CER. Finally, we were not
able to conduct a network meta-analysis to compare simul-
taneously all of the different fasting types (e.g. ADF,
restricted time feeding regimens), as we had planned in the
protocol of this study, due to the scarcity of the evidence.
Conclusion
In conclusion, IER may improve body weight, fat mass, TG,
and SBP as compared to a usual diet, but likely makes little
differences compared to CER. The improvements in
anthropometric outcomes in comparison to usual diet -if
true- are clinically relevant. Further research will likely pro-
vide important additional data to impact on the certainty of
the evidence, and will possibly change the effect estimate.
Well conducted long-term RCTs are needed to provide data
on persistence of effects, and strengthen the certainty of
the evidence.
Acknowledgements
SL participated in this project during her research stay at the Institute
for Evidence in Medicine, University of Freiburg, supported by the
Alexander von Humboldt Foundation, Germany.
Abbreviations
IER .intermittent energy restriction
RCTs randomized controlled trials
CER continuous energy restriction
MD mean difference
CI confidence interval
LDL-C low-density lipoprotein cholesterol
WHO World Health Organization
BMI body-mass index
IF intermittent fasting
ADF alternate-day fasting
TRF time restricted feeding
GRADE Grading of Recommendations, Assessment,
Development, and Evaluation
PROSPERO Prospective Register of Systematic Reviews
CENTRAL Cochrane Central Register of Controlled Trials
TG triacylglycerol

SBP systolic blood pressure
FG fasting glucose
HbA1c glycated hemoglobin
T2D type 2 diabetes
RoB risk of bias
Disclosure statement
The authors have no conflict of interest to declare.
Financial support
No funding to declare.
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