Do intermittent diets provide physiological benefits over ...373046/UQ373046_OA.pdf · Wood, R.E,...

Accepted Manuscript

Do intermittent diets provide physiological benefits over continuous diets for weightloss? A systematic review of clinical trials

Radhika V. Seimon, Jessica A. Roekenes, Jessica Zibellini, Benjamin Zhu, Alice A.Gibson, Andrew P. Hills, Rachel E. Wood, Neil A. King, Nuala M. Byrne, AmandaSainsbury

PII: S0303-7207(15)30080-0

DOI: 10.1016/j.mce.2015.09.014

Reference: MCE 9281

To appear in: Molecular and Cellular Endocrinology

Received Date: 21 April 2015

Revised Date: 14 September 2015

Accepted Date: 15 September 2015

Please cite this article as: Seimon, R.V, Roekenes, J.A, Zibellini, J., Zhu, B., Gibson, A.A, Hills, A.P,Wood, R.E, King, N.A, Byrne, N.M, Sainsbury, A., Do intermittent diets provide physiological benefitsover continuous diets for weight loss? A systematic review of clinical trials, Molecular and CellularEndocrinology (2015), doi: 10.1016/j.mce.2015.09.014.

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http://dx.doi.org/10.1016/j.mce.2015.09.014

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ACCEPTED MANUSCRIPTSeimon et al, 2015

1

Do intermittent diets provide physiological benefits over continuous diets for weight loss? A 1

systematic review of clinical trials 2

Radhika V Seimona, Jessica A Roekenesa, Jessica Zibellinia, Benjamin Zhua, Alice A 3

Gibsona, Andrew P Hillsb, Rachel E Woodc, Neil A Kingd, Nuala M Byrnec, Amanda 4

Sainsburya 5

aThe Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, Sydney Medical 6

School, The University of Sydney, Camperdown NSW 2006, Australia 7

bCentre for Nutrition and Exercise, Mater Research Institute, The University of Queensland, 8

South Brisbane QLD 4101, Australia 9

cBond Institute of Health and Sport, Faculty of Health Sciences and Medicine, Bond University, 10

Gold Coast, Australia 11

dInstitute of Health and Biomedical Innovation and School of Exercise and Nutrition Sciences, 12

Queensland University of Technology, Brisbane QLD 4059, Australia 13

Address for correspondence: Amanda Salis (nee Sainsbury) 14

The Boden Institute of Obesity, Nutrition, Exercise & Eating 15

Disorders 16

Sydney Medical School 17

The University of Sydney 18

Camperdown NSW 2006 19

Australia 20

Phone: +61 4 23777801 21

Email: [email protected] 22

23

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Running head: Intermittent versus continuous energy restriction 24

Abbreviations 25

ADF Alternate day fasting 26

BMI Body mass index 27

CER Continuous energy restriction 28

DHEAS Dehydroepiandrosterone sulphate 29

24-hour EE 24-hour Energy expenditure 30

EI Energy intake 31

ER Energy restriction 32

EX Exercise 33

FFM Fat-free mass 34

%FM Percent fat mass 35

FM Fat mass 36

HbA1C Glycated hemoglobin 37

Hip Hip circumference 38

HOMA-IR Homeostatic model assessment – [Insulin Resistance] 39

IER Intermittent energy restriction 40

IGF-1 Insulin-like growth factor-1 41

REE Resting energy expenditure 42

T3 Triiodothyronine or 3,3′,5-triiodothyronine 43

T4 Thyroxine or 3,5,3′,5′- tetraiodothyronine 44

TSH Thyroid stimulating hormone 45

Waist Waist circumference46

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ABSTRACT (150 words maximum) 47

Energy restriction induces physiological effects that hinder further weight loss. Thus, deliberate 48

periods of energy balance during weight loss interventions may attenuate these adaptive 49

responses to energy restriction and thereby increase the efficiency of weight loss (i.e. the amount 50

of weight or fat lost per unit of energy deficit). To address this possibility, we systematically 51

searched MEDLINE, PreMEDLINE, PubMed and Cinahl and reviewed adaptive responses to 52

energy restriction in 40 publications involving humans of any age or body mass index that had 53

undergone a diet involving intermittent energy restriction, 12 with direct comparison to 54

continuous energy restriction. Included publications needed to measure one or more of body 55

weight, body mass index, or body composition before and at the end of energy restriction. 31 of 56

the 40 publications involved ‘intermittent fasting’ of 1-7-day periods of severe energy restriction. 57

While intermittent fasting appears to produce similar effects to continuous energy restriction to 58

reduce body weight, fat mass, fat-free mass and improve glucose homeostasis, and may reduce 59

appetite, it does not appear to attenuate other adaptive responses to energy restriction or improve 60

weight loss efficiency, albeit most of the reviewed publications were not powered to assess these 61

outcomes. Intermittent fasting thus represents a valid – albeit apparently not superior – option to 62

continuous energy restriction for weight loss. 63

64

Keywords (maximum of 6 keywords, using British spelling and avoiding general and plural 65

terms and multiple concepts (avoid, for example, 'and', 'of'). 66

67

Intermittent energy restriction; alternate day fasting; appetite; energy expenditure; body 68

composition; glucose homeostasis 69

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Contents 70

71

1. Introduction 72

2. Methods for the systematic review of intermittent energy restriction 73

2.1. Inclusion and exclusion criteria 74

2.2. Search strategy 75

2.3. Data extraction and analysis 76

3. Results and discussion for the systematic review of intermittent energy restriction 77

3.1. Search results, sample sizes and intervention characteristics 78

3.2. Comparable dropout rates for interventions involving IER or CER 79

3.3. IER consistently reduces body weight, body size and adiposity 80

3.4. Comparable weight loss for interventions involving IER or CER 81

3.5. Effects of IER on the drive to eat and mood 82

3.6. No evidence that current IER protocols reduce other adaptive responses to energy 83

restriction 84

3.7. Comparable improvements in glucose homeostasis for interventions involving IER 85

or CER 86

3.8. Impact of exercise on effects of IER 87

3.9. Limitations and future directions 88

4. Summary and conclusions 89

Acknowledgements 90

References 91

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Graphical abstract (optional) 92

Not provided. 93

94

Highlights 95

Highlights are mandatory for this journal. They consist of a short collection of bullet points that 96

convey the core findings of the article and should be submitted in a separate editable file in the 97

online submission system. Please use 'Highlights' in the file name and include 3 to 5 bullet points 98

(maximum 85 characters, including spaces, per bullet point). See 99

http://www.elsevier.com/highlights for examples. 100

101

• Energy restriction induces adaptive physiological responses that hinder weight / fat loss. 102

• Intermittent energy balance periods might reduce adaptive responses during energy 103

restriction. 104

• Intermittent fasting reduces body weight and possibly appetite but not other adaptive 105

responses. 106

• Intermittent fasting is an equivalent alternative to continuous energy restriction for weight 107

loss. 108

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1. Introduction 109

110

Recent years have seen a surge in popularity of eating patterns involving intermittent energy 111

restriction (IER). Such eating patterns involve restricting energy intake by varying degrees for a 112

pre-defined period of time, and eating ad libitum (i.e. to satisfy appetite) – or at least more than 113

during the energy-restricted period – at all other times. The most common form of IER is 114

‘intermittent fasting’, where energy intake is severely restricted for short periods (typically 1 to 4 115

days per week). During periods of greater energy intake, there may or may not be restrictions 116

placed on the types and amounts of foods and beverages consumed. 117

118

While IER in varying forms has been used for health and religious reasons for thousands of years 119

(1, 2), it has more recently been popularised in a weight management context through various 120

forms of the media. IER contrasts with the conventional approach to weight management, or 121

continuous energy restriction (CER). The latter entails continuously trying to restrict energy 122

intake to below weight maintenance requirements for an extended and often open-ended period 123

of time, and usually also involves restrictions on the types of foods consumed (e.g. limiting the 124

intake of energy-dense, nutrient-poor foods). 125

126

A question that has not been extensively addressed is whether or not IER provides physiological 127

benefits over CER for weight management. For instance, is there a ‘metabolic advantage’ 128

associated with IER? Specifically, does energy restriction achieved via IER result in greater 129

weight or fat loss than the same overall amount of energy restriction achieved by CER? Or, do 130

people who follow IER lose the same amount of weight or fat per unit of energy restriction, on 131

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average, as those on CER? IER might be expected to result in more efficient weight loss than 132

CER, because of the known effects of energy restriction to induce physiological responses that 133

oppose ongoing weight loss, and because of emerging evidence that these adaptive responses can 134

be normalised or at least attenuated by a period of energy balance (i.e. where energy intake is 135

matched to energy requirements and weight remains constant) or by ad libitum food intake. 136

These considerations will be briefly reviewed in the next paragraph. 137

138

The adaptive responses to energy restriction in individuals that are overweight or obese are 139

numerous and have been reviewed elsewhere (Sainsbury A, Seimon RV, Hills AP, Wood RE, 140

King NA, Gibson AA, Byrne NM, submitted manuscript, (3-11). They include increased appetite 141

(12-15), reduced physical activity (16, 17) or the energy cost of physical activity (16, 18-21), 142

reduced energy expenditure greater than that expected from the reduction in body mass (22, 23), 143

and hormonal effects that can adversely affect body composition by promoting the accumulation 144

of adipose tissue (particularly central adiposity) and stimulating the loss of lean tissues (3, 24-145

27). Indeed, studies in lean animals and humans clearly show that negative energy balance 146

markedly inhibits activity of the hypothalamo-pituitary-thyroid (28), -gonadotropic and -147

somatotropic axes (or reduces circulating insulin-like growth factor-1 [IGF-1] levels) (29), while 148

concomitantly activating the hypothalamo-pituitary-adrenal axis (3, 26). There is little 149

information available as to the effects of weight loss in people that are overweight or obese on 150

the circulating concentrations of effector hormones of these neuroendocrine axes (notably 151

thyroid hormones, sex hormones, IGF-1 and cortisol), but available evidence suggests that 152

similar changes to those occurring during energy deficit in lean animals and humans may also 153

occur in overweight and obese people during weight loss interventions (3, 24-27). Such changes 154

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could conceivably hamper outcomes from weight loss interventions, by fostering a hormonal 155

milieu known to promote accretion of adipose tissue (particularly central adiposity) while 156

simultaneously promoting loss of lean tissues (3). Some research suggests that the greater the 157

deficit between energy requirements and intake, the greater the magnitude of these adaptive 158

responses (22, 23, 30-32). Interestingly, several lines of evidence from lean (33, 34) and 159

overweight or obese (17, 24, 35-39) humans suggest that some adaptive responses to energy 160

restriction may be deactivated or partially deactivated by well-controlled restoration of energy 161

balance and weight maintenance at the reduced body weight, at least in some individuals. This 162

phenomenon appears to be dependent upon restoration of true energy balance or even positive 163

energy balance (not continued energy restriction) (24), although positive energy balance was not 164

a panacea for all aspects of the adaptive response to energy restriction (13, 14), as reviewed 165

elsewhere (Sainsbury A, Seimon RV, Hills AP, Wood RE, King NA, Gibson AA, Byrne NM, 166

submitted manuscript). Deactivation of adaptive responses to energy restriction may also occur 167

more effectively when exercise is incorporated into the weight management regime (Sainsbury 168

A, Seimon RV, Hills AP, Wood RE, King NA, Gibson AA, Byrne NM, submitted manuscript, 169

(16, 40-43). Taken together, this literature would suggest that deliberate periods of energy 170

balance during weight loss interventions – as in IER – could attenuate or deactivate various 171

adaptive responses to energy restriction and thereby increase the efficiency of weight loss. But 172

what is the evidence for this in humans? 173

174

To this end, we conducted a systematic review of original human clinical trials involving IER. 175

We included studies with humans of any age or body mass index (BMI) incorporating a diet 176

involving IER, with or without comparison to CER or a control arm, in order to assess any 177

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evidence that IER may reduce or fail to induce adaptive responses to energy restriction, or 178

improve the efficiency of weight loss. To be included in the review, publications needed to 179

measure body weight, BMI or body composition both before commencement of the intermittent 180

diet, as well as upon completion of the diet. 181

182

2. Methods for the systematic review of intermittent energy restriction 183

184

2.1 Inclusion and exclusion criteria 185

Study designs included in this review were human clinical trials (randomized controlled trials 186

and pilot studies). Only original research studies were included; review articles, case studies, 187

surveys, as well as abstracts and conference papers, were excluded. To be included in this 188

systematic review, publications needed to have investigated humans of any age or BMI that had 189

undergone a diet involving IER. Ramadan fasting as a form of IER was excluded due to the 190

pattern of eating not matching that of common forms of intermittent diets, but Sunnah fasting (nil 191

by mouth, sunrise to sunset, typically 2 days per week) was included, as it is of a similar format 192

to other forms of IER. Studies that did and did not include a comparator group on CER or control 193

conditions were included, to give a broad perspective of the wide variety of ways in which IER is 194

being investigated. 195

196

No limit was placed on the duration of IER. Studies were excluded if participants had undergone 197

bariatric surgery, were diagnosed with cancer, Crohn’s disease or were taking medications 198

designed to induce weight loss. Any non-surgical, non-cancer or non-medication arms of any of 199

the above such studies could, however, be included if they met the inclusion criteria. 200

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201

To be included in this review, publications needed to measure one or more of the following 202

parameters both before commencement of the intermittent diet, as well as at a time point upon 203

completion of the diet: body weight, BMI or body composition. We used these broad outcome 204

measures as inclusion criteria rather than the adaptive responses to energy restriction, because 205

very few studies have investigated the latter outcomes (i.e. drive to eat, physical activity, energy 206

expenditure, and circulating concentrations of thyroid, adrenal, gonadal or somatotropic 207

hormones). 208

209

2.2 Search strategy 210

MEDLINE, PreMEDLINE, PubMed and Cinahl were searched from the inception date of each 211

database to November 2014. Both medical subject headings (MeSH) and free text search terms 212

were employed. Limitations were set so that only studies published in English and involving 213

human participants were found. Reference lists of relevant articles as well as review articles were 214

searched to help ensure that all relevant studies were found. 215

216

The following example shows the specific key words (or MeSH terms) used for the search of 217

MEDLINE: 218

Alternate day fast*.tw OR alternat* calori* diet*.tw OR alternate day diet*.tw OR 219

intermittent fast*.tw OR alternate day modified fast*.tw OR intermittent energy fast*.tw 220

OR intermittent energy restrict*.tw OR intermittent energy diet*.tw OR intermittent 221

energy restrict* diet*.tw OR (intermittent adj2 diet*).tw OR intermittent food depriv*.tw 222

OR intermittent calori* restrict*.tw OR (intermittent adj2 restrict*).tw 223

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The example search strategy for MEDLINE (above) was adapted to suit each database. 224

225

2.3 Data extraction and analysis 226

The titles and abstracts of the studies identified in the above search strategy were independently 227

screened by two authors (JAR and JZ). The full texts of potentially relevant studies were 228

retrieved and were independently screened by the same authors (JAR and JZ) according to the 229

inclusion and exclusion criteria. If discrepancies between the two screening authors arose as to 230

which studies to include or exclude, consensus was reached by consultation with a third author 231

(RVS). Additional articles that the authors knew about from other sources, but did not come up 232

in the search, were also included in this review. 233

234

Two authors (JAR and BZ) extracted the following data from each study, as summarized in 235

Table 1: author, year, sample size, participant characteristics (sex, age, BMI), the percent of 236

participants who dropped out of the intervention (as well as the percent that dropped out due to 237

inability to adhere to the intervention), duration and design of the intervention, description of 238

IER and CER or control arms, weight change, anthropometric changes, effects on glucose 239

homeostasis, as well as other changes related to the adaptive responses to energy restriction. Data 240

extraction was checked by two additional authors (RVS and AS). 241

242

Publications included in this review used different definitions, units and terminology to describe 243

the interventions, so the following standardized definitions were applied. Durations of 244

interventions were expressed in weeks, and all data provided in other units of time were 245

converted to weeks (1 month = 4.3 weeks; 1 year = 52 weeks). Severe energy restriction was 246

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defined as a prescribed or measured energy intake of less than 5,000 kJ per day (44, 45), and 247

moderate energy restriction was defined as a prescribed or measured energy intake of greater 248

than or equal to 5,000 kJ per day (32). All data that were provided in calories were converted to 249

kJ (1 calorie = 4.18 kJ). Energy intake (prescribed or measured) during the fast and feed days 250

was not reported in every publication, hence we made the following assumptions and estimations 251

when presenting daily energy intake. Namely, an energy-restricted intervention that prescribed a 252

meal replacement program was assumed to be severely energy restricted, and an intervention that 253

described a food-based diet emphasizing healthy food choices was assumed to be moderately 254

energy restricted. Additionally, some studies that did not report prescribed or measured energy 255

intake reported on the degree of energy intake or restriction relative to weight maintenance 256

requirements, and we presented these as percent energy restriction (e.g. 100% energy restriction 257

for an energy intake of 0% of requirements [complete fasting]; 75% energy restriction for an 258

energy intake of 25% of requirements). Energy restriction of 65% or more was designated as 259

severe energy restriction; less than that was deemed to be moderate energy restriction. Where it 260

was necessary to assume weight maintenance energy requirements, this was assumed to be 261

10,000 kJ per day for participants that were overweight or obese, and 8,700 kJ per day for those 262

that were lean. Data were extracted qualitatively according to the authors’ results and 263

conclusions about the change from baseline, with upwards arrows referring to statistically 264

significant increases, downwards arrows referring to statistically significant decreases, or 265

sideways arrows referring to no statistically significant changes from baseline. The dropout rates 266

reported in Table 1 were rates at the end of the total study period (including any follow up), not 267

the weight loss intervention period noted in the table. Also, the sample sizes reported in Table 1 268

represent the total number of participants enrolled in the study. These values were extracted from 269

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the methods section of each publication and not from the abstract, as the abstract of some 270

publications only reported on the number of participants that completed the study and not on the 271

number of participants initially enrolled. 272

273

274

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Figure 1. Flow diagram for the process of publication selection, inclusion and exclusion from 275

this systematic review 276

277

278

Publications discovered through electronic database search: n = 402

Publications excluded after application of inclusion and exclusion criteria: n = 40

Protocol: n = 22

Participants: n = 5

Ramadan fasting: n = 13

Number of articles screened (after duplicates removed): n = 308

Full text publications retrieved after screening titles and abstracts: n = 72

Publications included after application of inclusion and exclusion criteria: n = 32

Articles authors knew about from other sources: n = 8

Publications included in the systematic review: n = 40

Publications comparing IER with CER: n = 12

Publications comparing IER to a control arm: n = 8

Publications of IER alone with no comparator arm: n = 20

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3. Results and discussion for the systematic review of intermittent energy restriction 279

280

3.1 Search results, sample sizes and intervention characteristics 281

A total of 402 records were retrieved from the 4 databases searched, equating to 308 unique 282

publications. Following screening of titles and abstracts, the full texts of 72 potentially relevant 283

publications were retrieved and analyzed against the inclusion and exclusion criteria, resulting in 284

the exclusion of 40 publications for the reasons shown in Figure 1. No further publications were 285

identified from screening the reference lists of these 72 publications. As a result, 32 publications 286

from the search, plus 8 additional articles known to the authors (39, 46-52), were included in this 287

systematic review (Figure 1). These 40 included publications involved 32 independent clinical 288

trials, with results from some trials being reported on in more than one publication. Twelve 289

publications compared the effectiveness of IER to CER, 8 publications compared the 290

effectiveness of IER to a control arm, while 20 publications examined the effect of IER alone, as 291

shown in Figure 1 and the alphabetical listing of the included publications in Table 1. 292

293

Sample size for each publication varied from 4 to 334 participants, with the most common 294

sample size being between 30 to 60 participants. Of the 40 publications included, 17 publications 295

included females only, 6 included males only, while the remaining 17 publications included both 296

males and females. The lowest included age was 17 years and the greatest was 79 years. 297

Participants had a minimum included BMI of 20 kg/m2 and maximum included BMI of 45 298

kg/m2. In most trials, participants were overweight or obese, but 9 of the 40 publications in this 299

review included lean participants (51, 53-60). Of these 9 publications, 1 included lean 300

participants only in the control and not the intervention arm (60), 5 included a mixed population 301

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of lean and overweight participants (51, 54-56, 59), and 3 included lean participants only (53, 57, 302

58). 303

304

The overall duration of the interventions varied from 2 to 104 weeks, with the most common 305

duration being 12-13 weeks. The majority of included publications involved intermittent fasting 306

regimes, with short periods (1-7 days) of severe energy restriction alternating with periods of 307

moderate energy restriction or no energy restriction. Indeed, of the 40 publications, 31 308

publications used intermittent fasting regimes, 19 of which used alternate day fasting (ADF) as a 309

means of IER (47, 53, 55, 58, 61-75), which consisted of a ‘‘fast day’’ (where energy intake is 310

usually severely restricted to about 25% of energy requirements, or 75% energy restriction) 311

alternating with a ‘‘feed day’’ (usually involving a prescription of ad libitum food consumption). 312

The other 12 of the 31 publications that used intermittent fasting regimes used short periods of 313

severe energy restriction during a “fasting phase” of 2 to 7 days per week (48, 51, 56, 57, 59, 60, 314

76-81). Besides these 31 publications investigating intermittent fasting regimes, a further 7 of the 315

40 included publications used longer periods of severe energy restriction (2-12 consecutive 316

weeks) (39, 49, 50, 52, 82-84). Only 2 of the 40 publications reviewed used moderate energy 317

restriction during the “fasting phase” of the IER protocol (46, 85). 318

319

3.2 Comparable dropout rates for interventions involving IER or CER 320

Of the 12 publications that compared IER with CER, 10 publications reported the percentage of 321

participants that dropped out of the intervention. Of these 10 publications, 3 showed a greater 322

dropout rate in the IER compared with the CER arm (52, 66, 79), 5 showed the opposite result 323

(46, 48, 73, 78, 85), while 2 studies only reported the overall dropout rate of both arms combined 324

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(76, 84), indicating no clear difference in dropout rate with IER compared to CER. Of the 2 325

publications that reported on the proportion of people that dropped out due to inability to adhere 326

to the intervention, both publications showed a greater dropout rate due to inability to adhere to 327

the CER compared with the IER arm (78, 79). Only 4 of the 8 publications that compared IER 328

with a non-CER control arm reported the percentage of participants who dropped out of the trial. 329

Two publication showed a greater dropout rate in the IER than in the control arm (51, 62), one a 330

greater dropout in the control arm (56), while another showed no between-group difference (74). 331

Of the 20 publications that looked at IER alone, 15 reported dropout rates (39, 47, 49, 61, 67-72, 332

75, 80-83), which ranged from 0-65%. Of these 15 studies, 12 reported dropout rates due to 333

participants being unable to adhere to the diet, and this ranged from 3-10%. Reported dropout 334

rates in the treatment of obesity are heterogeneous and range from 10 to 80% depending on the 335

setting and type of program used (86, 87). As dropout is an indicator of non-adherence to an 336

intervention (as well as other factors), these data provide no clear evidence that IER is easier to 337

adhere to than other dietary weight loss approaches. Future trials of IER would benefit from 338

documentation of dropout as well as assessment of adherence rates. 339

340

3.3 IER consistently reduces body weight, body size and adiposity 341

The findings from this systematic review clearly show that IER is an effective method for weight 342

loss. All but 3 (53, 57, 58) of the 40 publications included in this review reported that IER 343

produced weight loss, with no reports of weight gain. The minimum weight loss was 2.1 kg after 344

3 weeks (54), and the maximum weight loss was 16.6 kg after 20 weeks (39), with the most 345

common weight loss being 3-5 kg after approximately 10 weeks of IER. All of the 3 publications 346

that reported no change in weight during IER involved only lean participants (53, 57, 58). Of 347

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these 3 studies in lean participants, 2 involved interventions of only 2 weeks, which may have 348

been insufficient to result in weight change (53, 58). 2 of these 3 publications in lean individuals 349

(53, 57) noted that the lack of weight loss may have been due to compensation for the fasting 350

phases, with participants eating more abundantly during non-fasting days as per protocol 351

instructions, or in compensation for previous restriction. 352

353

Besides body weight, IER also produced clear reductions in other indices of body size and 354

adiposity, namely BMI, waist circumference, hip circumference, FM and FFM. Of the 32 355

independent trials (40 publications) included in this review, 13 reported on BMI, with 10 of these 356

reporting a decrease following IER (39, 47, 51, 52, 56, 59, 63, 71, 77, 80), 2 reporting no change, 357

albeit both of these studies involved lean participants (53, 57), while 1 reported a decrease in 358

BMI following one form of IER and no change following another form of IER (61). Only 13 359

publications reported waist circumference: 12 reported a decrease in response to IER (39, 47-49, 360

63, 69, 76-79, 81, 85), and 1 reported a decrease in waist circumference following one form of 361

IER and no change following another form of IER (61). Hip circumference was reduced by IER 362

in all of the 3 interventions that reported it (48, 78, 79), albeit there was no effect of IER on the 363

ratio of waist to hip circumference (66). Twenty three (23) of the 32 independent trials reported 364

on FM, either as a percent of body weight or as absolute weight: 20 reported a decrease (39, 47, 365

49, 51, 55, 56, 59, 60, 63, 66, 70, 74, 76-80, 82, 83, 85), 2 trials, both in lean participants, 366

reported no change (53, 58), while 1 reported a decrease in FM following one form of IER and 367

no change following another form of IER (61). Finally, of the 32 independent trials included in 368

this review, 17 reported on FFM. Of these trials, 9 reported a decrease (39, 49, 55, 64, 66, 78, 79, 369

82, 85), while 8 reported no change (51, 58, 59, 61, 63, 70, 74, 80) in FFM following IER. On 370

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balance, the majority of publications reporting on various indicators of body size and 371

composition showed reductions in indices of size and adiposity, and only approximately half of 372

the publications showed reductions in FFM with IER. 373

374

3.4 Comparable weight loss for interventions involving IER or CER 375

Of the 12 publications covering 12 independent trials comparing the effectiveness of IER to 376

CER, 9 demonstrated that IER was not significantly different from CER with respect to weight 377

loss (46, 48, 50, 66, 73, 76, 78, 79, 85), but 1 reported a greater weight loss in the CER group 378

compared with the IER group (64), while another 2 reported the opposite result of greater weight 379

loss in the IER group compared with the CER group (52, 84). In the 12 publications that 380

compared IER with CER, 7 reported on BMI, waist circumference, hip circumference or the ratio 381

of waist to hip circumference (48, 52, 66, 76, 78, 79, 85). These publications unanimously 382

showed that IER and CER induced equivalent reductions in BMI (52), waist circumference (48, 383

76, 78, 79, 85) and hip circumference (48, 78, 79), with neither intervention inducing a reduction 384

waist to hip ratio (66). In the 12 publications that compared IER with CER, 5 reported on FM, 385

with no difference reported between IER and CER in 4 of these publications (66, 76, 79, 85), 386

while 1 publication reported a greater decrease in FM in the IER group (78). Of the 12 387

publications directly comparing IER with CER, 5 reported on FFM, with no difference reported 388

in 4 of these publications (64, 66, 78, 79), and 1 publication reporting a greater decrease in FFM 389

in the IER group (85). Taken together, it can be seen that IER appears to be comparable to CER 390

with respect to weight loss and the location and composition of the body weight lost. 391

392

3.5 Effects of IER on the drive to eat and mood 393

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Of the 32 independent trials included in this review, only 10 investigated aspects of the drive to 394

eat. Two of these 10 independent trials compared IER against CER, with both showing a greater 395

number of participants in the IER than the CER arm reporting hunger and / or preoccupation 396

with food, albeit the proportion of participants affected was low (only 3-15% in the IER arm and 397

0-7% in the CER arm) (78, 79). Two of these 10 independent trials compared IER with a non-398

CER control arm (62, 74). Despite significant weight loss in both trials, 1 reported decreases 399

from baseline in hunger and uncontrolled eating with concomitant increases in fullness, 400

satisfaction and restrained eating (with no difference in emotional eating) in the IER but not the 401

control group (62), and the other reported no difference from baseline in hunger and an increase 402

in fullness and satisfaction in the IER group, with no such change in the control group (74). The 403

other 6 publications that investigated appetite (55, 57, 67-69, 81) investigated IER without any 404

comparator arm. Of these, 2 publications reported a decrease from baseline in appetite (as 405

indicated by decreases in hunger and increases in fullness and / or satisfaction) despite 406

significant weight loss (68, 69), 2 publications, one in obese (55) and one in lean participants that 407

did not lose weight (57), reported an increase from baseline in measures of appetite (increased 408

hunger or ‘drive to eat’ or preoccupation with food, with concomitantly reduced fullness and no 409

change in satisfaction or the ‘desire to eat’), while 2 reported no change from baseline in appetite 410

measures (hunger, fullness, satisfaction) with concurrent weight loss (67, 81) following IER. In 411

sum, 4 of these 10 independent trials that investigated aspects of the drive to eat showed that IER 412

increased measures of appetite (55, 57, 78, 79), while 6 showed that IER either decreased (62, 413

68, 69, 74) or had no significant effect on appetite (67, 81). It is noteworthy that these decreases 414

or lack of change in overall appetite indices occurred despite significant weight loss in all of the 415

6 aforementioned IER interventions (62, 67-69, 74, 81), given that weight loss has been 416

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associated with increases in the drive to eat (11-15). It is also noteworthy that this apparent 417

suppression of the drive to eat occurred despite decreased circulating levels of the appetite-418

reducing hormone, leptin, following IER. Indeed, of the 8 publications that reported leptin 419

concentrations in IER, 7 showed significant reductions from baseline in circulating leptin levels 420

(39, 61, 69, 74, 78-80), with 1 of these studies showing no difference from baseline (67). Thus, it 421

would seem that IER may attenuate the effect of energy restriction to increase the drive to eat. 422

423

A decrease in hunger or increase in fullness or satiety – or no change in these parameters from 424

baseline despite significant weight loss and reduced leptin levels – is in keeping with the finding 425

that participants on IER protocols involving severe energy restriction exhibited no change from 426

baseline in fasting (55, 67) or meal-induced (54) circulating concentrations of the hunger-427

promoting hormone, ghrelin, albeit there was a significant increase in fasting ghrelin levels 428

during fast days in one trial (79), and is also in keeping with the increase (55, 57, 67, 79) or non-429

significant trend (P = 0.07) to an increase (53) in circulating concentrations of the ketone body, 430

β-hydroxybutyrate, that was observed in all but one (78) of the 6 trials that measured ketone 431

bodies. We have recently shown in a meta-analysis that ketogenic diets (severely energy 432

restricted VLEDs or very low carbohydrate ketogenic diets) significantly reduce the drive to eat 433

– or do not increase it – despite significant weight loss (88). The mechanism for this is unknown, 434

but may be due to elevated circulating concentrations of ketone bodies associated with such 435

diets, among other possible factors (88). Thus, the severe energy restriction used in intermittent 436

fasting protocols may contribute to the observed appetite suppression as indicated by subjective 437

measures. Besides subjective measures, 2 studies provided objective evidence of reduced drive to 438

eat in response to IER involving severe energy restriction (55, 68). In 1 such study, an ADF 439

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protocol, it was hypothesized that participants would increase their energy intake on feed days to 440

approximately 125% of their baseline energy requirements. However, no such response was 441

observed, with participants only consuming an average of 95% of their calculated energy needs 442

on feed days, resulting in overall weight loss (68). In the other study, which also constituted an 443

ADF protocol involving total fasting, participants were asked to double their energy intake on 444

feed days to maintain energy balance. However, participants did not consume enough food on the 445

feed days to maintain their weight, and in turn lost weight (55). It therefore seems likely that IER 446

has an effect to reduce food intake even after the fast day has ended, contrary to expectations that 447

such diets would lead to compensatory overeating. 448

449

As changes in the drive to eat can moderate moods such as anxiety or contentedness, we 450

therefore examined information on mood in the publications reviewed, notwithstanding that IER 451

could conceivably also have direct effects on mood. Only 5 of the 32 independent trials in 40 452

publications reported mood in response to IER (56, 57, 67, 78, 79). Of these 5 trials and 453

publications, 2 had a direct comparison of IER to CER (78, 79), with inconsistent results. While 454

one of these 2 publications showed a lower number of participants in the IER (32%) than the 455

CER (46%) arm reporting improved mood, with a greater number in IER than CER reporting bad 456

temper (79), the other showed that there was no difference between IER and CER in the number 457

of participants reporting improved mood and vigour, or in self-reported tension, depression and 458

anger, and there was a smaller number of participants in the IER (3%) than the CER (5%) arm 459

reporting mood swings / bad temper, albeit the proportion of participants affected was low (78). 460

The 3 other studies reporting on mood showed similarly mixed effects. While 2 studies involving 461

severe energy restriction showed positive effects of IER on mood, as indicated by reductions in 462

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mood disturbance, tension, anger and confusion (56), or improved mood (67), the other study, 463

which was in lean participants but also involving severe energy restriction, reported a worsening 464

of mood during the fast days of IER compared with baseline, with concomitant increases in 465

irritability, fatigue and concentration difficulties, along with increases in hunger, preoccupation 466

with food and the drive to eat (57). With only 5 out of 40 publications reporting on mood, and 467

given the inconsistent results from these studies where mood was not a primary outcome, it is not 468

possible to draw conclusions about the effects of IER on mood. 469

470

3.6 No evidence that current IER protocols reduce other adaptive responses to energy restriction 471

The publications included in the current review showed no clear evidence that current IER 472

protocols reduce any effect of energy restriction and weight loss to decrease physical activity or 473

energy expenditure, or to alter hormone concentrations, as outlined below. 474

475

In the 3 publications that reported on physical activity, 2 found no change from baseline in 476

participants on IER (53, 68), and the other study observed significant decreases in physical 477

activity in response to CER and one form of IER (severe ER on fast days, no restriction on feed 478

days), but not the other (ad libitum bread, water, coffee, tea on fast days, no restriction on feed 479

days), with no difference between groups (64). A finding of decreased physical activity with IER 480

is in keeping with the greater feeling of fatigue reported by participants on IER in one 481

publication involving severe energy restriction (57), albeit that publication only included lean 482

individuals. In the 2 studies that compared subjectively rated energy levels in people on IER 483

versus CER (78)(79), there was no indication of IER being superior. Indeed, one of these 2 484

studies (79) showed that more people on IER than CER reported feeling a lack of energy, and 485

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that fewer people on IER than CER reported feeling increased energy. The other one of these 2 486

studies (78) showed no difference between IER and CER with respect to the number of people 487

that reported feeling a lack of energy or fatigue. 488

489

Of the 32 independent trials included in this review, only 6 reported on energy expenditure. Of 490

these, 3 showed a decrease in 24-hour EE and / or REE – either in absolute values (58, 64, 66) or 491

adjusted for FFM (64), while 3 showed no change in REE (55, 83, 85) or REE adjusted for FFM 492

(55, 66, 83) relative to baseline following IER. Of these 6 publications that reported on energy 493

expenditure, 3 made a direct comparison between IER and CER (64, 66, 85). One such article 494

reported no difference from baseline in REE and no difference between the IER and CER groups 495

(85), one showed that with IER there was a decrease from baseline in absolute and adjusted 496

values of 24-hour EE and REE, with the decrease being greater, less than or no different from 497

that in the CER group depending on the parameter under investigation (64), while the third 498

article showed that the reduction in REE from baseline was similar between IER and CER (66). 499

Taken together, there was no evidence to suggest that the effect of energy restriction to reduce 500

energy expenditure was abated by IER. 501

502

In terms of hormonal effects, IER induced a decrease in circulating concentrations of the thyroid 503

hormone T3 (triiodothyronine or 3,3′,5-triiodothyronine) compared to baseline (57), similar to 504

changes that have been observed with CER in separate publications (11). In keeping with this, 505

there was no difference between IER and CER with respect to circulating concentrations of 506

thyroid stimulating hormone, thyroid hormones (or cortisol) when measured at the end of the 507

intervention (58). IER also induced apparently similar effects as CER to inhibit the gonadal axis 508

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(79). Indeed, IER and CER induced similar decreases in circulating concentrations of 509

testosterone, the free androgen index, androstenedione and prolactin, albeit IER induced a lesser 510

decrease in that of DHEAS (dehydroepiandrosterone sulphate, a metabolic intermediate in the 511

biosynthesis of the androgen and estrogen sex steroids), and similar increases in that of sex 512

hormone binding globulin (79). Interestingly, menstrual cycle length was significantly longer in 513

women on a 26-week IER than a CER intervention (79). IER also induced similar effects to CER 514

to inhibit the somatrotropic axes (as indicated by similar increases in the circulating 515

concentrations of IGF-1 binding proteins 1 and 2) (79), albeit with no change from baseline in 516

circulating IGF-1 levels in either group (78, 79). Another study, this one with no CER or control 517

comparator arm, showed a significant reduction in circulating IGF-1 concentrations with one 518

form of IER but not the other form (81). Taken together, these studies suggest that the effect of 519

energy restriction and weight loss to induce adaptive changes in neuroendocrine status may not 520

be different in current IER interventions compared to that observed with CER, albeit there is 521

very little research available to assess this. 522

523

A finding that currently reviewed IER protocols did not reduce the adaptive response to energy 524

restriction relative to the effects of CER would perhaps not be surprising when considering that 525

attenuation of these adaptive responses appears to be dependent upon restoration of true energy 526

balance or even positive energy balance (not continued energy restriction) (Sainsbury A, Seimon 527

RV, Hills AP, Wood RE, King NA, Gibson AA, Byrne NM, submitted manuscript) (24), and that 528

a significant proportion of IER interventions hereby reviewed did not attain neutral or positive 529

energy balance at any time during the intervention. Although all interventions involved periods 530

of energy restriction interspersed with periods of relatively greater actual or prescribed energy 531

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intake, 14 of the 40 publications included in this review (35%) prescribed a degree of energy 532

restriction even during these relative ‘feasts’ (50-52, 56, 59, 60, 66, 76, 78-82, 84). In other 533

studies, even though participants were instructed to increase their energy intake during ‘feast’ 534

days, participants consumed less than prescribed or expected. This was observed in 7 535

publications using protocols where energy intake during ‘feast’ times had been estimated from 536

food diary analysis and found to be below energy prescriptions or energy balance requirements 537

(47, 54, 55, 61, 69-71). This phenomenon of consuming less energy than the prescribed or 538

weight maintenance energy intake, which likely also occurred in other studies where food diaries 539

were not analysed, was possibly due to an effect of severe IER to reduce the drive to eat, as 540

discussed in Section 3.5, or a sentiment amongst participants that restricting energy intake would 541

maximise weight loss, a motivator for enrolling in a clinical weight loss trial in the first place. 542

Therefore, it seems unlikely that the ‘feast’ periods in commonly studied intermittent dieting 543

protocols involved sufficient energy intake to deactivate adaptive responses to energy restriction. 544

545

3.7 Comparable improvements in glucose homeostasis for interventions involving IER or CER 546

Overweight and obesity are major risk factors for the development of type 2 diabetes. As modest 547

weight loss is associated with improvements in glucose homeostasis in overweight or obese 548

individuals, including those with type 2 diabetes or pre-diabetes, we also compared the effects of 549

IER and CER on glucose homeostasis. In the 32 independent trials reported on in this review, 20 550

investigated various aspects of glucose homeostasis, with 17 reporting specifically on fasting 551

circulating glucose concentrations. Of these, 11 reported no change from baseline in fasting 552

glucose levels following IER (39, 47, 49, 53, 55, 59, 63, 67, 77, 78, 84), 4 reported a decrease 553

from baseline (52, 79, 80, 85), while 2 reported an increase from baseline (60, 66) following 554

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IER. Similarly to fasting glucose levels, results for HbA1c – which reflects longer-term 555

circulating glucose levels – showed inconsistent results, with 2 articles reporting no change (78, 556

84) and 2 reporting a decrease (52, 76) in HbA1c compared with baseline following IER. With 557

respect to the 13 independent trials that measured fasting circulating insulin concentrations, 4 558

found no change in this parameter relative to baseline following IER (53, 66, 67, 84), while 8 559

reported a decrease (39, 49, 52, 55, 60, 63, 78, 79) and 1 reported a decrease following one form 560

of IER and no change following another form of IER (80). This finding of little or no reduction 561

in fasting circulating glucose concentrations in response to IER in the face of a possible decrease 562

in fasting insulin suggests that insulin sensitivity may be increased following IER. In keeping 563

with this possibility, of the 5 independent trials that assessed homeostatic model assessment – 564

[Insulin Resistance] (HOMA-IR), an index of insulin resistance, 4 reported a decrease from 565

baseline with IER (39, 49, 78, 79), while one reported no change (63). 566

567

Of the 12 articles that compared IER against a CER comparator arm, 7 investigated aspects of 568

glucose homeostasis. Only 2 of these reported a greater decrease from baseline in fasting glucose 569

(79, 85), and only 1 reported a greater decrease from baseline in fasting insulin (79) and HOMA-570

IR (79) with IER compared to CER. The remaining 5 publications found no difference in fasting 571

circulating levels of glucose (52, 66, 78, 84), HbA1c (52, 76, 78, 84) or insulin (52, 66, 84) 572

between the IER and CER groups, while one reported a greater decrease in fasting insulin and 573

HOMA-IR with one form of IER compared with the other form of IER and CER (78). This 574

suggests that following an IER there are improvements in glucose homeostasis, but no more so 575

than in response to CER. 576

577

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3.8 Impact of exercise on effects of IER 578

Of the 32 independent trials included in this review, 3 trials (in 4 publications) combined IER 579

with exercise (62, 63, 66, 73). Two of these trials (in 3 publications) involved a direct 580

comparison between IER with and without exercise (62, 63, 66), while 1 trial included an 581

exercise only group as a comparison arm (73). Of the former 2 independent trials (62, 63, 66), 582

both showed that when IER was combined with exercise, even greater weight loss was achieved 583

– approximately 3 kg more than when achieved by IER alone. In the 1 publication that reported 584

BMI and waist circumference, the addition of exercise to IER decreased these parameters to a 585

greater extent from baseline than the IER intervention alone (63). In the 2 independent trials in 2 586

publications that reported on body composition (63, 66), the IER plus exercise intervention 587

produced greater reductions in %FM or FM when compared with IER alone, although there was 588

no difference in FFM between IER administered with or without exercise. In addition, the 589

combination of IER and exercise reduced emotional eating when compared with IER or exercise 590

alone (62). Apart from a decrease in emotional eating, which may suggest a manifestation of a 591

reduction in the drive to eat, there was no clear evidence that exercise attenuated other aspects of 592

the drive to eat, or other adaptive responses to energy restriction, as has been suggested 593

elsewhere (Sainsbury A, Seimon RV, Hills AP, Wood RE, King NA, Gibson AA, Byrne NM, 594

submitted manuscript). This is indicated by the observation that IER was no different from IER 595

plus exercise in terms of reducing uncontrolled eating and increasing restrained eating (62). In 596

fact, whereas hunger was decreased and fullness and satisfaction were increased by IER relative 597

to baseline, no such changes from baseline were seen when IER was combined with exercise 598

(62). Additionally, there were no differences in REE or REE adjusted for FFM reported with IER 599

or CER alone versus IER or CER with exercise added to the intervention (66). 600

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601

3.9 Limitations and future directions 602

There are a number of limitations to this systematic review that need to be addressed. Only 12 of 603

the 40 publications included in this review directly compared IER with CER: the lack of direct 604

comparison makes it difficult to determine whether IER is superior to CER, or for whom. 605

Another limitation is that 14 of the 40 publications included in this review were performed by the 606

same research group (47, 61-63, 68-75, 80, 81). Additionally, differences in study design, 607

intervention form, and participant characteristics and numbers makes it difficult to clarify which 608

form(s) of IER is (are) the most effective for weight loss. For example, although we were able to 609

categorize interventions as IER or CER, the diets were highly variable with respect to the levels 610

of prescribed energy intake, macronutrient composition, and timing of the ‘fast’ and ‘feast’ 611

phases. Furthermore, there is currently insufficient data to support the notion that IER influences 612

body weight, FM, FFM, adaptive responses to energy restriction or glucose homeostasis any 613

differently to CER, as most studies were not powered to specifically investigate these 614

parameters, with most having moderate sample sizes of 30-50 participants. Finally, only 5 of the 615

40 included publications followed up participants at 52 weeks or more after commencement of 616

the diet (48, 49, 52, 76, 85), so the longer-term impact of several weeks or months of IER on 617

body weight, body composition, or the adaptive responses to energy restriction is not precisely 618

known. Further investigation from more researchers is required, with larger sample sizes and 619

longer durations, to fully investigate the potential of IER versus the conventional approach of 620

CER for weight management. 621

622

4. Summary and conclusions 623

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624

Apart from a possible decrease in the drive to eat, likely associated with ketosis or other factors 625

concomitant with severe energy restriction, this work found no evidence that IER, as applied in 626

the clinical trials hereby reviewed, reduced adaptive responses to energy restriction relative to 627

effects of CER. While very little research has been done in this domain, this finding is in keeping 628

with the observation that a significant proportion of the IER interventions reviewed (most of 629

which were intermittent fasting regimes) did not attain neutral or positive energy balance at any 630

time during the intervention, and given that attenuation of adaptive responses to energy 631

restriction is likely to be dependent upon relief from negative energy balance. Consistent with 632

this is the finding that IER and CER produced apparently equivalent outcomes in terms of the 633

amount of weight, waist or hip circumference, FM or FFM lost, the improvements in parameters 634

related to glucose homeostasis, as well as the proportion of people dropping out of the 635

intervention. Intermittent diets, notably the intermittent fasting diets that comprised the bulk of 636

the trials hereby reviewed, thus represent an alternative and equivalent option to more 637

conventional diets involving CER as a means of weight reduction. 638

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Acknowledgements 639

This work was supported by the National Health and Medical Research Council (NHMRC) of 640

Australia via an Early Career Research Fellowship to RVS, a Project Grant to AS and NMB, and 641

a Senior Research Fellowship to AS. We are also grateful to the Endocrine Society of Australia 642

for a Postdoctoral Award to RVS. AS has received payment from Eli Lilly, the Pharmacy Guild 643

of Australia, Novo Nordisk and the Dietitians Association of Australia for seminar presentations 644

at conferences. She is also the author of The Don’t Go Hungry Diet (Bantam, Australia and New 645

Zealand, 2007) and Don’t Go Hungry For Life (Bantam, Australia and New Zealand, 2011). 646

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58. Soeters MR, Lammers NM, Dubbelhuis PF, Ackermans M, Jonkers-Schuitema CF, Fliers E, 826 et al. Intermittent fasting does not affect whole-body glucose, lipid, or protein metabolism. 827 Am J Clin Nutr. 2009;90(5):1244-51. 828

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61. Bhutani S, Klempel MC, Berger RA, Varady KA. Improvements in coronary heart disease 836 risk indicators by alternate-day fasting involve adipose tissue modulations. Obesity (Silver 837 Spring). 2010;18(11):2152-9. 838

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63. Bhutani S, Klempel MC, Kroeger CM, Trepanowski JF, Varady KA. Alternate day fasting 842 and endurance exercise combine to reduce body weight and favorably alter plasma lipids in 843 obese humans. Obesity (Silver Spring). 2013;21(7):1370-9. 844

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68. Klempel MC, Bhutani S, Fitzgibbon M, Freels S, Varady KA. Dietary and physical activity 859 adaptations to alternate day modified fasting: implications for optimal weight loss. Nutr J. 860 2010;9:35. 861

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71. Klempel MC, Kroeger CM, Varady KA. Alternate day fasting (ADF) with a high-fat diet 867 produces similar weight loss and cardio-protection as ADF with a low-fat diet. Metabolism. 868 2013;62(1):137-43. 869

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73. Varady KA, Bhutani S, Klempel MC, Kroeger CM. Comparison of effects of diet versus 873 exercise weight loss regimens on LDL and HDL particle size in obese adults. Lipids health 874 dis. 2011;10:119. 875

74. Varady KA, Bhutani S, Klempel MC, Kroeger CM, Trepanowski JF, Haus JM, et al. 876 Alternate day fasting for weight loss in normal weight and overweight subjects: a 877 randomized controlled trial. Nutr J. 2013;12(1):146. 878

75. Varady KA, Bhutani S, Klempel MC, Lamarche B. Improvements in LDL particle size and 879 distribution by short-term alternate day modified fasting in obese adults. Br J Nutr. 880 2011;105(4):580-3. 881

76. Ash S, Reeves MM, Yeo S, Morrison G, Carey D, Capra S. Effect of intensive dietetic 882 interventions on weight and glycaemic control in overweight men with Type II diabetes: a 883 randomised trial. Int J Obes Relat Metab Disord. 2003;27(7):797-802. 884

77. Eshghinia S, Mohammadzadeh F. The effects of modified alternate-day fasting diet on 885 weight loss and CAD risk factors in overweight and obese women. J. 2013;12(1):4. 886

78. Harvie M, Wright C, Pegington M, McMullan D, Mitchell E, Martin B, et al. The effect of 887 intermittent energy and carbohydrate restriction v. daily energy restriction on weight loss 888 and metabolic disease risk markers in overweight women. Br J Nutr. 2013;110(8):1534-47. 889

79. Harvie MN, Pegington M, Mattson MP, Frystyk J, Dillon B, Evans G, et al. The effects of 890 intermittent or continuous energy restriction on weight loss and metabolic disease risk 891 markers: a randomized trial in young overweight women. International journal of obesity 892 (2005). 2011;35(5):714-27. Epub 2010/10/06. 893

80. Klempel MC, Kroeger CM, Bhutani S, Trepanowski JF, Varady KA. Intermittent fasting 894 combined with calorie restriction is effective for weight loss and cardio-protection in obese 895 women. Nutr J. 2012;11:98. 896

81. Kroeger CM, Klempel MC, Bhutani S, Trepanowski JF, Tangney CC, Varady KA. 897 Improvement in coronary heart disease risk factors during an intermittent fasting/calorie 898 restriction regimen: Relationship to adipokine modulations. Nutr Metab. 2012;9(1):98. 899

82. Ball MF, Canary JJ, Kyle LH. Tissue changes during intermittent starvation and caloric 900 restriction as treatment for severe obesity. Arch Intern Med. 1970;125(1):62-8. Epub 901 1970/01/01. 902

83. Jebb SA, Goldberg GR, Coward WA, Murgatroyd PR, Prentice AM. Effects of weight 903 cycling caused by intermittent dieting on metabolic rate and body composition in obese 904 women. Int J Obes. 1991;15(5):367-74. 905

84. Williams KV, Mullen ML, Kelley DE, Wing RR. The effect of short periods of caloric 906 restriction on weight loss and glycemic control in type 2 diabetes. Diabetes Care. 907 1998;21(1):2-8. Epub 1998/04/16. 908

85. Arguin H, Dionne IJ, Senechal M, Bouchard DR, Carpentier AC, Ardilouze JL, et al. Short- 909 and long-term effects of continuous versus intermittent restrictive diet approaches on body 910 composition and the metabolic profile in overweight and obese postmenopausal women: a 911 pilot study. Menopause. 2012;19(8):870-6. 912

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87. Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ. Comparison of the Atkins, 916 Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a 917 randomized trial. Jama. 2005;293(1):43-53. Epub 2005/01/06. 918

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Author, year (Ref)

Sample size (n) and participant characteristics

Total duration and design of the intervention(s)

Description of IER and CER or control arms

Weight change Anthropometric changes

Effects on glucose homeostasis

Other changes

IER versus CER Arguin et al. (2012) (85)

n=25 Female, mean age 60.5±6.0 years, obese, postmenopausal Dropout: 15% IER; 25% CER

34 weeks IER 29 weeks CER (4 weeks weight maintenance plus 5 weeks ER plus 15-20 weeks of IER or CER plus 5 weeks weight maintenance), follow up at 52 weeks from start

IER (n=13): 2 cycles of 5 weeks of weight maintenance plus 5 weeks of moderate ER (20 weeks) CER (n=12): 15 weeks of moderate ER (15 weeks)

↓IER ≅ ↓CER Follow up versus baseline ↓IER ≅ ↓CER

Waist, %FM, FM: ↓IER ≅ ↓CER FFM: ↓IER > ↓CER Follow up versus baseline Waist, FFM: ↓IER, ↔CER %FM, FM: ↓IER ≅ ↓CER

Glucose: ↓IER, ↔CER Follow up versus baseline Glucose: ↓IER ≅ ↓CER

REE: ↔IER, ↔CER Follow up versus baseline REE: ↔IER, ↔CER

Ash et al. (2003) (76)

n=51 Male, aged <70 years, overweight/ obese (BMI 25-40 kg/m2), type 2 diabetes Dropout: 53% overall

12 weeks, follow up at 78 weeks from start

IER (n=14): 4 consecutive days/week of severe ER (4180 kJ/day prescribed), 3 days/week of moderate ER (6000-7000 kJ/day prescribed) CER: 1) CER A (n=20): Moderate ER via pre-portioned meals (6900 kJ/day allotted) 2) CER B (n=17): Moderate ER via self-selected meals (6000-7000 kJ/day prescribed)

↓IER ≅ ↓CER A ≅ ↓CER B Follow up versus baseline ↔IER, ↔CER A, ↔CER B

Waist: ↓IER ≅ ↓CER A ≅ ↓CER B %FM: ↓IER ≅ (↓CER A > ↓CER B) Follow up versus baseline Waist, %FM: ↔IER, ↔CER A, ↔CER B

HbA1C:

↓IER ≅ ↓CER A ≅ ↓CER B Follow up versus baseline HbA1C:

↔IER, ↔CER A, ↔CER B

de Groot et al. (1989) (64)

n=27 Female, aged 21-46 years, overweight (BMI >24.9 kg/m2)

5 weeks (1 week weight maintenance plus 4 weeks IER or CER)

IER: ADF 1) IER A (n=10): Severe ER (4886 ± 465 kJ/day measured) on fast days, no restriction (9772 ± 929 kJ/day measured) on feed days 2) IER B (n=10): Ad libitum bread, water, coffee, tea on fast days (energy intake not measured), no restriction (9772 ± 929 kJ measured) on feed days CER (n=7): Moderate to severe ER (4886 ± 465 kJ/day measured)

(↓IER A ≅↓IER B) < ↓CER

FFM: ↓IER A ≅ ↓IER B ≅ ↓CER

Physical activity: ↓IER A ≅↓CER, ↔IER B 24-hour EE, REE (sleeping): (↓IER A ≅↓IER B) < ↓CER 24-hour EE adjusted: ↓IER A ≅ ↓IER B ≅ ↓CER REE (sleeping) adjusted: ↔IER A, ↓IER B >

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Other changes

↓CER Harvie et al. (2011) (79)

n=107 Female, aged 30-45 years, overweight/ obese (mean BMI 30.6±5.1 kg/m2), premenopausal Dropout: 19% IER (4% unable to adhere); 13% CER (6% unable to adhere)

26 weeks IER (n=53): 75% ER (2060-2266 kJ/day prescribed) on 2 days/week, CER diet on 5 days/week CER (n=54): 25% ER (~6276 kJ/day prescribed)

↓IER ≅ ↓CER Waist, hip, %FM, FM, FFM: ↓IER ≅ ↓CER

Glucose: ↓IER, ↔CER Insulin, HOMA-IR: ↓IER > ↓CER

Leptin, free androgen index, testosterone, androstenedione, prolactin: ↓IER ≅ ↓CER IGF-1: ↔IER, ↔CER Ghrelin, sex hormone binding globulin, IGF-1 binding proteins 1, 2: ↑IER ≅ ↑CER β-hydroxybutyrate#: ↑IER, ↔CER DHEAS: ↓IER < ↓CER Menstrual cycle length: IER > CER No of participants reporting hunger, preoccupation with food, lack of energy, feeling cold, headaches, constipation, lack of concentration, bad temper: IER > CER No of participants reporting increased energy, improved mood: IER < CER

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Author, year (Ref)






Other changes

Harvie et al. (2013) (78)

n=115 Female, aged 20-69 years, overweight (BMI 24-45 kg/m2) Dropout: 11% IER A; 26% IER B (3% unable to adhere); 33% CER (8% unable to adhere)

17 weeks (13 weeks IER or CER plus 4 weeks weight maintenance)

IER: 1) IER A (n=37): 70% ER (2500-2717 kJ/day prescribed) on 2 days/week, CER diet on 5 days/week 2) IER B (n=38): IER plus 250 g protein-rich food (total of 5000 kJ/day prescribed) on 2 days/week, CER diet on 5 days/week CER (n=40): 25% ER (6000 kJ/day prescribed)

↓IER A ≅ ↓IER B ≅ ↓CER

Waist, hip, FFM: ↓IER A ≅ ↓IER B ≅ ↓CER FM: (↓IER A ≅ ↓IER B) > ↓CER

Glucose, HbA1c: ↔IER A, ↔IER B, ↔CER Insulin, HOMA-IR: ↓IER A > (↓IER B ≅ ↓CER)

Leptin: ↓IER A ≅ ↓IER B ≅ ↓CER β-hydroxybutyrate, IGF-1: ↔IER A, ↔IER B, ↔CER No of participants reporting preoccupation with food, headaches, constipation, feeling light-headed: IER > CER No of participants reporting lack of concentration, mood swings, bad temper, feeling cold: IER < CER No of participants reporting decreased energy levels, tension, depression, anger, fatigue and confusion, increased vigour, improved mood: IER ≅ CER

Hill et al. (1989) (66)

n=40 Female, mean age 37±8 years, obese (mean BMI 30±3 kg/m2) Dropout: 40% IER; 0% IER+EX; 20% CER; 20% CER+EX


IER (n=6): ADF Severe ER (2512 kJ/day prescribed) on fast days, moderate ER (7536 kJ/day prescribed) on feed days CER (n=8): moderate ER (5024 kJ/day prescribed) IER+EX (n=10): IER plus moderate aerobic training on 5 days/week

(↓IER ≅ ↓CER) < (↓IER+EX ≅ ↓CER+EX)

Waist hip ratio: ↔IER,↔CER, ↔IER+EX, ↔CER+EX %FM, FM: (↓IER ≅ ↓CER) < (↓IER+EX ≅ ↓CER+EX)

Glucose: ↑IER ≅ ↑CER ≅ ↑IER+EX ≅ ↑CER+EX Insulin: ↔IER, ↔CER, ↔IER+EX,

REE: ↓IER ≅ ↓CER ≅↓IER+EX ≅ ↓CER+EX REE adjusted: ↔IER, ↔CER, ↔IER+EX, ↔CER+EX

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Other changes

CER+EX (n=8): CER plus moderate aerobic training on 5 days/week

FFM: ↓IER ≅ ↓CER ≅ ↓IER+EX ≅ ↓CER+EX

↔CER+EX

Keogh et al. (2014) (48)

n=75 Female, overweight/ obese IER: mean age 59.5±8.7 years, mean BMI 33.3±3.8 kg/m2 CER: mean age 60.8±12.5 years, mean BMI 33.0±7.5 kg/m2 Dropout: 35% IER; 44% CER (40% overall)


IER (n=39): Alternating weeks of severe ER (5500 kJ/day less than weight maintenance requirements prescribed) for 1 week followed by 1 week of ad libitum consumption CER (n=36): severe ER (5500 kJ/day less than weight maintenance requirements prescribed)

↓IER ≅ ↓CER Follow up versus baseline ↓IER ≅ ↓CER

Waist, hip: ↓IER ≅ ↓CER Follow up versus baseline Waist, hip: ↓IER ≅ ↓CER

Rössner (1998) (50)

n=101 Male and female, aged 21-60 years, obese (BMI > 30 kg/m2)

18 weeks, follow up at 14 and 26 weeks from start

IER A (n=20): 3 cycles of 2 weeks severe ER (1757 kJ/day prescribed) separated by 4 weeks moderate ER (6592 kJ/day prescribed) IER B (n=29): 3 cycles of 2 weeks severe ER (2218 kJ/day prescribed) separated by 4 weeks moderate ER (6592 kJ/day prescribed) CER A (n=20): 6 weeks of severe ER (1757 kJ/day prescribed) CER B (n=32): 6 weeks of severe ER (2218 kJ/day prescribed)

↓IER A ≅ ↓CER A ↓IER B ≅ ↓CER B

Varady et al. (2011) (73)

n=60 Male and female, aged 35-65 years, overweight/obese (BMI 30-39.9 kg/m2) Dropout: 13% IER; 20% CER; 20% EX;

12 weeks IER (n=15): ADF Severe ER (75%) prescribed on fast days, ad libitum intake on feed days CER (n=15): Moderate ER (25%) prescribed Exercise (EX) (n=15): Moderate intensity training 3 times/week Control (n=15): maintained current lifestyle

↓IER ≅ ↓CER ≅↓EX, ↔Control

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Other changes

20% IER+EX Williams et al. (1998) (84)

n=54 Male and female, aged 30-70 years, obese, type 2 diabetes Dropout: 13% overall

20 weeks IER: Both groups on severe ER (1675-2512 kJ/day prescribed) for 20 days over 20 weeks, moderate ER (6280-7536 kJ/day prescribed) at all other times 1) IER A (n=18): In week 2, 5 consecutive days of severe ER then severe ER for 1 day/week for next 15 weeks 2) IER B (n=18): In week 2, 5 consecutive days of severe ER, then again every 5 weeks, a total of 4 times CER (n=18): Moderate ER (6280-7536 kJ/day prescribed) for 20 weeks

(↓IER A ≅ ↓IER B) > ↓CER

Glucose, HbA1C, Insulin: ↔IER A, ↔IER B, ↔CER

Wing et al. (1994) (52)

n=93 Male and female, obese, type 2 diabetes IER: mean age 52.3±10.7 years, mean BMI 37.4±6.1 kg/m2 CER: mean age 51.3±8.7 years, mean BMI 38.3±6.5 kg/m2 Dropout: 16% IER; 15% CER


IER (n=45): Severe ER (1675-2093 kJ/day prescribed) from weeks 1-12 and weeks 24-36. After week 12, prescribed intake increased over a 4 week period until participants consumed 4187-5024 kJ/day. CER (n=48): Moderate ER (4187-5024 kJ/day prescribed), dietary fat intake limited to less than 30% of calories

↓IER > ↓CER Follow up versus baseline ↓IER ≅ ↓CER

BMI: ↓IER ≅ ↓CER

Glucose, HbA1c, insulin: ↓IER ≅ ↓CER Follow up versus baseline Glucose, HbA1c, insulin: ↔IER, ↔CER

Wing et al. (2003) (46)

n=142 Male and female, mean age 42.6±9.3 years, obese (mean BMI 33.1±3.3 kg/m2) Dropout: 32% IER LB; 30% IER SB; 36 % CER

20 weeks of IER and 14 weeks of CER, follow up at both of 20 and 48 weeks from start

IER: 1) IER A: “Long break” (n=47): 7 weeks of moderate ER, 6 week break*, 7 weeks of moderate ER 2) IER B: “Short break” (n=47): 3 cycles of 3 weeks of moderate ER, 2 week break*, then 5 weeks of moderate ER *weight loss stopped during breaks CER (n=48): 14 weeks of moderate to severe ER (4187-6280 kJ/day prescribed

↓IER A ≅ ↓IER B ≅ ↓CER

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Other changes

plus restriction of 13 specified high-fat foods)

IER versus control Bhutani et al. (2013) (62)

n=83 Male and female, aged 25-65 years, obese (BMI 30-39.9 kg/m2) Dropout: 36% IER; 0% Control; 11% IER+EX; 33% EX

12 weeks

IER (n=25): ADF Severe ER (75%) prescribed on fast days, ad libitum intake on feed days. 4-week controlled feeding phase (all fast day meals were provided), then 8-week self-selected feeding phase (participants chose and prepared own meals based on a dietary prescription) IER+EX (n=18): IER plus moderate intensity exercise 3 times/week EX (n=24): moderate intensity exercise 3 times/week Control (n=16): Maintained current lifestyle

(↓IER ≅ ↓EX) < ↓IER+EX, ↔Control

Hunger: ↓IER, ↔IER+EX, ↔ EX, ↔Control Fullness, satisfaction: ↑IER, ↔IER+EX, ↔EX, ↔Control Uncontrolled eating: ↓IER ≅ ↓IER+EX, ↔EX, ↔Control Restrained eating: ↑IER ≅ ↑IER+EX, ↔EX, ↔Control Emotional eating: ↔ IER, ↓IER+EX, ↔EX, ↔Control

Bhutani et al. (2013) (63)

See Bhutani et al. (2013) (62)


See Bhutani et al. (2013) (62) See Bhutani et al. (2013) (62)

BMI: (↓IER ≅ ↓EX) < ↓IER+EX, ↔Control Waist: (↓IER ≅ ↓EX) < ↓IER+EX, ↔Control FM: ↓IER < ↓IER+EX, ↔EX, ↔Control FFM: ↔IER, ↔IER+EX, ↔ EX, ↔Control

Glucose, HOMA-IR: ↔IER, ↔IER+EX, ↔EX, ↔Control Insulin: ↓IER, ↔IER+EX, ↔EX, ↔Control

Hussin et al. (2013)

n=32 Male, aged 59.7±6.3

13 weeks IER (n=16): Moderate ER (25% prescribed) plus 2 days/week of Sunnah fasting (nil by

↓IER, ↔Control

BMI: ↓IER, ↔Control

Tension, anger, confusion, mood

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(56) years, lean/ overweight (mean BMI 26.7±2.2 kg/m2) Dropout: 0% IER; 6% Control

mouth, sunrise to sunset) Control (n=16): maintained current lifestyle

%FM: ↓IER, ↔Control

disturbance: ↓IER, ↑Control Vigour: ↑IER ≅ ↑Control

Soeters et al. (2009) (58)

n=8 Male, median age 23.5 years, lean (median BMI 21.3 kg/m2)

≥ 8 weeks (2 weeks of IER plus 2 weeks of Control, separated by ≥ 4 weeks) in randomized crossover design

IER (n=8): ADF Severe ER (100%) prescribed on fast days, no restriction (11108 kJ/day median prescribed energy intake) on feed days Control (same participants as IER): Energy intake equivalent to IER feed days

↔IER, ↔Control FM, FFM: ↔IER, ↔Control

REE: ↓IER, ↔Control TSH, T4, T3, reverse T3, cortisol (measured at end of intervention only): IER ≅ Control

Teng et al. (2011) (51)

n=28 Male, aged 50-79 years, lean/ overweight (BMI 23-29.9 kg/m2) Dropout: 14% IER; 7% Control

12 weeks IER (n=14): 5 days a week of moderate ER (1256-2093 kJ/day less than habitual intake prescribed) plus 2 days/week Sunnah fasting (nil by mouth, sunrise to sunset, ad libitum intake outside fasting hours) Control (n=14): Maintained current lifestyle

↓IER, ↔Control

BMI, % FM, FM: ↓IER, ↔Control FFM: ↔IER, ↔Control

Teng et al. (2013) (59)

n=56 Male, aged 50-70 years, lean/ overweight (BMI 23-29.9 kg/m2)

12 weeks IER (n=28): 5 days/week of moderate ER (1256-2093 kJ/day less than habitual intake prescribed) plus 2 days/week Sunnah fasting (nil by mouth, sunrise to sunset, ad libitum intake outside fasting hours) Control (n=28): Maintained current lifestyle

↓IER, ↔Control

BMI: ↓IER, ↔Control %FM, FM: ↓IER, ↑Control FFM: ↔IER, ↔Control

Glucose: ↔IER, ↔Control


n=32 Male and female, aged 35-65 years, overweight/obese (BMI 20-29.9 kg/m2) Dropout: 7% IER; 7% Control

12 weeks IER (n=15): ADF Severe ER (75%) prescribed on fast days, ad libitum intake prescribed on feed days Control (n=15): Maintained current lifestyle

↓IER, ↔Control FM: ↓IER, ↔Control FFM: ↔IER, ↔Control

Leptin: ↓IER, ↔Control Hunger: ↔IER, ↔Control Fullness, satisfaction: ↑IER, ↔Control

Vondra et al. (1976) (60)

n=31 Female IER: mean age 32.8 years (range 17-49

6.3 weeks (1 week preparatory period plus 5.3 weeks IER)

IER (n=21): 4 cycles of 5 fast days of severe ER (100%) then 3 days of severe ER (2093 kJ/day prescribed), followed by 5 fast days Control (n=10): Maintained current lifestyle

↓IER (Control data not reported)

FM: ↓IER (Control data not reported)

Glucose: ↑IER Insulin: ↓IER

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years), obese (mean weight 112.6 kg (range 93.8–154 kg), no standard deviation or BMI data reported) Control: mean age 31 years, lean (mean body fat 23.6%, no standard deviation or BMI data reported)

(Control data not reported)

IER with no comparison arm Ball et al. (1970) (82)

n=4 Female, mean age 34±8 years, overweight/obese (mean weight 126.1±22.2 kg) Dropout: 0%

16 weeks IER: 3 cycles of 16 fast days of severe ER (100%), alternating with 3 cycles of 16 days of severe ER (3347 kJ/day prescribed), followed by 16 fast days

↓IER

FM, FFM: ↓IER

Belza et al. (2009) (39)

n=41 Male and female, aged 24-62 years, overweight/obese (BMI 28-40 kg/m2) Dropout: 12% (10% unable to adhere)

20 weeks IER: 8 weeks of severe ER 1 (3400 kJ/day liquid diet prescribed) plus 4 weeks of weight maintenance plus 4 weeks of severe ER 2 (4200 kJ/day liquid diet plus 750 kJ/day free choice prescribed) plus 4 weeks of weight maintenance

↓IER BMI, waist, FM, FFM: ↓IER

Glucose: ↔IER Insulin, HOMA-IR: ↓IER

Leptin: ↓IER

Bhutani et al. (2010) (61)

n=20 Male and female, aged 35-65 years, obese (BMI 30-39.9 kg/m2) Dropout: 20% (10% unable to adhere)

10 weeks (2 weeks weight maintenance plus 4 weeks IER A then 4 weeks IER B) for all participants

IER: ADF 1) IER A: Controlled feeding Severe ER (75%) prescribed (2098±117 kJ/day measured) on fast days, ad libitum food intake prescribed on feed days (7540±950 kJ/day measured), all fast day meals were provided 2) IER B: Self-selected feeding Same as IER A, but participants chose and prepared their own meals at home based on a dietary prescription

↓IER A ≅ ↓IER B

BMI, waist, FM: ↔IER A ≅ ↓IER B FFM: ↔ IER A, ↔IER B

Leptin: ↓IER A, ↓IER B

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Eshghinia et al. (2013) (77)

n=15 Female, mean age 33.5±5.9 years, overweight/obese (mean BMI 33.2±5.2 kg/m2)

8 weeks (2 weeks weight maintenance plus 6 weeks IER)

IER: 6 x 1-week cycles of severe ER (70-75%) prescribed on 3 days, then 3 days of moderate ER (~7536 kJ/day prescribed), based on the Key Recommendations of Dietary Guidelines for Americans, then ad libitum intake for 1 day

↓IER

BMI, waist, %FM: ↓IER

Glucose: ↔IER

Halberg et al. (2005) (53)

n=8 Male, mean age 25.0±0.1 years (standard error), lean (mean BMI 25.7±0.4 kg/m2, standard error)

2 weeks IER: ADF Severe ER (100%) for 20 hours on fast days, ad libitum intake on feed days and at all other times

↔IER BMI, %FM: ↔IER

Glucose, insulin: ↔IER

β-hydroxybutyrate, physical activity: ↔IER

Heilbronn et al. (2005) (55)

n=16 Male and female, aged 23-53 years, lean/overweight (BMI 20-30 kg/m2)

3 weeks IER: ADF Severe ER (100%) on fast days, instructions to double usual intake on feed days

↓IER

FM, FFM: ↓IER

Glucose: ↔IER Insulin: ↓IER

Hunger, β-hydroxybutyrate: ↑IER Fullness: ↓IER Satisfaction, desire to eat, ghrelin, thirst, REE, REE adjusted: ↔IER

Heilbronn et al. (2005) (54)

See Heilbronn et al. (2005) (55)


See Heilbronn et al. (2005) (55) See Heilbronn et al. (2005) (55)


Ghrelin (meal-induced suppression): ↔IER

Jebb et al. (1991) (83)

n=14 Female, mean age 44 years, obese (mean BMI 31.4 kg/m2, no standard deviation reported) Dropout: 21% (7%

18 weeks

IER: 3 cycles of 2 weeks of severe ER (1871 kJ/day prescribed) and 4 weeks of ad libitum intake

↓IER %FM: ↓IER

REE, REE adjusted: ↔IER

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unable to adhere) Johnson et al. (2007) (67)

n=14 Male and female, age not reported, overweight/obese (BMI > 30 kg/m2) Dropout: 36% (7% unable to adhere)

8 weeks IER: ADF Severe ER (>80%) on fast days (1339 kJ/day prescribed for females; 1590 kJ/day prescribed for males), ad libitum intake on feed days

↓IER

Glucose, insulin: ↔IER

Leptin, hunger, ghrelin: ↔IER β-hydroxybutyrate, mood, energy, quality of life: ↑IER

Klempel et al. (2010) (68)





Hunger, fat intake: ↓IER A ≅ ↓IER B Fullness, physical activity: ↔IER A, ↔IER B Satisfaction: ↑IER A ≅ ↑IER B


n=60 Female, aged 35-65 years, overweight/ obese (BMI 30-39.9 kg/m2) Dropout: 7% IER A (3% unable to adhere); 13% IER B (7% unable to adhere)

10 weeks (2 weeks weight maintenance plus 8 weeks IER)

IER: 1) IER A (n=26): 6 days/week of moderate to severe ER (4680-5520 kJ/day prescribed) using partial meal replacement liquid formulae, 1 fast day/week of severe ER (502 kJ of juice powder provided) 2) IER B (n=28): Same as IER A, but food was used instead of partial meal replacement liquid formulae

↓IER A > ↓IER B

BMI, FM: ↓IER A ≅ ↓IER B FFM: ↔IER A, ↔IER B

Glucose, insulin: ↓IER A, ↔IER B

Leptin: ↓IER A ≅ ↓IER B


n=35 Female, aged 25-65 years, obese (BMI 30-39.9 kg/m2) Dropout: 12% IER A (6% unable to adhere); 6% IER B (6% unable to adhere)

10 weeks (2 weeks weight maintenance plus 8 weeks of IER A or IER B)

IER: ADF 1) IER A (n=17): Severe ER (75%) prescribed for fast days, 125% of energy requirements prescribed for feed days, using diet of 45% fat, 40% carbohydrate, 15% protein 2) IER B (n=18): same as IER A but using diet of 25% fat, 60% carbohydrate, 15% protein


FM: ↓IER A ≅ ↓IER B FFM: ↔IER A, ↔IER B


See Klempel et al. (2013) (70)


See Klempel et al. (2013) (70) See Klempel et al. (2013) (70)

Waist: ↓IER A ≅ ↓IER B

Leptin, hunger: ↓IER A ≅ ↓IER B Fullness:

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↓IER A, ↑IER B Satisfaction: ↔IER A, ↑IER B




See Klempel et al. (2013) (70) See Klempel et al. (2013) (70)

BMI: ↓IER A ≅ ↓IER B See Klempel et al. (2013) (70) and (69)

Kroeger et al. (2012) (81)





Waist: ↓IER A > ↓IER B

Hunger, fullness, satisfaction: ↔IER A, ↔IER B IGF-1: ↓IER A, ↔IER B

Laessle et al. (1996) (57)

n=9 Female, mean age 22.2±1.5 years, lean (mean BMI 20.3±1.4 kg/m2)

4 weeks IER: 4 consecutive days/week of severe ER (maximum 2512 kJ/day prescribed), 3 days/week of ad libitum food intake

↔IER BMI: ↔IER

Hunger, preoccupation with food, drive to eat, β-hydroxybutyrate, irritability, concentration difficulty, fatigue (fast days): ↑IER T3, mood (fast days): ↓IER

Lantz et al. (2003) (49)

n=334 Male and female, aged 18-60 years, obese (BMI >30 kg/m2) Dropout: 65% IER A; 65% IER B

104 weeks 16 16 weeks of severe ER (1883 kJ/day prescribed), followed by 3-weeks re-feeding period prior to randomization IER A (n=161): 2 weeks of severe ER (1883 kJ/day prescribed) every third month for remaining treatment period (up to 2 years) IER B (n=173): Severe ER (1883 kJ/day prescribed) whenever body weight passed an individualized cut-off level


BMI, waist, FM: ↓IER A ≅ ↓IER B FFM: ↓IER A < ↓IER B

Glucose: ↔IER A, ↔IER B Insulin, HOMA-IR: ↓IER A ≅ ↓IER B







No additional data of relevance to this review further to

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(61) Varady et al. (2011) (75)

See Bhutani et al. (2010)(61)



See Bhutani et al. (2010)(61)


No additional data of relevance to this review further to (61)


n=35 Female, aged 25-65 years, overweight/obese (BMI 30-39.9 kg/m2) Dropout: 17% overall

10 weeks (2 weeks weight maintenance plus 8 weeks of IER A or IER B)

See Klempel et al. (2013) (70) ↓IER A ≅ ↓IER B

BMI, waist, FM: ↓IER A ≅ ↓IER B

Glucose: ↔IER A, ↔IER B

Table 1: All ages and BMI have been expressed as mean ± standard deviation where provided, or as mean or as a range, unless otherwise specified. “Follow up” time points refer to the number of weeks from the start of the intervention. Differences in outcome measures refer to the difference between post intervention and baseline values, unless a different comparison is specified (e.g. follow up versus baseline). ↓: statistically significantly decreased; ↑: statistically significantly increased; ↔: not statistically significantly different from baseline as reported by the publication authors. The meaning of the >, < and ≅ are as in the following examples: ↓IER > ↓CER, the reduction from baseline in the IER group is statistically significantly greater than the reduction from baseline in the CER group; ↓IER < ↓CER, the reduction from baseline in the IER group is statistically significantly less than the reduction from baseline in the CER group; ↓IER ≅ ↓CER, the reduction from baseline in the IER group is not statistically significantly different from the reduction from baseline in the CER group. All analytes (e.g. glucose, insulin, ghrelin) were measured in the circulation in the fasting state unless otherwise stated. #Assay included acetoacetone as well as β-hydroxybutyrate. ADF: alternate day fasting; BMI: body mass index; CER: continuous energy restriction; DHEAS: dehydroepiandrosterone sulphate; 24-hour EE: 24-hour energy expenditure; 24-hour EE adjusted: 24-hour energy expenditure adjusted for FFM. ER: energy restriction; EX: exercise; FFM, fat-free mass; FM: fat mass; %FM: percent fat mass; HbA1C: glycated haemoglobin; Hip: hip circumference; HOMA-IR: homeostatic model assessment – [Insulin Resistance]; IER: intermittent energy restriction; IGF-1: insulin-like growth factor-1; REE: absolute resting energy expenditure; REE adjusted: resting energy expenditure adjusted for FFM; REE (sleeping): absolute sleeping energy expenditure; REE (sleeping) adjusted: sleeping energy expenditure adjusted for FFM; Waist: waist circumference; TSH, thyroid stimulating hormone; T3 triiodothyronine or 3,3′,5-triiodothyronine; T4, thyroxine or 3,5,3′,5′- tetraiodothyronine.

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