ArticlePDF Available

Abstract and Figures

The problems of adherence to energy restriction in humans are well known. To compare the feasibility and effectiveness of intermittent continuous energy (IER) with continuous energy restriction (CER) for weight loss, insulin sensitivity and other metabolic disease risk markers. Randomized comparison of a 25% energy restriction as IER (∼ 2710 kJ/day for 2 days/week) or CER (∼ 6276 kJ/day for 7 days/week) in 107 overweight or obese (mean (± s.d.) body mass index 30.6 (± 5.1) kg m(-2)) premenopausal women observed over a period of 6 months. Weight, anthropometry, biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, insulin-like growth factor (IGF)-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain-derived neurotrophic factor were assessed at baseline and after 1, 3 and 6 months. Last observation carried forward analysis showed that IER and CER are equally effective for weight loss: mean (95% confidence interval ) weight change for IER was -6.4 (-7.9 to -4.8) kg vs -5.6 (-6.9 to -4.4) kg for CER (P-value for difference between groups = 0.4). Both groups experienced comparable reductions in leptin, free androgen index, high-sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than with CER; difference between groups for fasting insulin was -1.2 (-1.4 to -1.0) μU ml(-1) and for insulin resistance was -1.2 (-1.5 to -1.0) μU mmol(-1) l(-1) (both P = 0.04). IER is as effective as CER with regard to weight loss, insulin sensitivity and other health biomarkers, and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk.
Content may be subject to copyright.
The effects of intermittent or continuous energy
restriction on weight loss and metabolic disease
risk markers: a randomized trial in young
overweight women
MN Harvie
, M Pegington
, MP Mattson
, J Frystyk
, B Dillon
, G Evans
, J Cuzick
, SA Jebb
B Martin
, RG Cutler
, TG Son
, S Maudsley
, OD Carlson
, JM Egan
, A Flyvbjerg
and A Howell
Genesis Prevention Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK;
of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, USA;
Clinical Institute of Medicine
& Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark;
Department of
Statistics University Hospital of South Manchester, Manchester, UK;
CRUK Centre for Epidemiology, Mathematics and
Statistics, Wolfson Institute of Preventive Medicine, Queen Mary’s School of Medicine, London, UK and
MRC Human
Nutrition Research Group, Cambridge, UK
Background: The problems of adherence to energy restriction in humans are well known.
Objective: To compare the feasibility and effectiveness of intermittent continuous energy (IER) with continuous energy
restriction (CER) for weight loss, insulin sensitivity and other metabolic disease risk markers.
Design: Randomized comparison of a 25% energy restriction as IER (B2710 kJ/day for 2 days/week) or CER (B6276 kJ/day for
7 days/week) in 107 overweight or obese (mean (±s.d.) body mass index 30.6 (±5.1) kg m
) premenopausal women
observed over a period of 6 months. Weight, anthropometry, biomarkers for breast cancer, diabetes, cardiovascular disease and
dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, insulin-like growth factor (IGF)-1 and IGF
binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids,
blood pressure and brain-derived neurotrophic factor were assessed at baseline and after 1, 3 and 6 months.
Results: Last observation carried forward analysis showed that IER and CER are equally effective for weight loss: mean (95%
confidence interval ) weight change for IER was 6.4 (7.9 to 4.8) kg vs 5.6 (6.9 to 4.4) kg for CER (P-value for difference
between groups ¼0.4). Both groups experienced comparable reductions in leptin, free androgen index, high-sensitivity
C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin,
IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with
IER than with CER; difference between groups for fasting insulin was 1.2 (1.4 to 1.0) mUml
and for insulin resistance
was 1.2 (1.5 to 1.0) mU mmol
(both P¼0.04).
Conclusion: IER is as effective as CER with regard to weight loss, insulin sensitivity and other health biomarkers, and may be
offered as an alternative equivalent to CER for weight loss and reducing disease risk.
International Journal of Obesity (2011) 35, 714–727; doi:10.1038/ijo.2010.171; published online 5 October 2010
Keywords: intermittent; continuous energy restriction; randomized; premenopausal women; insulin sensitivity
Excess weight and weight gain during adult life increase the
risk of several diseases, including diabetes,
and certain forms of cancer including
breast cancer,
and can contribute to premature death.
Observational and some randomized trials indicate that
modest weight reduction (45% of body weight) reduces the
Received 5 May 2010; revised 15 July 2010; accepted 19 July 2010; published
online 5 October 2010
Correspondence: Dr MN Harvie, Senior Research Dietitian, Nightingale Centre
and Genesis Prevention Centre, University Hospital of South Manchester NHS
Foundation Trust, Manchester M23 9LT, UK.
International Journal of Obesity (2011) 35,714– 727
2011 Macmillan Publishers Limited All rights reserved 0307-0565/11
and progression
of many of these diseases.
Although weight control is beneficial, the problem of poor
compliance in weight loss programmes is well known.
when reduced weights are maintained, many of the benefits
achieved during weight loss, including improvements in
insulin sensitivity, may be attenuated because of non-
compliance or adaptation.
Sustainable and effective energy
restriction strategies are thus required. One possible
approach may be intermittent energy restriction (IER), with
short spells of severe restriction between longer periods of
habitual energy intake. For some subjects, such an approach
may be easier to follow than a daily or continuous energy
restriction (CER) and may overcome adaption to the weight-
reduced state by repeated rapid improvements in metabolic
control with each spell of energy restriction.
The effect of IER on disease prevention and lifespan has
been studied mainly in rodent models using a range of
experimental protocols, from fasting every other day to
3 weeks of partial energy restriction and refeeding. In these
studies, IER seems to be equally or more effective than
isoenergetic CER for improving insulin sensitivity,
preventing spontaneous or genetically engineered mammary
delaying the onset of prostate cancer,
increasing resistance to neuronal damage,
reducing cogni-
tive impairment,
protecting the heart
and increasing the
lifespan of rodents.
IER may even produce benefits similar
to those observed following more stringent CER.
human studies have examined the effects of IER, possibly
because of concerns of disordered eating patterns and
overconsumption on non-restricted days. Several short-term
studies suggest that this does not occur.
We report a
randomized trial of 25% energy restriction delivered as IER vs
CER in overweight or obese premenopausal women over a
6-month period, exploring the relative effects of the two
dietary approaches on anthropomorphic and metabolic
Subjects and methods
We studied 107 premenopausal women aged 30–45 years
with adult weight gain exceeding 10 kg since the age of
20 years, and a body mass index between 24 and 40 kg m
We recruited women from our Breast Cancer Family History
Clinic, and women from the general population. As such,
54% of recruits had a family history of breast cancer (lifetime
risk 41 in 6) (the Tyrer Cuzick model).
Participants were
non-smokers, not currently dieting or losing weight, with
regular menstrual cycles and no evidence of hyperandrogen-
ism or polycystic ovary syndrome,
and no oral contra-
ceptive use during the previous 6 months. They did not have
high intakes of alcohol (428 units per week) or phyto-
oestrogens, and were not suffering from diagnosed diabetes,
cardiovascular disease, major psychiatric morbidity or
cancer. We solicited participants from our Family History
Clinic by mail shot, and women in the general population
using media and institution-wide e-mails. Potential partici-
pants were screened by the study dietitians (MH, MP) to
assess their physical and psychological health and motiva-
tion to lose weight, and successfully completed a 2-day trial
of the very low-calorie diet (VLCD) before recruitment. Of
the 135 who were eligible after screening, 13 (9%) did not
believe they could tolerate the diet for the 6-month trial
period, and a further 14 (10%) decided not to participate
because of social, health or work-related factors (Figure 1).
All participants gave informed consent. The protocol was
approved by the South Manchester Ethics Committee
(reference 05/Q1403/243).
Study protocol
Participants were stratified according to body mass index
(above or below the predicted median value 28 kg m
family history of breast cancer, sedentary lifestyle (either o
or 41 h moderate activity per week) and also according
to the evaluating study dietitian to ensure that the two
dietitians saw equal proportions of patients from the two
treatment groups. Women were randomly assigned to
6 months of either the CER of 25% restriction below
estimated requirements for 7 days per week, or the IER
of 25% restriction delivered as a VLCD for 2 days per week,
with no restriction on the other 5 days per week.
Measurements were made before starting and at 1, 3 and
6 months. These included weight, total body fat, fat-free
mass determined by impedance (Tanita TBF-300A, Tanita
Europe BV, Yiewsley, UK) waist, hip, bust and thigh
circumference, systolic and diastolic blood pressure (Omron
M5-1 Omron Healthcare Limited, Milton Keynes, UK) and
blood sampling. All assessments were conducted in the
morning after a 12-h fast. Weight and body fat were assessed
wearing light clothing. Body circumferences were measured
in triplicate according to study protocols.
Blood pressure
was measured in triplicate after 10 min at rest and the mean
value was calculated. The IER group was assessed at least 5
days after their weekly 2-day VLCD to avoid any potential
acute effects of the 2-day restriction on serum markers.
However, additional fasting serum samples were collected in
a subset of the IER group (n¼15) after either 1 or 3 months
of dietary intervention to ascertain acute effects of the diet
on serum markers. Samples were collected after 5 days of
normal intake (Monday) on the morning after the 2-day
VLCD (Wednesday) and after 2 days of normal intake
(Friday), and also on these days of the week in a subset of
the CER group (n¼9) for comparison.
Adherence to the dietary interventions at 1, 3 and
6 months was assessed using 7-day food diaries checked for
completeness with the respondent. Mean energy, protein, fat
and carbohydrate intakes were estimated using the Compeat
4 Nutrition Analysis System (Carlson Bengston Consultants,
London, UK). In addition, the IER group was asked to record
Intermittent vs continuous energy restriction
MN Harvie et al
International Journal of Obesity
whether they had successfully completed a 2-, 1- or 0-day
VLCD each week during the study period. We estimated the
proportion of the IER and CER groups adhering to the diets at
each time point as the number of IER subjects reporting
2- or 1-day VLCD each week and the number of CER subjects
achieving a 25% energy restriction. Physical activity was
assessed using the validated international physical activity
questionnaire expressed as metabolic energy turnover in
minutes per day and kJ per day.
Throughout the 6-month
trial period, participants were asked to report any adverse or
positive physical or psychosocial effects of the interventions.
Quality of life was assessed using the RAND SF-36 scale,
reported as physical and mental component summary scores.
Participants were asked to record the first day of each
menstrual cycle to ascertain any effects of the diets on
menstrual cycle length. We did not attempt to time assess-
ments in relation to the menstrual cycle, but the day of
the cycle was recorded and adjusted for in the analysis
to account for variation in hormone and lipid biomarkers
related to the cycle.
Experimental diets
Both diets involved a 25% energy restriction from estimated
baseline energy requirements using reported metabolic
energy turnovers estimated basal metabolic rate.
The CER group was prescribed a daily 25% restriction
based on a Mediterranean-type diet (30% fat, 15% mono-
unsaturated, 7% saturated fat, 7% polyunsaturated fatty
acids, 45% low glycaemic load carbohydrate and 25%
564 persons were screened
134 attended pre-trial appointment
107 randomised
53 assigned to IER
3 withdrew
3 withdrew
2 withdrew
2 withdrew
1 withdrew
1 month appointment
n = 50
2 month appointment
n = 47
3 month appointment
n = 45
4 month appointment
n = 43
5 month appointment
n = 43
6 month appointment
n = 42
6 month appointment
n = 47
5 month appointment
n = 47
4 month appointment
n = 47
3 month appointment
n = 47
2 month appointment
n = 47
1 month appointment
n = 51
- 1 pregnant
- 1 illness in family
- 1 work reasons
- 1 stress
- 1 lost contact
- 1 pregnant
- 1 work reasons
- 1 lack of motivation
- 2 couldn’t keep to diet
- 1 il-health
54 assigned to CER
430 Were excluded:
27 Were excluded:
3 withdrew
4 withdrew
- 1 pregnant
- 2 couldn’t keep to diet
- 1 lost contact
- 1 stress
- 1 couldn’t keep to diet
-1 work reasons
- 13 could not tolerate IER diet
- 14 declined to participate
- 322 did not meet inclusion criteria
- 108 declined to participate
Figure 1 Uptake and recruitment to trial.
Intermittent vs continuous energy restriction
MN Harvie et al
International Journal of Obesity
The IER group was asked to undertake a VLCD
(75% restriction) on two consecutive days and to consume
estimated requirements for weight maintenance for the
remaining 5 days according to the nutrient composition
above. The VLCD provided 2700 kJ of energy and 50 g
protein per day and comprised 1.136 l (two pints) of semi-
skimmed milk, four portions of vegetables (B80 g per
portion), one portion of fruit, a salty low-calorie drink and
a multivitamin and mineral supplement. Participants were
advised to maintain their current activity levels throughout
the trial, and did not receive specific exercise counselling.
Energy prescriptions were reviewed throughout the trial to
account for changes in weight and exercise levels to
maintain a 25% restriction below estimated requirements
for weight maintenance.
Diets were not provided to participants, but were self-
selected using detailed individualized food portion lists,
meal plans and recipes. To maximize compliance, patients
received fortnightly motivational phone calls and monthly
clinical appointments, in which weight and anthropo-
metrics were measured and reported back to patients. All
subjects were encouraged to use cognitive behavioural
techniques, such as self-monitoring, obtaining peer/family
support and stimulus control to maintain diets.
Serum markers of disease risk
Fasting insulin, glucose, lipid levels and sex steroid
hormones were measured at the Clinical Biochemistry
Department at the University Hospital of South Manchester
NHS Foundation Trust using the following methods: insulin
using electrochemoluminescence immunoassay (Elecsys
Roche Diagnostics, Lewes, UK, within-batch coefficient of
variation (CV) 1.9%); glucose using hexokinase/glucose-
6-phosphate interassay dehydrogenase method (Bayer,
Newbury, UK, CV 3%); sex hormone binding globulin
(SHBG) using non-competitive IRMA (IRMA-Orion
Diagnostica Oy, Espoo, Finland, CV 2.7%), prolactin using
electrochemoluminescence immunoassay (Elecsys Roche
Diagnostics, CV 0.8%). Androgens were assessed using
liquid chromatography and tandem mass spectrometry
(LC-MS/MS) with the following CVs: testosterone (6.9%),
dehydroepiandrosterone sulphate (DHEAS) (7.3%), andro-
stenedione (2.5%). Fasting insulin and glucose were
combined to calculate the insulin resistance index using
the homoeostasis model assessment,
whereas free
androgen index was also estimated by the equation
100 serum testosterone/serum SHBG.
enzyme reactions were used to measure total cholesterol
(CV 0.8%), triglycerides (CV 1.5%) and high-density
lipoprotein cholesterol (CV 1.0%) (all Roche Modular E170,
Roche, Welwyn Garden City, UK). Levels were measured
spectrophotometrically by an automated Olympus AU600
analyser. Low-density cholesterol was calculated using
the formula of Friedewald et al.
Adipokines leptin and
adiponectin and inflammatory markers high-sensitivity
C-reactive protein and sialic acid were determined at the
MRC Human Nutrition Research Unit, Cambridge. Plasma
leptin concentration was measured using an ELISA method
(R&D Systems, Minneapolis, MN, USA, Quantikine Human
Leptin kit, R&D Systems; CV 10%), whereas plasma adipo-
nectin was measured using radioimmunoassay (LINCO
Research, St Charles, MO, USA; CV 10%). We also deter-
mined the ratio of leptin:adiponectin, which has been linked
to insulin sensitivity and breast cancer risk.
Sialic acid was assayed using a colorimetric assay (Roche;
CV 1.2%) adapted for use on the Hitachi 912 Clinical
Analyser (Roche) and high-sensitivity C-reactive protein
using a high-sensitivity particle enhanced turbidometric
assay (Dade-Behring, Walton, UK; CV 4.5%).
Total insulin-like growth factor (IGF)-1 (CV 3.2%), ultra-
filtered free IGF-1 (CV 12%) and binding proteins IGFBP-1
(CV 5.3%) and IGFBP-2 (CV 5.0%) were assayed at the
Medical Research Laboratories, Aarhus University Hospital,
Denmark, as previously described.
Serum total ketone
bodies (b-hydroxybutyric acid (B80%) and acetoacetone)
(CV 1.6%), brain-derived neurotrophic factor (CV 2.9%) and
ghrelin (CV 6.7%) were measured at the National Institute
on Ageing (Baltimore, MD, USA) as previously described.
Serum advanced oxidation protein products were measured
using a modified method of Selmeci et al.
(CV 2.2%). All
serum and plasma samples were stored at 4 1C for no longer
than 4 h, aliquoted and frozen at 70 1C within 24 h and
batched, so that all samples from a participant were included
in the same assay.
Laboratory personnel were blinded to
the sample identity.
Statistical analysis
Data at baseline, 1, 3 and 6 months are presented as the
mean (95% confidence intervals (CIs)) or geometric mean
(95% CI) for the log-transformed variables (fasting insulin,
insulin resistance, adiponectin, high-sensitivity C-reactive
protein, total IGF-1, IGFBP-1, IGFBP-2, ghrelin, total ketone
bodies, fast- and slow-acting advanced oxidation protein
products, androstenedione, DHEAS, SHBG, free androgen
index, leptin, leptin:adiponectin ratio and physical activity
(metabolic energy turnover in min/day and kJ/day)).
The primary aim of this study was to determine changes in
weight and insulin resistance between IER and CER over the
6-month weight loss period. Power calculations suggested an
80% power to detect a 25% difference in change in mean
insulin resistance, allowing for a 15% dropout. The primary
analysis was a last observation carried forward (LOCF)
analysis of variance at 6 months between the groups defined
at randomization adjusted for baseline levels of each
parameter, day of menstrual cycle at assessment and change
in physical activity over 6 months. A baseline observation
carried forward analysis and a per protocol analysis of
completers only showed comparable results to the LOCF.
We also assessed changes in weight, biomarkers, dietary
intake and physical activity within each group using paired
Intermittent vs continuous energy restriction
MN Harvie et al
International Journal of Obesity
t-tests at baseline and LOCF at 6 months. Statistical
significance was accepted at Po0.05 for 6-month analysis
and Po0.01 for other time points to adjust for multiple
comparisons. Data were analysed using SPSS (version 14
SPSS, Chicago, IL, USA).
Changes in weight, body fat, waist and insulin resistance,
over the trial period, were also measured using generalized
estimating equations to allow all three time points to be
analysed simultaneously, and to incorporate data from
subjects with less than three time points without the need
for substitution, thus increasing statistical power and a more
efficient comparison across the various time points. These
generalized estimating equations models were constructed
in Stata 10 (StataCorp LP, College Station, TX, USA) with an
exchangeable correlation structure; the predictors used were
the three time points (1, 3, 6 months), the group variable
(IER vs CER) and group-by-time interaction.
Baseline data
Characteristics of the groups at baseline are reported in
Table 1. The groups were of comparable age, weight and
demographics and were mainly Caucasian. A small number
had comorbidities, which were equally frequent in the
two groups. In total, 6 IER (11%) and 10 CER (18%) met
the Diabetes Federation Criteria for metabolic syndrome.
The majority of subjects reported previous attempts at
dieting (IER 92%, CER 78%), with a comparable number of
previous attempts between the groups: IER 2.8 (2.1) and CER
2.4 (1.9) (P¼0.29).
Eighteen women withdrew from the study before 6
months (IER ¼11, CER ¼7), representing 21% IER and 13%
CER subjects (w
¼1.16, P¼0.28). The main reasons for
dropout were comparable between the groups: stress
(IER ¼3, CER ¼2), pregnancy (IER ¼2, CER ¼1), change in
employment (IER ¼2, CER ¼1), problems adhering to the
diet (IER ¼3, CER ¼3) and personal illness (infected pace-
maker, IER ¼1).
Changes in weight, body composition and circumferences
Weight loss was comparable between the groups. LOCF
analysis at 6 months showed weight reduced from mean
(95% CI) 81.5 (77.5–85.4) to 75 (71.2–78.8) kg in the IER
group compared with a reduction from 84.4 (79.7–89.1) to
78.7 (74.2–83.2) kg in the CER group. The percentage of
women in the IER and CER groups losing 5–10% body weight
were 30 and 33%, respectively, and losing 10% or more body
weight were 34 and 22%, respectively (w
¼1.89, P¼0.39).
Both groups experienced comparable reductions in body
fat, fat-free mass, hip, bust and thigh circumference and
composition of weight loss. The percentage of weight lost,
which was fat in the IER and CER groups, was 79 (±24) and
79 (±26)%, respectively (P¼0.99) (Table 2). Generalized
estimating equations modelling over 6 months showed no
group or group-by-month interactions for weight (P¼0.41)
(Figure 2a) or body fat (Figure 2b) (P¼0.36), but a
nonsignificant greater decline in waist measurement
with IER at 3 months (mean difference between groups
(95% CI) 1.1 (2.3 to 0.1) cm, group-by-month-3 inter-
action P¼0.07) (Figure 2c).
Weekly dietary records were available for 82 (76%) subjects at
baseline, for 72 (67%) at 1 month, 65 (60%) at 3 months and
58 (54%) at 6 months. There were no significant differences
in energy or macronutrient intakes between the groups at
baseline. Changes in dietary intake during the study are
reported in Table 3. Both groups reported reductions in
average weekly energy and macronutrient intakes; how-
ever, the IER group reported greater reductions for average
daily intake of energy (mean difference between groups
(95% CI) 716 (1240 to 192) kJ, 9(14 to 2)%,
(Po0.01), protein 5.5 (10.0 to 0.8) g, 6(13.0 to
0.0)%, (P¼0.02) and carbohydrate 24 (41 to 8) g, 11
(18 to 3)%, (P¼0.004).
Table 1 Baseline characteristics of subjects
IER (N¼53) CER (N¼54) P-value
Age at start (years)
40.1 (4.1) 40.0 (3.9) 0.85
Baseline BMI (kg m
30.7 (5.0) 30.5 (5.2) 0.77
Weight gain since age 18 (kg)
20.1 (11.0) 19.8 (10.5) 0.90
Family history of breast cancer
(lifetime risk 41in6)
28 (54%) 30 (56%) 0.85
Sedentary o1 h moderate activity
per week
23 (44%) 22 (41%) 0.70
Ethnic origin
Caucasian 50 (94%) 53 (98%)
Afro-Caribbean 1 (2%) 1 (2%)
Other 2 (4%) 0 (0%)
37 (69%) 39 (72%) 0.12
Children living at home
52 (98%) 50 (92%) 0.55
Full-time 47 (88%) 41 (76%)
Part-time 5 (9%) 10 (19%)
Asthma 5 (9%) 5 (9%)
Hypertension 3 (6%) 2 (3%)
Mild depression 0 (0%) 1 (2%)
Antihypertensive 3 (6%) 4 (7%)
Antiinflammatory 2 (4%) 4 (7%)
Steroid inhalers 5 (9%) 1 (2%)
Thyroxin 1 (2%) 2 (4%)
Antidepressants 1 (2%) 1 (2%)
Beta blockers 2 (4%) 1 (2)
Abbreviations: BMI, body mass index; CER, continuous energy restriction;
IER, intermittent energy restriction.
Mean (s.d.), Independent sample t-test.
Tyrer–Cuzick model.
21 c
N(%), w
Intermittent vs continuous energy restriction
MN Harvie et al
International Journal of Obesity
Intention-to-treat analysis assuming that women who left
the study or who did not complete food diaries did not adhere
to the diets shows reported adherence to 2-day VLCD among
the IER group to be 63% at 1 month, 43% at 3 months and
44% at 6 months. A further 7, 24 and 13% of IER subjects
completed 1 day of VLCD at 1, 3 and 6 months, respectively.
The proportion of CER subjects who reported to adhere to the
25% CER was 46% at 1 month, 37% at 3 months and 32% at
6 months. Completers-only analysis showed adherence to
2-day or 1-day VLCD in the IER group to be, respectively,
70 and 8% at 1 month, 56 and 32% at 3 months and 64 and
19% at 6 months, whereas 25% CER was achieved by 71% at
1 month, 61% at 3 months and 55% at 6 months. At the end
of the trial, 31 of IER (58%) and 46 (85%) of CER subjects
planned to continue the diet allocated at randomization.
Neither group received counselling on exercise; there was no
overall change in physical activity in either group.
Changes in insulin sensitivity and associated markers
Both groups experienced modest declines in fasting serum
insulin and improvements in insulin sensitivity, which were
greater among the IER group (Table 4). Mean difference
between groups (95% CI) for fasting insulin was 1.2 (1.4
to 1.0) mUml
,16 (19 to 13)%, (P¼0.04); and for
insulin resistance was 1.2 (1.5 to 1.0) mU mmol
(86 to 3)%, (P¼0.04) (Table 4). Generalized estimating
equations modelling showed that the IER group had greater
reductions in insulin resistance than the CER group at
3 months (mean difference (95% CI) between groups 17
(33.2 to 0.2)%, group-by-month-3 interaction, P¼0.046)
and 6 months (23 (38.1 to 8.6)%, group-by-month-6
interaction, P¼0.001) (Figure 2d). Correspondingly, there was a
modest increase in adiponectin in the IER group, but not in the
CER group (mean difference (95% CI) þ9(2 to 21)%,
P¼0.08). Changes in the IGF axis were comparable between
the groups with increased IGFBP-1 and IGFBP-2, but negligible
changes were observed in total and free IGF-1.
Both groups experienced modest decreases in the inflam-
matory marker high-sensitivity C-reactive protein, but no
change in sialic acid levels. The groups had comparable
reductions in the oxidative stress marker, fast-acting advanced
oxidation protein products, by 6 months, which appeared to
occur earlier in IER compared with CER. Slow-acting advanced
Table 2 Change in weight and circumferences over 6 months
Parameter Baseline 1 month 3 months 6 months P-value
Weight (kg)
IER 81.5 (77.5–85.4) 79.7 (75.3–84.2) 77.4 (73.0–81.8) 75.8
(71.4–80.2) 0.26
CER 84.4 (79.7–89.1) 83.4 (78.1–88.6) 81.4 (76.2–86.7) 79.9
Body fat (kg)
IER 33.6 (30.9–36.4) 32.5 (29.3–35.7) 30.6 (27.5–33.8) 29.1
(26.0–32.3) 0.34
CER 35.3 (31.9–38.7) 34.6 (30.8–38.3) 32.9 (29.1–36.6) 31.7
Body fat (%)
IER 40.5 (39.0–42.0) 39.9 (38.0–41.7) 38.5 (36.5–40.5) 37.3
(35.2–39.3) 0.35
CER 40.5 (38.7–42.3) 40.2 (38.2–42.2) 39.0 (36.9–41.1) 38.0
Fat-free mass (kg)
IER 47.6 (46.3–49.0) 46.9 (45.4–48.4) 46.5 (45.0–47.9) 46.4
(44.9–47.9) 0.21
CER 49.1 (47.7–50.5) 48.8 (47.2–50.4) 48.5 (46.9–50.2) 48.3
Waist (cm)
IER 101.5 (97.8–105.2) 99.5 (95.5–103.4) 97.3 (93.4–101.1) 95.4
(91.3–99.5) 0.13
CER 102.5 (98.7–106.3) 101.3 (97.0–105.6) 99.8 (95.6–104.0) 98.6
Hip (cm)
IER 111.0 (108.2–113.8) 109.3 (106.2–112.4) 107.3 (104.2–110.5) 106.2
(103.0–109.5) 0.23
CER 111.6 (108.5–114.8) 111.0 (107.6–114.4) 109.2 (105.7–112.7) 108.2
Bust (cm)
IER 105.3 (102.4–108.3) 103.9 (100.8–107.1) 102.0 (98.8–105.1) 100.5
(97.4–103.7) 0.19
CER 105.5 (102.4–108.6) 103.9 (100.6–107.2) 102.4 (99.1–105.8) 101.2
Thigh (cm)
IER 60.1 (58.2–62.0) 59.2 (57.3–61.1) 58.1 (56.1–60.0) 57.2
(55.2–59.1) 0.29
CER 60.6 (58.5–62.8) 60.0 (57.8–62.2) 59.2 (57.0–61.5) 58.2
Abbreviations: IER, intermittent energy restriction, CER, continuous energy restriction.
Analysis of variance (ANOVA) for LOCF at 6 months between groups adjusted
for baseline levels of each parameter, change in physical activity over 6 months and day of menstrual cycle.
Change from baseline to LOCF is statistically significant
at 6 months within group Po0.05 Mean (95% CI) for baseline and last observation carried forward (LOCF) values at 1, 3 and 6 months. Baseline, 53 IER and 54 CER;
1 month, 51 IER and 51 CER; 3 months 45 IER and 47 CER; 6 months, 42 IER and 47 CER.
Intermittent vs continuous energy restriction
MN Harvie et al
International Journal of Obesity
oxidation protein products appeared to decrease in the IER
group and to have a slight increase in the CER group (mean
difference between groups at 6 months (95% CI) 10 (19
to 2)%, P¼0.12). Women in the IER group had a nonsigni-
ficant greater increase in serum total ketone bodies at
6 months compared with the CER group, suggesting higher
rates of fat oxidation (mean difference between groups
(95% CI) 33 (8to93)%,P¼0.12). There were no significant
changes in either group for ghrelin, the growth factor brain-
derived neurotrophic factor or for fasting glucose.
Breast cancer risk markers
Both groups experienced large reductions in serum leptin,
decreases in the ratio of leptin:adiponectin, and no changes in
serum levels of testosterone, androstenedione and prolactin.
The CER group had a greater reduction in DHEAS compared
with IER (mean difference (95% CI) CER vs IER 6(14
to 1)%, P¼0.08); however, both groups experienced compar-
able increases in SHBG and a decrease in free androgen index
(Table 5). Menstrual cycle data were available for 44 IER (83%)
and 47 CER (87%) subjects. During the 6-month study period,
the mean (±s.d.) length of menstrual cycle was significantly
longer in the IER group compared with the CER group
(29.7 (±3.8) vs 27.4 (±2.7) days, P¼0.002).
Cardiovascular risk markers
Both diets led to comparable reductions in total and
low-density lipoprotein cholesterol, triglycerides, systolic
and diastolic BP. Neither group experienced changes in
high-density lipoprotein levels (Table 5).
Effects of IER and CER on serum markers over 1 week
A subset of women (15 IER and 9 CER) provided fasting
serum samples over 1 week during the study period. The IER
group demonstrated acute reductions in fasting insulin
(23%), homoeostasis model assessment (29%) and trigly-
cerides (18%) in the morning after the 2-day VLCD, which
normalized within 2 days of resuming a normal diet. There
were no significant changes in the CER group (Figure 3).
Quality of life
There were no major adverse effects of the diets. A small
number of subjects in the IER group (4, 8%), but none in the
CER group, experienced minor adverse physical symptoms,
including lack of energy, headache, feeling cold and
constipation. Eight (15%) of the IER and none of the CER
subjects complained of hunger, whereas a further three (6%)
of the IER and seven (13%) subjects of the CER group
reported increased energy and improved health. Around 8
(15%) subjects of the IER and 4 (7%) of the CER group
reported minor adverse psychological effects, including lack
of concentration, bad temper and preoccupation with food,
whereas 17 (32%) of the IER and 25 (46%) of the CER group
reported increased self-confidence and a positive mood.
Predictably, both groups acknowledged the limited food
choice of the diets: 55% IER and 53% CER. More subjects of
P =0.23
P =0.07
P =0.11
P =0.046 P =0.001
Insulin sensitivity (HOMA)
P =0.41
01 3 6
01 3 6
01 3 6
13 6
Body fat
P =0.55 P =0.36
% change
Figure 2 GEE modelling of changes in weight, body fat, waist and insulin sensitivity (HOMA) with intermittent energy restriction (N¼53) and continuous energy
restriction (N¼54) over 6 months.
Intermittent vs continuous energy restriction
MN Harvie et al
International Journal of Obesity
the IER group reported problems fitting the diet into daily
routine: 51% IER vs 30% CER. RAND SF-36 quality of life
scores were available for 96 patients at baseline (88%), for 91
at 1 and 3 months (84%) and for 75 at 6 months (69%).
There was a modest increase in the physical component
summary score in the IER but not in the CER group (mean
difference (95% CI) 2.1 (0.1 to 4.3) units, 4 (0.0–8.0)%,
P¼0.06). In comparison, there was a slightly greater
increase in the mental component summary score in the
CER compared with the IER group (2.8 (0.1–5.6) units,
5 (0.0–12.0)%, P¼0.04).
Main findings
This is the largest randomized comparison of an isocalorific
intermittent vs continuous energy restriction to date in
free-living humans. Both approaches achieved comparable
weight loss and improvements in a number of risk markers
for cancer, diabetes and cardiovascular disease; for example,
reductions in fasting insulin, insulin resistance, leptin, the
leptin:adiponectin ratio, free androgen index, inflammatory
markers, lipids, blood pressure, increases in SHBG, IGFBP1
and -2. IER was no easier to adhere to than CER; however, it
may be offered as an equivalent alternative to CER for weight
loss and reducing disease risk.
Comparison with other studies
There has only been limited research of IER in humans.
Two small short-term (12 weeks) randomized studies have
reported the effects of IER vs CER. Ash et al.
compared an
IER (4180 kJ liquid VLCD 4 days per week, 3 days ad libitum)
vs CER (6000–7000 kJ/day) among nine men with type 2
diabetes and showed no difference in terms of weight or
Table 3 Changes in dietary intake and physical activity over 6 months
Parameter Baseline 1 month 3 months 6 months P-value
Energy (kcal/day)
IER 1908.4 (1773.2–2043.5) 1348.6 (1254.8–1442.5) 1341.0 (1257.5–1424.6) 1340.9 (1243.9–1437.9)
CER 1894.3 (1770.1–2018.4) 1425.5 (1315.0–1536.0) 1484.3 (1367.0–1601.7) 1506.8 (1390.9–1622.7)
Energy (kJ/day)
IER 7984.7 (7419.2–8550.1) 5642.7 (5249.9–6035.6) 5610.9 (5261.2–5960.5) 5610.4 (5204.5–6016.3)
CER 7925.7 (7406.2–8445.2) 5964.3 (5502.0–6426.6) 6210.5 (5719.4–6701.5) 6304.5 (5819.6–6789.5)
Protein (g/day)
IER 80.3 (75–85.3) 73.2 (69.2–77.2) 72.1 (68.0–76.2) 70.7 (65.6–75.9)
CER 77.3 (73.0–81.6) 71.9 (67.5–76.2) 74.6 (70.2–79.0) 73.4 (69.4–77.4)
Fat (g/day)
IER 73.0 (66.47–79.5) 43.3 (38.7–47.8) 43.7 (39.5–47.8) 43.7 (38.7–48.8)
CER 73.2 (66.9–79.6) 48.1 (41.5–54.7) 51.6 (44.4–58.9) 50.4 (43.6–57.2)
Saturated fat (g/day)
IER 27.1 (24.0–30.2) 14.3 (12.39.5) 15.5 (13.7–8.7) 15.1 (13.1–8.7)
CER 26.4 (23.8–29.1) 16.3 (13.8–18.8) 17.1 (14.2–20.0) 16.8 (14.1–19.5)
Carbohydrates (g/day)
IER 220.9 (202.0–239.7) 164.7 (154.3–175.1) 163.8 (153.3–174.2) 165.0 (153.5–176.5)
CER 227.5 (212.6–242.4) 180.0 (167.1–192.9) 184.2 (171.1–197.3) 189.8 (174.5–205.0)
Fibre (g/day)
IER 13.6 (12.4–14.7) 13.2 (12.2–14.2) 12.8 (11.8–13.8) 13.1 (12.1–14.2) 0.00
CER 13.9 (12.9–14.9) 14.9 (13.7–16.1) 14.9 (13.8–16.1) 15.9 (14.6–17.3)
MET (mins/day)
IER 178.1 (140.4–225.6) 245.3 (182.8–307.8) 236.7 (183.6–289.7) 243.5 (189.2–297.8) 0.98
CER 218.0 (160.4–296.0) 300.0 (239.3–360.7) 326.2 (259.2–393.2) 373.9 (297.5–450.3)
Energy expenditure for activity (kJ/day)
IER 988.7 (776.3–1259.1) 1307.2 (948.5–1666.0) 1200.1 (922.3–1477.8) 1140.2 (880.6–1399.8) 0.75
CER 1215.6 (845.1–1748.1) 1719.4 (1383.1–2055.7) 1865.0 (1439.4–2290.6) 2082.0 (1625.1–2538.8)
Abbreviations: IER, intermittent energy restriction; CER, continuous energy restriction.
Analysis of variance (ANOVA) for (last observation carried forward) LOCF at
6 months between groups adjusted for baseline levels of each parameter.
Mean (95% CI) for baseline and LOCF values at 1, 3 and 6 months.
Change from baseline
to LOCF at 6 months within group is statistically significant within group Po0.05.
Geometric mean (95% CI) for baseline values and LOCF values at 1, 3 and
6 months. Dietary intake data: Baseline, 40 IER and 42 CER; 1 month, 37 IER and 35 CER; 3 months, 32 IER and 33 CER; 6 months, 27 IER and 31 CER. Physical
activity data: Baseline, 50 IER and 52 CER; 1 month, 49 IER and 47 CER; 3 months, 42 IER and 46 CER; 6 months, 38 IER and 43 CER.
Intermittent vs continuous energy restriction
MN Harvie et al
International Journal of Obesity
fasting insulin. Hill et al.
compared alternating weeks of
2508, 3762, 5016 or 7254 kJ/day as compared with constant
restriction of 5016 kJ/day in 16 moderately obese women
and reported greater reductions in cholesterol in the IER
group compared with the CER group (14 vs 6%). A further
study among patients with type 2 diabetes showed bene-
ficial effects of periodic VLCD (either 1 day per week or
5 consecutive days every 5 weeks), in addition to, and not
instead of, a normal daily restriction (6180–7416 kJ/day).
Predictably, additional periods of VLCD led to greater weight
loss; however, the 5-day VLCD period had a beneficial effect
on long-term glycaemic control, which was independent
of weight change,
suggesting possible metabolic benefits
of IER.
In our study, both IER and CER led to modest reductions in
fasting serum insulin and improvements in insulin sensitiv-
ity, which appeared greater in the IER group even 5 days
after the 2-day VLCD. These parameters were predictably
improved further during the 2-day VLCD, most likely linked
to acute decreased levels of insulin and increased insulin
receptor affinity with energy restriction.
The biological
significance of these improvements in insulin sensitivity in
Table 4 Changes in insulin and related parameters over 6 months
Parameter Baseline 1 month 3 months 6 months P-value
Insulin (mUml
IER 7.3 (6.3–8.4) 6.4 (5.7–7.3) 5.6 (4.7–6.5) 5.2 (4.5–6.0)
CER 7.4 (6.4–8.6) 6.5 (5.7–7.5) 6.3 (5.4–7.3) 6.3 (5.4–7.4)
HOMA (mU mmol
IER 1.5 (1.3–1.8) 1.4 (1.2–1.6) 1.1 (1.0–1.4) 1.1 (0.9–1.3)
CER 1.6 (1.3–1.8) 1.3 (1.2–1.6) 1.3 (1.1–1.5) 1.3 (1.1–1.6)
Glucose (mmol l
IER 4.8 (4.7–4.9) 4.8 (4.7–4.9) 4.7 (4.6–4.8) 4.7 (4.6–4.8)
CER 4.8 (4.6–4.9) 4.7 (4.6–4.8) 4.7 (4.6–4.8) 4.7 (4.6–4.9)
IER 10.6 (9.5–11.8) 9.9 (8.8–11.0) 10.5 (9.3–11.9) 11.7 (10.3–13.4)
CER 10.8 (9.7–12.1) 9.4 (8.3–10.6) 10.4 (9.1–11.9) 10.9 (9.7–12.3)
Ghrelin (pg ml
IER 136.0 (116.7–158.5) 159.4 (136.9–185.5) 167.8 (139.1–202.4) 153.3 (123.5–190.3) 0.92
CER 132.5 (110.6–158.8 155.1 (130.8–184.0) 159.0 (131.4–192.3) 147.5 (120.7–180.3)
BDNF (pg ml
IER 9539 (8960–10118) 9435 (8890–9980) 9438 (8897–9978) 9214 (8722–9706) 0.87
CER 9898 (9394–10402) 9606 (9144–10069) 9615 (9130–10101) 9528 (9093–9963)
CRP (mg l
IER 4.5 (3.8–5.4) 3.9 (3.3–4.6) 3.7 (3.0–4.4) 4.0 (3.3–4.8)
CER 3.7 (3.2–4.3) 3.1 (2.7–3.5) 3.0 (2.6–3.4) 2.9 (2.5–3.4)
Sialic acid (mg l
IER 72.6 (70.3–75.0) 70.5 (67.9–73.1) 71.2 (68.7–73.7) 71.1 (68.3–73.9) 0.73
CER 71.0 (68.6–73.3) 68.4 (65.9–70.9) 69.9 (67.6–72.2) 69.4 (66.8–71.9)
AOPP fast-acting (mM)
IER 41.5 (34.8–49.5) 34.4 (29.7–39.9) 33.3 (28.2–39.3) 34.9 (30.1–40.4)
CER 43.2 (36.7–51.0) 41.9 (35.4–49.7) 37.9 (32.9–43.7) 36.9 (31.5–43.2)
AOPP aggregates, slow-acting (mM)
IER 1.7 (1.5–2.0) 1.8 (1.6–2.1) 1.8 (1.5–2.1) 1.6 (1.4–1.9) 0.12
CER 1.4 (1.2–1.7) 1.6 (1.4–1.9) 1.6 (1.3–1.9) 1.7 (1.5–1.9)
Ketones (mM)
IER 40.8 (31.5–52.7) 77.1 (58.0–102.5) 73.0 (52.9–100.6) 67.6 (49.7–91.9)
CER 48.0 (37.8–61.0) 71.1 (52.5–96.2) 63.3 (49.2–81.5) 49.6 (38.2–64.3)
Abbreviations: IER, intermittent energy restriction; CER, continuous energy restriction.
Analysis of variance (ANOVA) for LOCF at 6 months between groups adjusted
for baseline levels of each parameter, change in physical activity over 6 months and day of menstrual cycle.
Geometric mean (95% CI) for baseline values and LOCF
values at 1, 3 and 6 months.
Change from baseline to LOCF at 6 months within group is statistically significant Po0.05.
Mean (95% CI) for baseline and LOCF
values at 1, 3 and 6 months. Dietary intake data: Baseline 40 IER and 42 CER, 1 month 37 IER and 35 CER, 3 months 32 IER and 33 CER, 6 months 27 IER and 31 CER.
Physical activity data: Baseline, 50 IER and 52 CER; 1 month, 49 IER and 47 CER; 3 months, 42 IER and 46 CER; 6 months 38 IER and 43 CER.
Intermittent vs continuous energy restriction
MN Harvie et al
International Journal of Obesity
Table 5 Changes in risk markers for breast cancer and cardiovascular disease
Parameter Baseline 1 month 3 months 6 months P-value
Cardiovascular disease risk markers
Cholesterol (mmol l
IER 5.1 (4.9–5.4) 4.6 (4.4–4.9) 4.8 (4.5–5.0) 4.8 (4.5–5.0)
CER 5.2 (5.0–5.4) 4.8 (4.5–5.0) 4.8 (4.5–5.0) 4.7 (4.5–5.0)
Triglycerides (mmol l
IER 1.2 (1.0–1.4) 1.0 (0.9–1.2) 1.2 (0.9–1.5) 1.0 (0.9–1.2)
CER 1.3 (1.1–1.4) 1.1 (0.9–1.3) 1.0 (0.9–1.1) 1.0 (0.8–1.2)
HDL (mmol l
IER 1.5 (1.4–1.5) 1.3 (1.2–1.4) 1.4 (1.3–1.5) 1.5 (1.4–1.6) 0.34
CER 1.6 (1.4–1.7) 1.4 (1.3–1.5) 1.5 (1.3–1.6) 1.5 (1.4–1.6)
LDL (mmol l
IER 3.1 (2.9–3.3) 2.8 (2.6–3.1) 2.9 (2.6–3.1) 2.8 (2.6–3.1)
CER 3.1 (2.8–3.3) 2.8 (2.6–3.0) 2.8 (2.6–3.1) 2.8 (2.6–3.0)
BP systolic (mm Hg)
IER 115.2 (111.2–119.2) 111.6 (107.9–115.2) 110.2 (106.9–113.5) 111.5 (107.7–115.2)
CER 116.8 (113.1–120.4) 110.0 (106.7–113.4) 110.9 (107.7–114.1) 109.3 (105.3–113.2)
BP diastolic (mm Hg)
IER 76.7 (73.9–79.4) 72.6 (69.4–75.7) 72.2 (68.7–75.6) 72.4 (68.9–76.0)
CER 75.4 (72.3–78.4) 71.1 (67.8–74.4) 70.5 (67.6–73.3) 69.7 (66.4–72.9)
Breast cancer risk markers
Leptin (ng ml
IER 28.5 (23.2–35.0) 19.4 (15.5–24.4) 18.0 (14.2–122.8) 17.0 (13.4–21.5)
CER 28.2 (23.5–33.8) 19.2 (15.3–24.2) 19.3 (15.7–23.8) 18.0 (14.1–22.8)
Leptin/adiponectin ratio (ng mg
IER 1.5 (1.3–1.6) 1.4 (1.2–1.5) 1.3 (1.2–1.4) 1.2 (1.1–1.4) 0.18
CER 1.5 (1.3–1.6) 1.3 (1.2–1.5) 1.2 (1.1–1.4) 1.2 (1.0–1.3)
Testosterone (nmol l
IER 0.8 (0.7–0.9) 0.9 (0.8–1.0) 0.8 (0.7–0.9) 0.8 (0.7–0.9) 0.54
CER 0.9 (0.8–1.0) 1.0 (0.8–1.1) 0.8 (0.7–0.9) 0.8 (0.7–0.9)
Androstendione (mmol l
IER 2.7 (2.4–3.0) 2.8 (2.4–3.1) 2.8 (2.5–3.1) 2.9 (2.6–3.2) 0.87
CER 3.1 (2.8–3.4) 3.2 (2.9–3.6) 3.0 (2.7–3.4) 3.1 (2.8–3.4)
DHEAS (mmol l
IER 3.2 (2.8–3.7) 3.4 (2.9–3.9) 3.3 (2.9–3.8) 3.3 (2.8–3.8) 0.08
CER 3.4 (3.0–3.8) 3.4 (3.1–3.9) 3.2 (2.8–3.6) 3.2 (2.8–3.6)
SHBG (nmol l)
IER 43.2 (38.2–49.0) 49.3 (42.8–56.6) 48.6 (42.3–55.9) 49.2 (43.2–56.1)
CER 42.0 (37.5–46.9) 46.1 (41.5–51.2) 44.3 (39.9–49.2) 44.6 (39.7–50.2)
FAI (testosterone/(SHBG 100))
IER 1.7 (1.5–2.1) 1.6 (1.4–2.0) 1.6 (1.4–1.9) 1.6 (1.4–1.9)
CER 2.0 (1.7–2.3) 2.0 (1.7–2.3) 1.8 (1.5–2.1) 1.8 (1.5–2.1)
Prolactin (mIU l
IER 269.6 (230.8–308.4) 244.2 (208.5–279.9) 244.0 (207.6–280.3) 267.1 (228.4–305.7) 0.98
CER 245.3 (218.4–272.2) 259.6 (230.3–288.9) 270.6 (236.5–304.7) 257.4 (226.4–288.4)
IGF-1 total (mgl
IER 201.3 (185.3–218.7) 210.8 (192.7–230.6) 207.7 (188.7–228.6) 191.6 (172.7–212.5) 0.17
CER 202.9 (191.5–215.0) 212.9 (199.3–227.5) 211.4 (198.6–225.0) 203.7 (189.7–218.7)
IGF-1 free (mgl
IER 0.7 (0.6–0.8) FF0.6 (0.5–0.8) 0.71
CER 0.6 (0.5–0.7) FF0.6 (0.5–0.8)
IGF BP-1 (mgl
IER 21.4 (18.4–24.8) 23.3 (19.6–27.6) 26.3 (21.6–32.0) 27.0 (22.4–32.4)
CER 22.6 (18.8–27.1) 22.7 (19.3–26.6) 25.4 (21.5–29.9) 29.0 (24.4–34.4)
IGF BP-2 (mgl
IER 108.8 (93.9–126.0) 125.6 (108.9–144.8) 140.2 (120.3–163.3) 148.4 (126.4–174.1)
CER 112.6 (99.2–127.8) 122.3 (105.6–141.6) 125.7 (109.9–143.7) 134.9 (115.8–157.2)
Abbreviations: BP, blood pressure; CER, continuous energy restriction; DHEAS, dehydroepiandrosterone sulphate; IER, intermittent energy restriction; IGF, insulin-
like growth factor, FAI, free androgen index, HDL, high-density lipoprotein; LDL, low-density lipoprotein; SHBG, sex hormone binding globulin.
Analysis of variance
(ANOVA) for last observation carried forward (LOCF) at 6 months between groups adjusted for baseline levels of each parameter, change in physical activity over
6 months and day of menstrual cycle.
Mean (95% CI) for baseline and LOCF values at 1, 3 and 6 months.
Change from baseline to LOCF at 6 months within group
is statistically significant Po0.05.
Geometric mean (95% CI) for baseline values and LOCF values at 1, 3 and 6 months. Baseline, 53 IER and 54 CER; 1 month, 51 IER
and 51 CER; 3 months, 45 IER and 47 CER; 6 months, 42 IER and 47 CER.
Intermittent vs continuous energy restriction
MN Harvie et al
International Journal of Obesity
our population, which was not particularly insulin resistant
(16% of subjects met the Diabetes Federation Criteria for
the metabolic syndrome), is not known. IER seemed to
bring about a modest increase in adiponectin, which has a
pivotal role in insulin sensitivity and in the development
and progression of cancer, heart disease and diabetes.
did not, however, observe any acute effects of IER on
adiponectin, which contrasts to the 37% increase on
alternate fasting days, previously reported among healthy
weight men.
Neither IER nor CER led to appreciable changes in total or
free IGF-1. Animal studies have shown reductions in IGF-1
with CER, but not consistently with IER.
neurotrophic factor is upregulated in inflammatory condi-
tions and in the metabolic syndrome. Levels did not change
with either of our test diets. Earlier studies have linked
weight loss to decreased serum levels among overweight
but increased levels among healthy overweight
In our study, both CER and IER led to anticipated
increases in serum levels of ghrelin.
Reductions in circulating sex steroid levels may reduce
risk of breast cancer. The declines in free androgen index
observed in both groups have been reported previously in
premenopausal women.
The greater reduction in DHEAS
with CER may be advantageous and may translate into
greater reductions in breast cancer risk in women,
contrast to men, in whom higher levels of DHEAS are linked
to longevity.
Conversely, the greater average cycle length
among IER women may reduce breast cancer risk and reflect
increased follicular length due to perturbations of the
neuroendocrine axis.
Neither group experienced changes
in prolactin. Reductions in prolactin have previously been
reported with much larger weight loss (15%),
thought to
be due to enhanced dopamine 2 receptor activation.
Reductions in the leptin:adiponectin ratio in both groups
may be linked to improved insulin sensitivity
and reduced
breast cancer risk.
Recent reviews speculate that IER may be associated with
greater disease prevention than CER because of increased
cellular stress resistance, in particular, increased resistance
to oxidative stress. This is thought to be mediated by
‘hormesis’, whereby the moderate stress of energy restriction
increases the production of cytoprotective, restorative
proteins, antioxidant enzymes and protein chaperones.
Alternate day fasting has been linked to increased SIRT-1
gene expression in muscle,
and to greater neuronal
resistance to injury compared with CER in C57BL/6 mice.
The tendency for greater improvements in oxidative stress
markers in our IER than in the CER group may support these
assertions. Declines in long-term protein oxidation product
aggregates suggest IER as a possible activator of catabolism
and autophagy.
Both of our groups demonstrated good adherence and
weight loss at 6 months (64% IER and 55% CER subjects
achieved 45% weight loss), which may reflect the motiva-
tion of the participants and ongoing monitoring and
motivational calls. A number of subjects of the IER group
experienced minor adverse physical and mental symptoms
with IER. Despite this, 57% were still undertaking either 1 or
2 milk days at 6 months, which is comparable but no better
than adherence to long-term popular diets.
A recent blinded
trial of a 2-day VLCD (1311 kJ per day) reported no adverse
effects on cognition, energy levels, sleep or mood,
suggesting that symptoms are expected with VLCD, and
therefore experienced, and could potentially be overcome
with appropriate counselling. Importantly, IER did not lead
to overeating on non-VLCD days. A similar lack of energy
compensation has been reported after a 36 h fast among
healthy weight subjects.
Strengths of this study
Previously reported weight loss and benefits of intermittent
restriction have been reported from single-arm studies.
Our randomized trial allows the effects of IER to be directly
compared with those of the standard CER approach and
shows comparable benefits. Good retention to the study
(83% at 6 months) and completeness of trial assessments
Insulin sensitivity (HOMA) Triglyceride
Monday Wednesday Friday Monday Wednesday Friday
2 day IER 2 day IER
% change
% change
Figure 3 Changes in insulin sensitivity and triglycerides over the week with intermittent energy restriction (N¼15) and continuous energy restriction (N¼9).
Intermittent vs continuous energy restriction
MN Harvie et al
International Journal of Obesity
indicate that our LOCF analysis informs the relative accept-
ability and efficacy of the diets. We chose a pragmatic IER
regimen, which provided a 25% energy restriction and
required a simple non-proprietary VLCD to be taken over 2
days per week. We believe this to be more achievable than
previously studied regimens of alternate-day fasting or
We tested the diets among overweight and
obese free-living individuals, as this group is likely to derive
metabolic benefit from energy restriction. We studied
premenopausal women only to avoid the potential effects
of sex or menopausal status on metabolic biomarkers. The
benefits of IER and CER in older women or men cannot be
extrapolated; however, earlier reports suggest that accept-
ability of intermittent VLCD may be greater among men
than among women.
Study limitations
Although longer than previous studies, we did not assess the
effects of IER and CER beyond 6 months to investigate their
relative effects for maintenance of weight loss. Fewer subjects
of the IER group (58%) planned to continue with the
regimen beyond 6 months compared with the CER group
(85%), suggesting difficulties with long-term adherence to
IER. Further studies are needed to address issues related to
We assessed the effects of the two diets on a compre-
hensive range of serum biomarkers of disease risk. This
approach does not take into account any local changes in the
production of these factors, which may be more relevant to
disease risk.
Nor does it consider different isoforms of the
hormones, such as high-molecular-weight adiponectin and
aceylated ghrelin (which are specifically linked to insulin
Implications and future studies
Insulin sensitivity was assessed using homoeostasis model
assessment, which is an accepted method among non-
Future trials should, however, compare the
effects of IER with CER in a pre-diabetic population using
more rigorous methods to study insulin and glucose
metabolism; for example, glucose clamp techniques. The
overall effects of IER on glycaemic control, for example, both
during and after IER each week, compared with CER, could
also be ascertained from measuring HBA1c and fructosa-
mine. Such studies could also examine the relative effects
of IER and CER on visceral, hepatic, intramuscular fat
stores and fat cell size, which could preferentially decrease
during the weekly spells of acute negative energy balance
with IER.
Our data suggest that periods of severe restriction may
have different effects, which may be important in the long
term for disease prevention. However, IER was no easier
to adhere to than CER, particularly in the longer term.
Predictably, ease of following the diets varied between
individuals. IER can be offered as an alternative to CER
for reducing obesity and obesity-related disorders in some
individuals. Psychosocial studies are required to better
understand behavioural factors, which can promote or
reduce compliance to IER and CER regimens.
Conflict of interest
The authors declare no conflict of interest.
Michelle N Harvie: study conception and design, trial
management and manuscript preparation. Mary Pegington:
running the trial, statistical analysis and manuscript
preparation. Mark P Mattson: consultation, assays at NIH
and manuscript preparation. Jan Frystyk and Allan Flyvbjerg:
consultation, IGF-1 assays and manuscript preparation.
Bernice Dillon: GEE modelling. Jack Cuzick: design of the
trial, statistical advice and manuscript preparation. Gareth
Evans: recruitment of subjects, consultation and manuscript
preparation. Susan Jebb: MRC HNR assays, consultation and
manuscript preparation. Bronwen Martin: BDNF and ghrelin
assays and manuscript preparation. Roy G Cutler: AOPP and
total ketone bodies assays. Tae G Son: AOPP and total ketone
bodies assays. Stuart Maudsley: BDNF and ghrelin assay
validation. Olga D Carlson: technical assistance with NIH
assays. Josephine M Egan: BDNF and ghrelin assay validation
and manuscript preparation. Anthony Howell: study con-
ception and design, manuscript preparation. We thank Julie
Morris for her invaluable statistical advice, Helen Sumner for
coordinating sample storage and processing, Rosemary
Greenhaugh and Jenny Affen for assisting in recruitment
and sample collection, Emma Campbell for quality-of-life
analysis, Lorraine Darmody, Angela Foster, Jane Eaton and
Philippa Quirk for clerical support, Padraig McQuaid for help
with dietary analysis. Aram Rudenski for advice on the
HOMA model. We dedicate this paper to Andrew Shenton
(database manager) who died tragically at a young age on 19
February 2008. Funding:Breast Cancer Campaign, World
Cancer Research Fund, Genesis Appeal Manchester UK,
Intramural Research Program of the National Institute on
Aging of the NIH, the Danish Research Council for Health
and Disease, Tanita Europe BV Middlesex UK for provision of
Tanita TBF-300.
1 Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as
a risk factor for clinical diabetes mellitus in women. Ann Intern
Med 1995; 122: 481–486.
2 Willett WC, Manson JE, Stampfer MJ, Colditz GA, Rosner B,
Speizer FE et al. Weight, weight change, and coronary heart
disease in women. Risk within the ‘normal’ weight range. JAMA
1995; 273: 461–465.
Intermittent vs continuous energy restriction
MN Harvie et al
International Journal of Obesity
3 Beydoun MA, Beydoun HA, Wang Y. Obesity and central obesity
as risk factors for incident dementia and its subtypes: a systematic
review and meta-analysis. Obes Rev 2008; 9: 204–218.
4 Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-
mass index and incidence of cancer: a systematic review and
meta-analysis of prospective observational studies. Lancet 2008;
371: 569–578.
5 Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun
A, Bonneux L. Obesity in adulthood and its consequences for life
expectancy: a life-table analysis. Ann Intern Med 2003; 138: 24–32.
6 HarvieM, Howell A, Vierkant RA, Kumar N,Cerhan JR, Kelemen LE
et al. Association of gain and loss of weight before and after
menopause with risk of postmenopausal breast cancer in the Iowa
women’s health study. Cancer Epidemiol Biomarkers Prev 2005; 14:
7 Lindstrom J, Uusitupa M. Lifestyle intervention, diabetes, and
cardiovascular disease. Lancet 2008; 371: 1731–1733.
8 Chlebowski RT, Blackburn GL, Thomson CA, Nixon DW, Shapiro A,
Hoy MK et al. Dietary fat reduction and breast cancer outcome:
interim efficacy results from the Women’s Intervention Nutrition
Study. JNatlCancerInst2006; 98: 1767–1776.
9 Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ.
Comparison of the Atkins, Ornish, Weight Watchers, and Zone
diets for weight loss and heart disease risk reduction: a
randomized trial. JAMA 2005; 293: 43–53.
10 Henry RR, Scheaffer L, Olefsky JM. Glycemic effects of intensive
caloric restriction and isocaloric refeeding in noninsulin-depen-
dent diabetes mellitus. J Clin Endocrinol Metab 1985; 61: 917–925.
11 Kelley DE, Wing R, Buonocore C, Sturis J, Polonsky K, Fitzsimmons
M. Relative effects of calorie restriction and weight loss in
noninsulin-dependent diabetes mellitus. JClinEndocrinolMetab
1993; 77: 1287–1293.
12 Anson RM, Guo Z, de Cabo R, Iyun T, Rios M, Hagepanos A et al.
Intermittent fasting dissociates beneficial effects of dietary
restriction on glucose metabolism and neuronal resistance to
injury from calorie intake. Proc Natl Acad Sci USA 2003; 100:
13 Cleary MP, Jacobson MK, Phillips FC, Getzin SC, Grande JP,
Maihle NJ. Weight-cycling decreases incidence and increases
latency of mammary tumors to a greater extent than does
chronic caloric restriction in mouse mammary tumor virus-
transforming growth factor-alpha female mice. Cancer Epidemiol
Biomarkers Prev 2002; 11: 836–843.
14 Berrigan D, Perkins SN, Haines DC, Hursting SD. Adult-onset
calorie restriction and fasting delay spontaneous tumorigenesis
in p53-deficient mice. Carcinogenesis 2002; 23: 817–822.
15 Bonorden MJ, Rogozina OP, Kluczny CM, Grossmann ME,
Grande JP, Lokshin A et al. Cross-sectional analysis of inter-
mittent versus chronic caloric restriction in the TRAMP mouse.
Prostate 2009; 69: 317–326.
16 Halagappa VK, Guo Z, Pearson M, Matsuoka Y, Cutler RG,
Laferla FM et al. Intermittent fasting and caloric restriction
ameliorate age-related behavioral deficits in the triple-transgenic
mouse model of Alzheimer’s disease. Neurobiol Dis 2007; 26:
17 Mattson MP, Wan R. Beneficial effects of intermittent fasting and
caloric restriction on the cardiovascular and cerebrovascular
systems. J Nutr Biochem 2005; 16: 129–137.
18 Sogawa H, Kubo C. Influence of short-term repeated fasting on
the longevity of female (NZB x NZW)F1 mice. Mech Ageing Dev
2000; 115: 61–71.
19 Hill JO, Schlundt DG, Sbrocco T, Sharp T, Pope-Cordle J, Stetson B
et al. Evaluation of an alternating-calorie diet with and without
exercise in the treatment of obesity. Am J Clin Nutr 1989; 50:
20 Ash S, Reeves MM, Yeo S, Morrison G, Carey D, Capra S. Effect of
intensive dietetic interventions on weight and glycaemic control
in overweight men with Type II diabetes: a randomised trial.
Int J Obes Relat Metab Disord 2003; 27: 797–802.
21 Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model
incorporating familial and personal risk factors. Stat Med 2004;
23: 1111–1130.
22 Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-
Morreale HF, Futterweit W et al. Positions statement: criteria for
defining polycystic ovary syndrome as a predominantly hyper-
androgenic syndrome: an Androgen Excess Society guideline.
J Clin Endocrinol Metab 2006; 91: 4237–4245.
23 Seiddell J. Waist/hip and waist/thigh ratios. In: Fidanza (ed).
Chapman and Hall: London, 1991, pp 24–29.
24 Ekelund U, Sepp H, Brage S, Becker W, Jakes R, Hennings M et al.
Criterion-related validity of the last 7-day, short form of the
International Physical Activity Questionnaire in Swedish adults.
Public Health Nutr 2006; 9: 258–265.
25 Hays RD, Morales LS. The RAND-36 measure of health-related
quality of life. Ann Med 2001; 33: 350–357.
26 Anttila L, Koskinen P, Irjala K, Kaihola HL. Reference intervals for
serum sex steroids and gonadotropins in regularly menstruating
women. Acta Obstet Gynecol Scand 1991; 70: 475–481.
27 Tonolo G, Ciccarese M, Brizzi P, Milia S, Dessole S, Puddu L et al.
Cyclical variation of plasma lipids, apolipoproteins, and lipo-
protein(a) during menstrual cycle of normal women. Am J Physiol
1995; 269 (6 Pt 1): E1101–E1105.
28 Schofield WN. Predicting basal metabolic rate, new standards and
review of previous work. Hum Nutr Clin Nutr 1985; 39 (Suppl 1):
29 Shai I, Schwarzfuchs D, Henkin Y, Shahar DR, Witkow S,
Greenberg I et al. Weight loss with a low-carbohydrate,
Mediterranean, or low-fat diet. N Engl J Med 2008; 359: 229–241.
30 Avenell A, Sattar N, Lean M. ABC of obesity. Management: Part IF
behaviour change, diet, and activity. BMJ 2006; 333:740743.
31 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF,
Turner RC. Homeostasis model assessment: insulin resistance and
beta-cell function from fasting plasma glucose and insulin
concentrations in man. Diabetologia 1985; 28: 412–419.
32 Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of
simple methods for the estimation of free testosterone in serum.
J Clin Endocrinol Metab 1999; 84: 3666–3672.
33 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the
concentration of low-density lipoprotein cholesterol in plasma,
without use of the preparative ultracentrifuge. Clin Chem 1972;
18: 499–502.
34 Chen DC, Chung YF, Yeh YT, Chaung HC, Kuo FC, Fu OY et al.
Serum adiponectin and leptin levels in Taiwanese breast cancer
patients. Cancer Lett 2006; 237: 109–114.
35 Finucane FM, Luan J, Wareham NJ, Sharp SJ, O’Rahilly S, Balkau B
et al. Correlation of the leptin:adiponectin ratio with measures of
insulin resistance in non-diabetic individuals. Diabetologia 2009;
52: 2345–2349.
36 Frystyk J, Skjaerbaek C, Dinesen B, Orskov H. Free insulin-like
growth factors (IGF-I and IGF-II) in human serum. FEBS Lett 1994;
348: 185–191.
37 Krassas GE, Pontikides N, Kaltsas T, Dumas A, Frystyk J, Chen JW
et al. Free and total insulin-like growth factor (IGF)-I, -II, and
IGF binding protein-1, -2, and -3 serum levels in patients
with active thyroid eye disease. J Clin Endocrinol Metab 2003;
88: 132–135.
38 Johnson JB, Summer W, Cutler RG, Martin B, Hyun DH, Dixit VD
et al. Alternate day calorie restriction improves clinical findings
and reduces markers of oxidative stress and inflammation in
overweight adults with moderate asthma. Free Radic Biol Med
2007; 42: 665–674.
39 Selmeci L, Seres L, Antal M, Lukacs J, Regoly-Merei A, Acsady G.
Advanced oxidation protein products (AOPP) for monitoring
oxidative stress in critically ill patients: a simple, fast and
inexpensive automated technique. Clin Chem Lab Med 2005; 43:
40 Tworoger SS, Yasui Y, Chang L, Stanczyk FZ, McTiernan A.
Specimen allocation in longitudinal biomarker studies: controlling
Intermittent vs continuous energy restriction
MN Harvie et al
International Journal of Obesity
subject-specific effects by design. Cancer Epidemiol Biomarkers Prev
2004; 13: 1257–1260.
41 Alberti KG, Zimmet P, Shaw J. Metabolic syndromeFa new world-
wide definition. A Consensus Statement from the International
Diabetes Federation. Diabet Med 2006; 23:469480.
42 Williams KV, Mullen ML, Kelley DE, Wing RR. The effect of short
periods of caloric restriction on weight loss and glycemic control
in type 2 diabetes. Diabetes Care 1998; 21: 2–8.
43 Bar RS, Gorden P, Roth J, Kahn CR, De Meyts P. Fluctuations in
the affinity and concentration of insulin receptors on circulating
monocytes of obese patients: effects of starvation, refeeding, and
dieting. J Clin Invest 1976; 58: 1123–1135.
44 Oh DK, Ciaraldi T, Henry RR. Adiponectin in health and disease.
Diabetes Obes Metab 2007; 9: 282–289.
45 Halberg N, Henriksen M, Soderhamn N, Stallknecht B, Ploug T,
Schjerling P et al. Effect of intermittent fasting and refeeding
on insulin action in healthy men. J Appl Physiol 2005; 99:
46 Varady KA, Roohk DJ, Hellerstein MK. Dose effects of modified
alternate-day fasting regimens on in vivo cell proliferation and
plasma insulin-like growth factor-1 in mice. J Appl Physiol 2007;
103: 547–551.
47 Araya AV, Orellana X, Espinoza J. Evaluation of the effect of
caloric restriction on serum BDNF in overweight and obese
subjects: preliminary evidences. Endocrine 2008; 33: 300–304.
48 Hayes MR, Miller CK, Ulbrecht JS, Mauger JL, Parker-Klees L,
Gutschall MD et al. A carbohydrate-restricted diet alters gut
peptides and adiposity signals in men and women with metabolic
syndrome. J Nutr 2007; 137: 1944–1950.
49 Turcato E, Zamboni M, De Pergola G, Armellini F, Zivelonghi A,
Bergamo-Andreis IA et al. Interrelationships between weight loss,
body fat distribution and sex hormones in pre- and postmeno-
pausal obese women. J Intern Med 1997; 241: 363–372.
50 Key T, Appleby P, Barnes I, Reeves G. Endogenous sex hormones
and breast cancer in postmenopausal women: reanalysis of nine
prospective studies. J Natl Cancer Inst 2002; 94: 606–616.
51 Enomoto M, Adachi H, Fukami A, Furuki K, Satoh A, Otsuka M
et al. Serum dehydroepiandrosterone sulfate levels predict long-
evity in men: 27-year follow-up study in a community-based
cohort (Tanushimaru study). J Am Geriatr Soc 2008; 56: 994–998.
52 Alvero R, Kimzey L, Sebring N, Reynolds J, Loughran M,
Nieman L et al. Effects of fasting on neuroendocrine function
and follicle development in lean women. J Clin Endocrinol Metab
1998; 83: 76–80.
53 Kok P, Roelfsema F, Langendonk JG, de Wit CC, Frolich M,
Burggraaf J et al. Increased circadian prolactin release is blunted
after body weight loss in obese premenopausal women. Am J
Physiol Endocrinol Metab 2006; 290: E218–E224.
54 Mattson MP. Hormesis defined. Ageing Res Rev 2008; 7: 1–7.
55 Heilbronn LK, Civitarese AE, Bogacka I, Smith SR, Hulver M,
Ravussin E. Glucose tolerance and skeletal muscle gene expression
in response to alternate day fasting. Obes Res 2005; 13:574581.
56 Lieberman HR, Caruso CM, Niro PJ, Adam GE, Kellogg MD,
Nindl BC et al. A double-blind, placebo-controlled test of 2 d of
calorie deprivation: effects on cognition, activity, sleep, and inter-
stitial glucose concentrations. Am J Clin Nutr 2008; 88: 667–676.
57 Johnstone AM, Faber P, Gibney ER, Elia M, Horgan G, Golden BE
et al. Effect of an acute fast on energy compensation and feeding
behaviour in lean men and women. Int J Obes Relat Metab Disord
2002; 26: 1623–1628.
58 Varady KA, Bhutani S, Church EC, Klempel MC. Short-term
modified alternate-day fasting: a novel dietary strategy for weight
loss and cardioprotection in obese adults. Am J Clin Nutr 2009; 90:
59 Heilbronn LK, Smith SR, Martin CK, Anton SD, Ravussin E.
Alternate-day fasting in nonobese subjects: effects on body
weight, body composition, and energy metabolism. Am J Clin
Nutr 2005; 81: 69–73.
60 Truby H, Baic S, deLooy A, Fox KR, Livingstone MB, Logan CM
et al. Randomised controlled trial of four commercial weight loss
programmes in the UK: initial findings from the BBC ‘diet trials’.
BMJ 2006; 332: 1309–1314.
61 Liu YM, Lacorte JM, Viguerie N, Poitou C, Pelloux V, Guy-Grand B
et al. Adiponectin gene expression in subcutaneous adipose tissue
of obese women in response to short-term very low calorie diet
and refeeding. J Clin Endocrinol Metab 2003; 88: 5881–5886.
62 St Pierre DH, Karelis AD, Coderre L, Malita F, Fontaine J, Mignault D
et al. Association of acylated and nonacylated ghrelin with insulin
sensitivity in overweight and obese postmenopausal women. J Clin
Endocrinol Metab 2007; 92: 264–269.
63 Varady KA, Roohk DJ, Loe YC, McEvoy-Hein BK, Hellerstein MK.
Effects of modified alternate-day fasting regimens on adipocyte
size, triglyceride metabolism, and plasma adiponectin levels in
mice. J Lipid Res 2007; 48: 2212–2219.
64 Kreier F, Fliers E, Voshol PJ, Van Eden CG, Havekes LM, Kalsbeek A
et al. Selective parasympathetic innervation of subcutaneous and
intra-abdominal fatFfunctional implications. JClinInvest2002;
110: 1243–1250.
Intermittent vs continuous energy restriction
MN Harvie et al
International Journal of Obesity
... TWF is less restrictive and thus potentially more realistic compared to ADF by virtue of substantially fewer fasting days throughout the week. Despite the disparity in fasting days, weight loss via TWF is surprisingly comparable to that of ADF, ranging~4 to 8% in trials spanning 3 to 12 months [21][22][23][24][25][26][27][28][29][30]. In the TWF trials that assessed body composition [21][22][23]25,[28][29][30], changes in the lean mass range from −0.7 to −2.2 kg. ...
... Despite the disparity in fasting days, weight loss via TWF is surprisingly comparable to that of ADF, ranging~4 to 8% in trials spanning 3 to 12 months [21][22][23][24][25][26][27][28][29][30]. In the TWF trials that assessed body composition [21][22][23]25,[28][29][30], changes in the lean mass range from −0.7 to −2.2 kg. The majority of these trials show greater lean mass losses in TWF compared to DCR, although these differences tend to lack statistical significance. ...
... As in the case of ADF, studies combining exercise with TWF are scarce. Harvie et al. [21] conducted a four-month trial (three months of weight loss, one month of maintenance) on overweight women. Subjects were assigned a gradual increase in exercise frequency and intensity to reach five 45-min sessions of moderate activity ("walking, strengthening, toning and flexibility exercises") per week. ...
Full-text available
The practice of fasting recently has been purported to have clinical benefits, particularly as an intervention against obesity and its related pathologies. Although a number of different temporal dietary restriction strategies have been employed in practice, they are generally classified under the umbrella term “intermittent fasting” (IF). IF can be stratified into two main categories: (1) intra-weekly fasting (alternate-day fasting/ADF, twice-weekly fasting/TWF) and (2) intra-daily fasting (early time-restricted eating/eTRE and delayed time-restricted eating/dTRE). A growing body of evidence indicates that IF is a viable alternative to daily caloric restriction (DCR), showing effectiveness as a weight loss intervention. This paper narratively reviews the literature on the effects of various commonly used IF strategies on body weight and body composition when compared to traditional DCR approaches, and draws conclusions for their practical application. A specific focus is provided as to the use of IF in combination with regimented exercise programs and the associated effects on fat mass and lean mass.
... Ни один из тестируемых режимов ИГ не связан с компенсаторной гиперфагией в дни с привычным рационом. Вместо этого отмечался «переходящий» эффект снижения потребления энергии на ~20% в дни без ограничений, что аналогично запланированному 25% уменьшению при постоянном ограничении калорийности [28,29]. ...
... Неблагоприятные эффекты ИГ в этих работах, возможно, связаны с тем, что животные на фоне подобного рациона могут переедать в дни кормления ad libitum, что приводит к накоплению абдоминальных и внутрипеченочных жировых отложений [36]. В отличие от исследований на грызунах люди с ИзбМТ или ожирением, придерживающиеся ИГ, по-видимому, снижают потребление пищи в дни ad libitum и не страдают гиперфагией [28,29]. ...
... ПОК приводило также к бóльшему снижению индекса HOMA после 5 дней привычного рациона. Эти различия в ИЧ наблюдались на фоне сопоставимого сокращения доли висцерального жира между группами (-4,5 кг на фоне ПОК против -3,6 кг при постоянном ограничении калорийности; p=0,34) [28]. ...
Full-text available
The increasing number of overweight and obese people makes the search for new effective ways to reduce body weight extremely urgent. Recently, intermittent fasting has received a lot of attention, as a dietary protocol, presumably effective in reducing body weight. Despite the large number of studies, the effects of intermittent fasting on the human body are controversial, since studies differ in dietary options, design, and often have a small sample size. In this review of the literature, the authors cite the results of studies of the effectiveness of intermittent fasting in patients with obesity, diabetes mellitus, and high risks of developing cardiovascular diseases.
... Energy restriction feeding protects from diet-induced obesity as a result of reduced energy intake and increased fat oxidation (1,2). Intermittent energy restriction (IER) and continuous energy restriction (CER) have received considerable recent interest as dietary restriction strategies for weight loss and improving glucose and lipid metabolism (3)(4)(5). Although IER and CER were both restricted diets, implementation details vary greatly. ...
... However, the relative contributions of IER and CER protocols for weight loss are controversial. Previous studies reported that IER and CER have the equivalent effect on body weight (BW) loss (13), but showed different effects on body composition (14)(15)(16) and glycolipid metabolism (4,16). ...
Full-text available
Background: Intermittent energy restriction (IER) and continuous energy restriction (CER) are increasingly popular dietary approaches used for weight loss and overall health. These energy restriction protocols combined with exercise on weight loss and other health outcomes could achieve additional effects in a short-term intervention. Objectives: To evaluate the effects of a 4-week IER or CER program on weight, blood lipids, and CRF in overweight/obese adults when combined with high-intensity interval training (HIIT). Methods: Forty-eight overweight/obese adults [age: 21.3 ± 2.24 years, body mass index (BMI): 25.86 ± 2.64 kg⋅m-2] were randomly assigned to iER, cER, and normal diet (ND) groups (n = 16 per group), each consisting of a 4-week intervention. All of the groups completed HIIT intervention (3 min at 80% of V̇O2max followed by 3 min at 50% of V̇O2max ), 30 min/training sessions, five sessions per week. iER subjects consumed 30% of energy needs on 2 non-consecutive days/week, and 100% of energy needs on another 5 days; cER subjects consumed 70% of energy needs; and ND subjects consumed 100% of energy needs. Body composition, waist circumference (WC) and hip circumference (HC), triglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), high-density lipoprotein-cholesterol (HDL-c), and cardiorespiratory fitness (CRF) were measured before and after the intervention. Results: Of the total 57 participants who underwent randomization, 48 (84.2%) completed the 4-week intervention. After intervention body composition and body circumference decreased in three groups, but no significant differences between groups. The iER tends to be superior to cER in the reduction of body composition and body circumference. The mean body weight loss was 4.57 kg (95% confidence interval [CI], 4.1-5.0, p < 0.001) in iER and 2.46 kg (95% CI, 4.1-5.0, p < 0.001) in iER. The analyses of BMI, BF%, WC, and HC were consistent with the primary outcome results. In addition, TG, TC, HDL-c, and CRF improved after intervention but without significant changes (p > 0.05). Conclusion: Both IER and CER could be effective in weight loss and increased CRF when combined with HIIT. However, iER showed greater benefits for body weight, BF%, WC, and HC compared with cER.
... Even though the IF regimen suggests ad libitum feeding on non-fasting days, there is no full compensation for the fasting days/time, and overall there is an energy deficit or lack of calories. Various studies have compared IF approaches to continuous CR and reported comparable or better weight loss and improvement in metabolic health [189,[221][222][223][224][225][226][227][228]. ...
Full-text available
Obesity is a chronic and relapsing public health problem with an extensive list of associated comorbidities. The worldwide prevalence of obesity has nearly tripled over the last five decades and continues to pose a serious threat to wider society and the wellbeing of future generations. The pathogenesis of obesity is complex but diet plays a key role in the onset and progression of the disease. The human diet has changed drastically across the globe, with an estimate that approximately 72% of the calories consumed today come from foods that were not part of our ancestral diets and are not compatible with our metabolism. Additionally, multiple nutrient-independent factors, e.g., cost, accessibility, behaviours, culture, education, work commitments, knowledge and societal set-up, influence our food choices and eating patterns. Much research has been focused on ‘what to eat’ or ‘how much to eat’ to reduce the obesity burden, but increasingly evidence indicates that ‘when to eat’ is fundamental to human metabolism. Aligning feeding patterns to the 24-h circadian clock that regulates a wide range of physiological and behavioural processes has multiple health-promoting effects with anti-obesity being a major part. This article explores the current understanding of the interactions between the body clocks, bioactive dietary components and the less appreciated role of meal timings in energy homeostasis and obesity.
... Intermittent fasting using the eTRF (early time-restricted feeding) method for five weeks with a 6-hour eating period improved insulin levels, insulin sensitivity, and oxidative stress levels in prediabetic subjects [28]. Subjects with excess body weight who did intermittent fasting 5:2 for six months with calorie consumption of 500-600 calories on fasting days experienced decreased body fat, increased insulin sensitivity, and reduced blood pressure [29]. Ramadan fasting in subjects with metabolic syndrome showed reduced energy intake, decreased plasma glucose levels, and increased insulin sensitivity [30]. ...
... By contrast, well-timed eating and fasting windows (8-10 h eating/ > 14 fasting) enhance fat loss, reduce oxidative stress, improve cardiovascular endpoints, and decrease glucose and insulin levels [155][156][157][158][159][160][161][162][163][164][165][166][167]. In a seminal study, mice were randomized to eat throughout the day or to eat within an 8 h period. ...
Full-text available
Purpose of Review Youth-onset obesity is associated with negative health outcomes across the lifespan including cardiovascular diseases, type 2 diabetes, obstructive sleep apnea, dyslipidemias, asthma, and several cancers. Pediatric health guidelines have traditionally focused on the quality and quantity of dietary intake, physical activity, and sleep. Recent Findings Emerging evidence suggests that the timing (time of day when behavior occurs) and composition (proportion of time spent allocated to behavior) of food intake, movement (i.e., physical activity, sedentary time), and sleep may independently predict health trajectories and disease risks. Several theoretically driven interventions and conceptual frameworks feature behavior timing and composition (e.g., 24 h movement continuum, circadian science and chronobiology, intermittent fasting regimens, structured day hypothesis). These literatures are, however, disparate, with little crosstalk across disciplines. In this review, we examine dietary, sleep, and movement guidelines and recommendations for youths ages 0–18 in the context of theoretical models and empirical findings in support of time-based approaches. Summary The review aims to inform a unifying framework of health behaviors and guide future research on the integration of time-based recommendations into current quantity and quality-based health guidelines for children and adolescents.
Full-text available
Introduction: Obesity is now becoming a growing problem and challenge for medicine. The number of people with excessive body weight has now reached more than 2 billion, or about 30% of the world's population. The purpose of this article is to identify and describe some of the already known treatments for obesity, along with the latest research on the subject, in order to show the importance of developing and introducing new methods of weight loss. Aim of the study: The purpose of this article is to review the impact of obesity on health and the diets offered to people struggling with the disease. Materials and methods: We reviewed the literature available in the PubMed database up to November 2022, using the keywords. Results: Consistently limiting caloric intake is a must when losing weight. There are also diets such as low-carbohydrate, low-fat and high-protein diets, but following them can also have some side effects. For example, a high-protein diet can lead to kidney stones. The Mediterranean diet is also a good option for people with obesity. It lowers the risk of cardiovascular disease and cancer. All obesity treatment suggestions consistently recommend a balanced and low-calorie diet with reduced fat (along with saturated fatty acids) and optimal amounts of fiber. In addition to diet, physical activity is an important topic. The primary recommendation for people with obesity is at least moderate to vigorous physical activity of at least 150 minutes per week. Summary: In conclusion, the overarching goal of obesity treatment is to improve quality of life. Calorie restriction, regular exercise or a combination of both is accepted as an effective strategy for preventing or treating obesity.
İmmünite organizmanın hastalık etkenlerine karşı kendini savunmak için geliştirdiği mekanizmalar bütünüdür. İmmünite ve beslenme arasındaki etkileşim oldukça karmaşıktır. İmmün yanıtın her aşamasında birçok makro ve mikro besin ögesi ile biyoaktif bileşen kilit rol oynar. Yapılan çalışmalar neticesinde amino asitler, yağ asitleri, vitaminler ve mineraller gibi immün yanıtı etkileyen birçok besin ögesi saptanmıştır. Beslenme paternlerinin immünite üzerine etkisi doğal ve adaptif immün sistem, mukoza ve mikrobiyom düzeyinde olabilir. Yetersiz ve dengesiz beslenme sonucu vücuda enfeksiyon girişi kolaylaşır ve hastalık etkenlerine yanıt olarak gelişen immün mekanizmalar sekteye uğrar. Başta obezite olmak üzere çeşitli sağlık problemleri ve estetik kaygılar nedeniyle yaygınlığı artan popüler diyetler sağlık etkileri yönünden tartışılmaktadır. Özellikle, akdeniz diyeti ve aralıklı açlık gibi popüler diyetlerin immünite ile ilişkisi birçok araştırmaya konu olmuştur. Ancak, literatürde farklı popüler diyet türlerinin immün fonksiyon üzerine etkilerini derleyen makalelere rastlanmamıştır. Çalışmalar daha çok besin desteklerinin immünite ile ilişkisine odaklanmıştır. Bu çalışmada ketojenik diyet, vejetaryenizm/veganizm, glutensiz diyet, akdeniz diyeti, aralıklı açlık ve detoksifikasyon diyetleri gibi popüler diyet türlerinin immün fonksiyon üzerine etkileri güncel literatür ışığında gözden geçirilmiştir.
Objective: The objective of this meta-analysis was to compare the effectiveness of different intermittent fasting (IF) regimens on weight loss, in the general population, and compare these to traditional caloric energy restriction (CER). Methods: Three databases were searched from 2011 to June 2021 for randomized controlled trials (RCTs) that assessed weight loss and IF, including alternate day fasting (ADF), the 5:2 diet, and time-restricted eating (TRE). A random effect network analysis was used to compare the effectiveness between the three regimens. Meta-regression analysis was presented as weighted mean differences of body weight loss. Results: The exploratory random effects network analysis of 24 RCTs (n = 1768) ranked ADF as the most effective, followed by CER and TRE. The meta-analysis showed that IF regimens resulted in similar weight loss to CER (mean difference 0.26 kg, 95% CI: -0.31 to 0.84; p = 0.37). Compliance was generally high (>80%) in trials shorter than 3 months. Conclusions: The present meta-analysis concludes that IF is comparable to CER and a promising alternative for weight loss. Among the three regimens, ADF showed the highest effectiveness for weight loss, followed by CER and TRE. Further well-powered RCTs with longer durations of intervention are required to draw solid conclusions.
Background. Obesity is a problem present in almost all societies, which has led to the search for different methods to combat it. One of them is intermittent fasting (IF), characterized by periods without eating (16 to 24 hours), limited or no caloric intake, combined with normal eating windows. Target. To determine the effectiveness of intermittent fasting on biochemical and anthropometric markers in obese adults. Materials and methods. A systematic review was proposed that postulated to study blinded or open clinical trials of IA interventions, compared with a control group. The response variables were: systolic and diastolic blood pressure, total cholesterol, LDL, HDL and triglycerides, blood glucose, fat mass, weight, waist circumference, BMI and heart rate. The search and identification of studies was masked. The risks of bias for the Cochrane collaboration were assessed. They underwent meta-analysis (random effect), with R 4.0.0. Results. Six studies were included, involving 10-48 weeks of intervention with alternate-day fasting and time-restricted feeding, reporting some statistically significant changes for different variables. Conclusion. Intermittent fasting could intervene in the reduction of cardiovascular risk due to improvement in BMI and biochemical parameters.
Full-text available
Objective: To examine the relation between adult weight change and the risk for clinical diabetes mellitus among middle-aged women. • Design: Prospective cohort study with follow-up from 1976 to 1990. • Setting: 11 U.S. states. • Participants: I'll 281 female registered nurses aged 30 to 55 years who did not have diagnosed diabetes mellitus, coronary heart disease, stroke, or cancer in 1976. • Outcome Measures: Non-insulin-dependent diabetes mellitus. • Results: 2204 cases of diabetes were diagnosed during 1.49 million person-years of follow-up. After adjustment for age, body mass index was the dominant predictor of risk for diabetes mellitus. Risk increased with greater body mass index, and even women with average weight (body mass index, 24.0 kg/m 2) had an elevated risk. Compared with women with stable weight (those who gained or lost less than 5 kg between age 18 years and 1976) and after adjustment for age and body mass index at age 18 years, the relative risk for diabetes mellitus among women who had a weight gain of 5.0 to 7.9 kg was 1.9 (95% CI, 1.5 to 2.3). The corresponding relative risk for women who gained 8.0 to 10.9 kg was 2.7 (CI, 2.1 to 3.3). In contrast, women who lost more than 5.0 kg reduced their risk for diabetes mellitus by 50% or more. These results were independent of family history of diabetes. • Conclusion: The excess risk for diabetes with even modest and typical adult weight gain is substantial. These findings support the importance of maintaining a constant body weight throughout adult life and suggest that the 1990 U.S. Department of Agriculture guidelines that allow a substantial weight gain after 35 years of age are misleading.
Background: Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk. We reanalyzed the worldwide data from prospective studies to examine the relationship between the levels of endogenous sex hormones and breast cancer risk in postmenopausal women. Methods: We analyzed the individual data from nine prospective studies on 663 women who developed breast cancer and 1765 women who did not. None of the women was taking exogenous sex hormones when their blood was collected to determine hormone levels. The relative risks (RRs) for breast cancer associated with increasing hormone concentrations were estimated by conditional logistic regression on case–control sets matched within each study. Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate. Results: The risk for breast cancer increased statistically significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non-sex hormone-binding globulin (SHBG)-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. The RRs for women with increasing quintiles of estradiol concentrations, relative to the lowest quintile, were 1.42 (95% confidence interval [CI] = 1.04 to 1.95), 1.21 (95% CI = 0.89 to 1.66), 1.80 (95% CI = 1.33 to 2.43), and 2.00 (95% CI = 1.47 to 2.71; Ptrend<.001); the RRs for women with increasing quintiles of free estradiol were 1.38 (95% CI = 0.94 to 2.03), 1.84 (95% CI = 1.24 to 2.74), 2.24 (95% CI = 1.53 to 3.27), and 2.58 (95% CI = 1.76 to 3.78; Ptrend<.001). The magnitudes of risk associated with the other estrogens and with the androgens were similar. SHBG was associated with a decrease in breast cancer risk (Ptrend = .041). The increases in risk associated with increased levels of all sex hormones remained after subjects who were diagnosed with breast cancer within 2 years of blood collection were excluded from the analysis. Conclusion: Levels of endogenous sex hormones are strongly associated with breast cancer risk in postmenopausal women.
Objective. —To assess the validity of the 1990 US weight guidelines for women that support a substantial gain in weight at approximately 35 years of age and recommend a range of body mass index (BMI) (defined as weight in kilograms divided by the square of height in meters) from 21 to 27 kg/m2, in terms of coronary heart disease (CHD) risk in women.Design. —Prospective cohort study.Setting. —Female registered nurses in the United States.Participants. —A total of 115 818 women aged 30 to 55 years in 1976 and without a history of previous CHD.Main Outcome Measure. —Incidence of CHD defined as nonfatal myocardial infarction or fatal CHD.Results. —During 14 years of follow-up, 1292 cases of CHD were ascertained. After controlling for age, smoking, menopausal status, postmenopausal hormone use, and parental history of CHD and using as a reference women with a BMI of less than 21 kg/m2, relative risks (RRs) and 95% confidence intervals (CIs) for CHD were 1.19 (0.97 to 1.44) for a BMI of 21 to 22.9 kg/m2, 1.46 (1.20 to 1.77) for a BMI of 23 to 24.9 kg/m2,2.06 (1.72 to 2.48) for a BMI of 25 to 28.9 kg/m2, and 3.56 (2.96 to 4.29) for a BMI of 29 kg/m2 or more. Women who gained weight from 18 years of age were compared with those with stable weight (±5 kg) in analyses that controlled for the same variables as well as BMI at 18 years of age. The RRs and CIs were 1.25 (1.01 to 1.55) for a 5- to 7.9-kg gain, 1.64 (1.33 to 2.04) for an 8- to 10.9-kg gain, 1.92 (1.61 to 2.29) for an 11-to 19-kg gain, and 2.65 (2.17 to 3.22) for a gain of 20 kg or more. Among women within the BMI range of 18 to 25 kg/m2, weight gain after 18 years of age remained a strong predictor of CHD risk.Conclusions. —Higher levels of body weight within the "normal" range, as well as modest weight gains after 18 years of age, appear to increase risks of CHD in middle-aged women. These data provide evidence that current US weight guidelines may be falsely reassuring to the large proportion of women older than 35 years who are within the current guidelines but have potentially avoidable risks of CHD.(JAMA. 1995;273:461-465)
Context: The scarcity of data addressing the health effects of popular diets is an important public health concern, especially since patients and physicians are interested in using popular diets as individualized eating strategies for disease prevention. Objective: To assess adherence rates and the effectiveness of 4 popular diets (Atkins, Zone, Weight Watchers, and Ornish) for weight loss and cardiac risk factor reduction. Design, Setting, and Participants: A single-center randomized trial at an academic medical center in Boston, Mass, of overweight or obese (body mass index: mean, 35; range, 27-42) adults aged 22 to 72 years with known hypertension, dyslipidemia, or fasting hyperglycemia. Participants were enrolled starting July 18, 2000, and randomized to 4 popular diet groups until January 24, 2002. Intervention: A total of 160 participants were randomly assigned to either Atkins (carbohydrate restriction, n=40). Zone (macronutrient balance, n=40), Weight Watchers (calorie restriction, n=40), or Ornish (fat restriction, n=40) diet groups. After 2 months of maximum effort, participants selected their own levels of dietary adherence. Main Outcome Measures: One-year changes in baseline weight and cardiac risk factors, and self-selected dietary adherence rates per self-report. Results: Assuming no change from baseline for participants who discontinued the study, mean (SD) weight loss at 1 year was 2.1 (4.8) kg for Atkins (21 [53 %] of 40 participants completed, P=.009), 3.2 (6.0) kg for Zone (26 [65%] of 40 completed, P=.002), 3.0 (4.9) kg for Weight Watchers (26 [65%] of 40 completed, P<.001), and 3.3 (7.3) kg for Ornish (20 [50%] of 40 completed, P=.007). Greater effects were observed in study completers. Each diet significantly reduced the low-density lipoprotein/high-density lipoprotein (HDL) cholesterol ratio by approximately 10% (all P<.05), with no significant effects on blood pressure or glucose at 1 year. Amount of weight loss was associated with self-reported dietary adherence level (r=0.60; P<.001) but not with diet type (r=0.07; P= .40). For each diet, decreasing levels of total/HDL cholesterol, C-reactive protein, and insulin were significantly associated with weight loss (mean r=0.36, 0.37, and 0.39, respectively) with no significant difference between diets (P= .48, P= .57, P= .31, respectively). Conclusions: Each popular diet modestly reduced body weight and several cardiac risk factors at 1 year. Overall dietary adherence rates were low, although increased adherence was associated with greater weight loss and cardiac risk factor reductions for each diet group.