Impact of intermittent fasting on the lipid profile: Assessment associated with diet and weight loss

Abstract

Intermittent fasting, whose proposed benefits include the improvement of lipid profile and the body weight loss, has gained considerable scientific and popular repercussion. This review aimed to consolidate studies that analyzed the lipid profile in humans before and after intermittent fasting period through a detailed review; and to propose the physiological mechanism, considering the diet and the body weight loss. Normocaloric and hypocaloric intermittent fasting may be a dietary method to aid in the improvement of the lipid profile in healthy, obese and dyslipidemic men and women by reducing total cholesterol, LDL, triglycerides and increasing HDL levels. However, the majority of studies that analyze the intermittent fasting impacts on the lipid profile and body weight loss are observational based on Ramadan fasting, which lacks large sample and detailed information about diet. Randomized clinical trials with a larger sample size are needed to evaluate the IF effects mainly in patients with dyslipidemia.

Full text

Review
Impact of intermittent fasting on the lipid profile: Assessment
associated with diet and weight loss
Heitor O. Santos
a
,
*
, Rodrigo C.O. Macedo
b
a
School of Medicine, Federal University of Uberlandia (UFU), Uberlandia, Minas Gerais, Brazil
b
University of Santa Cruz do Sul (UNISC), Santa Cruz do Sul, Brazil
article info
Article history:
Received 6 January 2018
Accepted 8 January 2018
Keywords:
Fasting
Lipids
Clinical analysis
Diet
abstract
Intermittent fasting, whose proposed benefits include the improvement of lipid profile and the body
weight loss, has gained considerable scientific and popular repercussion. This review aimed to consol-
idate studies that analyzed the lipid profile in humans before and after intermittent fasting period
through a detailed review; and to propose the physiological mechanism, considering the diet and the
body weight loss. Normocaloric and hypocaloric intermittent fasting may be a dietary method to aid in
the improvement of the lipid profile in healthy, obese and dyslipidemic men and women by reducing
total cholesterol, LDL, triglycerides and increasing HDL levels. However, the majority of studies that
analyze the intermittent fasting impacts on the lipid profile and body weight loss are observational based
on Ramadan fasting, which lacks large sample and detailed information about diet. Randomized clinical
trials with a larger sample size are needed to evaluate the IF effects mainly in patients with dyslipidemia.
©2018 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights
reserved.
1. Introduction
Human fasting is considered as food abstinence and even bev-
erages between 4 h to three weeks [1,2]. Practical application of
human fasting encompasses the pre-analytical phase of several
laboratory testing, preoperative and postoperative which the dis-
continue intake is necessary, as gastrointestinal trauma [2e6].
Intermittent fasting (IF) is a restricted feeding period originates
in religious and spiritual traditions [7]. The most studied type of IF
occurs in the holy month of Ramadan, which is a period that mil-
lions of Muslims abstain from caloric and water intake from sunrise
to sunset. On average, the Ramadan day is divided in 12 h of fasting
and 12 h of non-fasting [7]. Other types of IF are also studied, such
as alternate day fasting ee.g., 1 day or more a week fasting eand IF
with a longer fasting period during the day, for example, 16 h of
fasting for 8 h of non-fasting [1]. These types of IF do not require
restriction of water intake because they have no connection with
religion [8e10].
IF has gained considerable scientific and popular repercussion,
being introduced as a feeding method under certain conditions in
the clinical practice. Studies that elaborate pathways created on the
basis of the animal experiments may lead to overestimation of IF
regarding biochemical markers, such as the traditional lipid
profile eincluding high-density lipoprotein (HDL), low-density li-
poprotein (LDL), total cholesterol and triglycerides [11,12].
IF can be considered an energy deficit protocol that leads to lipid
profile improve by energy deficit and/or body weight reduction
[13]. Hence, the caloric intake and weight loss evaluations are
important to investigate the biological effects of IF on lipid profile.
This review aimed to consolidate studies that analyzed the effects
of IF on lipid profile in humans, emphasizing the physiological
mechanisms.
2. Methods
A detailed literature research in English was carried with a view
to identify relevant studies and to describe and consolidate obser-
vational and intervention data that provided parameters of the
lipid profile through humans, such as HDL, VLDL, LDL, total
cholesterol and triglycerides. In parallel, body weight and dietary
information were also considered as data.
In order to improve the evidences regarding biological support,
studies that used more detailed markers than the traditional lipid
profile were also explored, thus suggesting physiological mecha-
nisms to clarify the improvement of the lipid profile through IF. For
this purpose, using the Pubmed, Cochrane and Web of Science
databases, the following keywords were used: “Intermittent fast-
ing”,“Ramadan”,“Alternate day fasting”,“lipid profile”and
*Correspondingauthor. Av.Par
a, nº1720Bloco 2U Campus, Umuarama, 38400-902,
Uberlandia, MG, Brazil.
E-mail address: heitoroliveirasantos@gmail.com (H.O. Santos).
Contents lists available at ScienceDirect
Clinical Nutrition ESPEN
journal homepage: http://www.clinicalnutritionespen.com
https://doi.org/10.1016/j.clnesp.2018.01.002
2405-4577/©2018 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Clinical Nutrition ESPEN 24 (2018) 14e21

“intermittent fasting and human metabolic health”. The search for
the data involved studies published until October 2, 2017.
3. To what extent can intermittent fasting affect the lipid
profile in humans?
Intermittent fasting (IF) is a restricted feeding period emerged
from religious and spiritual traditions [7]. The most studied type of
IF occurs in the holy month of Ramadan. In the meantime, millions
of Muslims cease foods and beverages consumption from sunrise to
sunset. Overall, Ramadan day consist in 12 h fasting and 12 h
feeding [7].
Besides Ramadan, other types of IF are also studied. Alternate
day fasting is a broad term so have several definitions. One day or
two intervals days a week fasting are most extended examples
[1,14,15]. The presence of caloric intake in the fasting day is
controversial. Some studies consider high calorie restriction as a
fasting day, for example, 25% ingestion of total caloric expenditure
in one day, and caloric overcompensation intake on another day e
i.e. non-fasting day [8,10]. An interest daily type of IF is 16 h fasting
for 8 h feeding [1], however, there can be daily types with more
fasting duration, as 16e20 h fasting for 4e8 h feeding. These types
of IF do not require restriction of water intake because they have no
connection with religion [8e10].
Weight loss methods are important for lipid profile improve-
ment. There is an important link between obesity and dyslipidemia
over pro-inflammatory gradient from adipose tissue. The patho-
physiology of the typical dyslipidemia observed in obesity is
multifactorial, in which overconsumption of calories is crucial [13].
Low-calorie diets can enhance the lipid profile [16]; likewise, IF can
leads to lipid profile improve by energy deficit and/or body weight
reduction [13].
Lipid profile improvement through IF can occur with or without
changes in weight loss (Table 1). Observational studies based on
Ramadan are the majority, undoubtedly exhibiting many limita-
tions, such as the lack of food recall from calories to macronutrients
(Table 1).
Comparing the pre and post IF period, HDL levels can increase
between 1 and 14 mg/dL, LDL levels decrease between 1 and 47 mg/
dL, total cholesterol levels decrease between 5 and 88 mg/dL and
triglycerides levels decrease between 3 and 64 mg/dL (Table 1).
Although observational studies are the majority of IF research,
there are randomized clinical trials showing enhanced lipid profile
association with weight loss by virtue of IF program [8,10]. Klempel
et al. tested two types of alternate day fasting: 1) High-fat, Low-
Carb diet; 2) Low-fat, High-Carb diet. They showed decreased
cholesterol, LDL triglycerides and cholesterol, levels and body
weight in both groups [8]. Recent study by Trepanowski et al. also
tested High-fat, Low-Carb diet and Low-fat, High-Carb diet over
alternate day fasting with greater follow-up, corresponding to six
months. In contrast to Klempel et al., authors found just improves
in HDL levels, while did not decrease LDL, triglycerides and
cholesterol levels [10]. Moro et al. found lipid profile improvement
in healthy resistance-trained males during two months of normo-
caloric IF. There was increased HDL and decreased LDL levels in the
IF group, whereas normal diet group did not change [9].
4. Proposed mechanisms
The increase of tumor necrosis factor alpha (TNF-
a
) and several
proinflammatory cytokines are associated with worsening of the
lipid profile [17]. In the study by Unalacaket al. interleukin (IL)-2 and
IL-8 and TNF-
a
levels were decreased after the period of Ramadan in
eutrophic and obese, however, IL-1 and IL-6 levels weren't
decreased. Although there was a decrease in the serum triglycerides
of both groups, the other markers of lipid profile did not change,
therefore, beinginaccurate to affirm that the decrease of TNF-
a
levels
by IF is impacts the improve of the lipid profile [18]. It is known that
the antioxidant system is substantial in the lipid profile, thus
modulating the lipoproteins [19e21]. However, glutathione, gluta-
thione peroxidaseand catalase analyzed in the red blood cells did not
improve after Ramadan, according to a study by Ibrahim et al. [22]
IF may increase hepatic production of apolipoprotein A (apo A)
and apolipoprotein B (apo B) [23,24]. By means of the apo A pro-
duction, the serum HDL increases, since apo A is a precursor of HDL.
The increase of the PPAR
a
expression is also responsible for the
increase in the serum HDL. Through reducing apo B production the
serum levels of VLDL, LDL and small and dense LDL (sdLDL) are
decreased [25,26] (Fig. 1). In 1993, Maislos et al. analyzed the apo A
ea percussive molecule of HDL, which increased after Ramadan
and could be one of the mechanisms that supports the increase of
HDL by IF [27]. Five years later, Maislos et al. analyzed the lipo-
protein (a) ea harmful lipoprotein to the organism [28], which in
turn did not change after Ramadan fasting [29]. In this way, Ham-
mouda et al. also did not find alteration of lipoprotein (a) after
Ramadan; in addition, they also did not find alterations of the
C-reactive protein [24]. Adlouni et al. and Hammouda et al. found
an increase of the Apo AI and a decrease of the apo B after Ramadan,
reflecting the HDL increase and LDL reduction [23,24]. Akanji et al.
also found an increase of the apo AI after Ramadan, however, it
wasn't observed neither increase in HDL nor decrease in apo B in
patients with dyslipidemia [30].
Klempel et al. measured LDL subtypes. At the end of two months
of alternate day fasting, the diameter of the LDL subtypes increased,
whereas there was decrease of the serum levels of sdLDL [8], which
is beneficial in the cardiovascular scope, because the lower the LDL,
the more susceptible to arterial penetration [21,31].
All things considered, the mechanisms that justify the
improvement of the lipid profile through IF are not surprising.
Probably the mechanism of IF for the improvement of lipoproteins,
cholesterol and serum triglycerides are similar to the classics that
occur through fat mass loss (Figs. 1 and 2). Above all, dietary quality
should be considered. The type of normocaloric or hypocaloric IF
improves lipoproteins by greater efficacy of fatty acid oxidation and
modulation of apolipoproteins [8,23,24]. In the liver, the oxidation
of fatty acids is increased through higher expression of peroxisome
proliferator-activated receptor alpha (PPAR
a
) and peroxisome
proliferator-activated receptor-gamma coactivator 1-alpha (PGC-
1
a
) in the fasting state [26]. Through increase of fatty acid oxidation
in the liver, the accumulation of triglycerides in the hepatocytes
decreases, thus decreasing the production of very low density li-
poprotein (VLDL). By means of decreasing the VLDL production
thus reducing levels of VLDL and TG in the bloodstream, Since apo B
composes VLDL, serum apo B levels are also reduced [13,32].
Through reducing these factors that involve VLDL, consequently the
LDL and sdLDL are also reduced. In parallel, serum apo B levels are
also reduced, for apo B is part of LDL as well as sdLDL and VLDL [21]
(Fig. 1).
IF may also decrease the expression of cholesteryl ester transfer
protein (CETP) when associated with fat mass loss [33]. The CETP is
a protein responsible for transferring cholesterol esters from HDL to
VLDL, being responsible for lowering HDL levels and increasing
VLDL levels. Therefore, the decrease in CETP through fasting can be
another fact that can increase HDL [34,35] (Fig. 1).
Inherent in the improvement of serum cholesterol, the probable
mechanism of fasting and cholesterol reduction occurs by means of
enzymatic action. Fasting decreases the expression of sterol regu-
latory element-binding protein 2 (SREPB-2) [36], diminishing the
action of several enzymes responsible for cholesterol synthesis
[37,38] (Fig. 2).
H.O. Santos, R.C.O. Macedo / Clinical Nutrition ESPEN 24 (2018) 14e21 15

Table 1
Impact on lipid profile and body weight in comparison to pre and post intermittent fasting.
Study Participants (n) Duration
(month)
Type of
intermittent fasting
Diet composition
(CHO:FAT:PROT)
Outcomes Type of study
Adlouni et al., 1997 [39] 32 health men 1 12 h fasting/12 h
feeding
52:33:15 HDL: [14% (5 mg/dL) Observational
LDL: Y12% (14 mg/dL)
TC: Y25% (38 mg/dL)
TG: Y30% (27 mg/dL)
BW: Y2.4% (1.7 kg)
Afrasiabi et al., 2003 [40] 22 men 1 12 h fasting/12 h
feeding. Low fat
and hypocaloric
diet
62:24:14 HDL: [12% (5 mg/dL) Non-randomized
controlled trialLD: 4
TC: 4
TG: Y13% (34 mg/dL)
BW: Y1.6% (1.4 kg)
Afrasiabi et al., 2003 [40] 16 men 1 12 h fasting/12 h
feeding. Without
any special diet
interference
61:26:13 HDL: 4Non-randomized
controlled trialLDL: 4
TC: 4
TG: Y27% (64 mg/dL)
BW: 4
Aksungar et al., 2005 [55] 12 health men 1 12 h fasting/12 h
feeding
zHDL: [14% (7 mg/dL) Observational
LDL: 4
TC: 4
TG: 4
BW: 4
Aksungar et al., 2005 [55] 12 health women 1 12 h fasting/12 h
feeding
zHDL: [16% (9 mg/dL) Observational
LDL: 4
TC 4
TG: 4
BW: 4
Akanji et al., 2000 [30] 31 dyslipidemic women 1 12 h fasting/12 h
feeding
zHDL: 4Observational
LDL: 4
TC: 4
TG: 4
BW: 4
Akanji et al., 2000 [30] 33 dyslipidemic men 1 12 h fasting/12 h
feeding
zHDL: 4Observational
LDL: 4
TC: 4
TG: 4
BW: 4
Akaberi et al., 2014 [56] 43 (22 men and 21 women) 1 12 h fasting/12 h
feeding
zHDL: [27% (9 mg/dL) Observational
LDL: 4
TC: 4
TG: 4
Ara et al., 2016 [41] 61 health men 1 12 h fasting/12 h
feeding
zLDL: Y7% (7 mg/dL) Observational
TC: Y5% (8 mg/dL)
BW: Y4.1% (2.5 kg)
Bilto, 1998 [57] 43 (34 men and 9 women)
health
1 12 h fasting/12 h
feeding
zHDL: Y18% (9 mg/dL) Observational
LDL: Y16% (19 mg/dL)
TC: Y14% (27 mg/dL)
TG: 4
BW: 4
Fakhrzadeh et al., 2003 [58] 41 health women 1 12 h fasting/12 h
feeding
zHDL: [29% (14 mg/dL) Observational
LDL: Y37% (47 mg/dL)
TC: Y29% (59 mg/dL)
TG: Y19% (25 mg/dL)
BW: 4
Fakhrzadeh et al., 2003 [58] 50 health men 1 12 h fasting/12 h
feeding
zHDL: [23% (9 mg/dL) Observational
LDL: Y36% (43 mg/dL)
TC: Y24% (43 mg/dL)
TG: Y37% (44 mg/dL)
BW: 4
Gur et al., 2015 [59] 78 health pregnant 1 12 h fasting/12 h
feeding
57:25:18 HDL: [9% (6 mg/dL) Observational
LDL: 4
TC: 4
TG: 4
BW: 4
Hammouda et al., 2013 [24] 15 athletes men 1 12 h fasting/12 h
feeding
55:32:13 HDL: [3% (1 mg/dL) Observational
LDL: Y2% (1 mg/dL)
TC: 4
TG: Y3% (3 mg/dL)
BW: Y4% (2.4 kg)
Attarzadeh Hosseini and Hejazi,
2013 [60]
13 physically active health men 1 12 h fasting/12 h
feeding
zHDL: [5% (2 mg/dL) Observational
LDL: Y4% (4 mg/dL)
TC: Y3% (5 mg/dL)
TG: 4
H.O. Santos, R.C.O. Macedo / Clinical Nutrition ESPEN 24 (2018) 14e2116

Table 1 (continued )
Study Participants (n) Duration
(month)
Type of
intermittent fasting
Diet composition
(CHO:FAT:PROT)
Outcomes Type of study
Attarzadeh Hosseini and Hejazi,
2013 [60]
13 sedentary men 1 12 h fasting/12 h
feeding
zHDL: [3% (1 mg/dL) Observational
LDL: Y9% (11 mg/dL)
TC: Y5% (10 mg/dL)
TG: 4
Ibrahim et al., 2008 [22] 14 (9 men and 4 women) health 1 12 h fasting/12 h
feeding
56:30:14 TC: 4Observational
TG: Y11% (13 mg/dL)
BW: 4
Kassab et al., 2003 [46] 6 eutrophic women 1 12 h fasting/12 h
feeding
zTC: 4Observational
TG: 4
BW: 4
Kassab et al., 2003 [46] 18 obese women 1 12 h fasting/12 h
feeding
zTC: 4Observational
TG: 4
BW: 4
Klempel et al., 2013 [8] 17 obese women 2 Alternate days of
high fat
intermittent fasting
40:45:15 HDL: 4Randomized
clinical trialLDL: 4
TC: Y13% (26 mg/dL)
TG: Y15% (15 mg/dL)
BW: Y5% (4.3 kg)
Klempel et al., 2013 [8] 18 obese women 2 Alternate days of
low fat intermittent
fasting
60:25:15 HDL: 4Randomized
clinical trialLDL: Y25% (28 mg/dL)
TC: Y16% (31 mg/dL)
TG: Y14% (14 mg/dL)
BW: Y4% (3.7 kg)
Maislos et al., 1993 [27] 24 (16 men and 8 women)
health
1 12 h fasting/12 h
feeding
zHDL: [32 (9 mg/dL) Observational
LDL: 4
TC: 4
TG: 4
BW: 4
Maislos et al., 1998 [29] 22 (14 men and 8 women)
health
1 12 h fasting/12 h
feeding
65:14:21 HDL: [26% (9 mg/dL) Observational
LDL: 4
TC: 4
TG: 4
BW: 4
Mirzaei et al., 2012 [42] 14 athletes men 1 12 h fasting/12 h
feeding
zHDL: [4% (2 mg/dL) Observational
LDL: Y20% (20 mg/dL)
TC: Y9% (15 mg/dL)
TG: 4
BW: Y2% (1.65 kg)
Moro et al., 2016 [9] 17 resistance-trained men 2 16 h fasting/8 h
feeding
51:25:24 HDL:
c
7% (4 mg/dL) Randomized
clinical trialLDL: 4
TC: 4
TG: Y7% (8 mg/dL)
BW: 4
Nematy et al., 2012 [61] 82 (34 men and 44 women)
metabolic syndrome
1 12 h fasting/12 h
feeding
52:34:14 HDL: [12% (5 mg/dL) Observational
LDL: Y12% (13 mg/dL)
TC: Y5% (9 mg/dL)
TG: Y19% (42 mg/dL)
BW: 4
Ramadan et al., 1999 [62] 7 health men 1 12 h fasting/12 h
feeding
zTC: 4Observational
TG: 4
BW: 4
Ramadan et al., 1999 [62] 6 physically active health men 1 12 h fasting/12 h
feeding
zTC: 4Observational
TG: 4
BW: 4
Sadiya et al., 2011 [43] 19 (14 women and 5 men)
metabolic syndrome
1 12 h fasting/12 h
feeding
45:42:13 HDL: 4Observational
LDL: 4
TC: 4
TG: 4
BW: Y2% (1.8 kg)
Salehi and Neghab, 2007 [44] 28 overweight men 1 12 h fasting/12 h
feeding
70:16:14 TC: Y38% (88 mg/dL) Observational
TG: 4
BW: Y6% (5.1 kg)
Temizhan et al., 2000 [63] 25 health men 1 12 h fasting/12 h
feeding
zHDL: 4Observational
LDL: 4
TC: Y8% (15 mg/dL)
TG: 4
Temizhan et al., 2000 [63] 27 health women 1 12 h fasting/12 h
feeding
zHDL: 4Observational
LDL: Y12% (15 mg/dL)
TC: Y10% (20 mg/dL)
TG: Y28% (26 mg/dL)
Trepanowski et al., 2017 [10] 25
y
obese 6 Alternate days
fasting
55:30:15 HDL: 11% (6 mg/dL) Randomized
clinical trialLDL: 4
TC: 4
TG: 4
BW: Y7% (6.5 kg)
(continued on next page)
H.O. Santos, R.C.O. Macedo / Clinical Nutrition ESPEN 24 (2018) 14e21 17

5. Weight loss analysis
Regarding the dietary intake and weight loss, when comparing
the pre and post IF periods showed in Table 1, eleven studies had a
significant decrease in the body weight, which changed between
1.1 and 6.5 kg [8,10,18,24,39e45]. Interventions resulted in a greater
decrease of body weight, as the Klempel et al. and Trepanowski
et al. studies, both occurring during 2 and 6 months, respectively
[8,10].
Within the groups that analyzed the changes of the fat mass
after the IF (Table 2), six of them showed statistical significance in
the decrease when compared to the baseline [8e10,42,46]. Two
Table 1 (continued )
Study Participants (n) Duration
(month)
Type of
intermittent fasting
Diet composition
(CHO:FAT:PROT)
Outcomes Type of study
Unalacak et al., 2011 [18] 10 obese men 1 12 h fasting/12 h
feeding
zHDL: 4Observational
LDL: 4
TC: 4
TG: Y15% (22 mg/dL)
BW: Y3% (2.9 kg)
Unalacak et al., 2011 [18] 10 eutrophics men 1 12 h fasting/12 h
feeding
zHDL: 4Observational
LDL: 4
TC: 4
TG: 4
BW: 4
Ziaee et al., 2006 [45] 41 health men 1 12 h fasting/12 h
feeding
zHDL: Y11% (4 mg/dL) Observational
LDL: 4
TC: 4
TG: 4
BW: Y2% (1.2 kg)
Ziaee et al., 2006 [45] 39 health women 1 12 h fasting/12 h
feeding
zHDL: 4Observational
LDL: 4
TC: 4
TG: 4
BW: Y2% (1.1 kg)
BW, body weight; CHO, carbohydrates; HDL, high density lipoprotein; LDL, low density lipoprotein; PROT, protein; TC, Total cholesterol; TG, triglycerides; y, gender not
specified after final sample; z, not analyzed data by the study; [, statistical significance of increased levels; Y, statistical significance of decreased levels; 4, not statistical
significance.
Fig. 1. Proposed mechanisms for the increase of HDL and decrease of the lipoproteins directly related to LDL through intermittent fasting. Lipid profile improvement over inter-
mittent fasting is caused by molecules modulation in the liver. Nuclear expression of PPAR
a
and PGC-1
a
primarily occurs, which leads to increased fatty acid oxidation and apoA
production, whereas apoB decreases. Boosted fatty acid oxidation leads to the decreased hepatic triglycerides, hence decreasing VLDL production and serum levels of VLDL, LDL and
sdLDL. Increased HDL levels are due to raised apoA production. As a result of decreased VLDL, LDL and sdLDL levels, there is loss of transported cholesterol and triglycerides within
them, which reflects in reduction of serum cholesterol and triglycerides through intermittent fasting. ApoA, apolipoprotein A; apoB, apolipoprotein B; CE, cholesteryl ester; CETP,
cholesteryl ester transfer protein; HDL, high density lipoprotein; LDL, low density lipoprotein; PGC-1
a
, Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha;
PPAR
a
, Peroxisome proliferator-activated receptor alpha; TG, triglycerides; VLDL, very low density lipoprotein. Dotted express transport and metabolic actions; solid arrows indicate
changes in the lipoprotein levels.
H.O. Santos, R.C.O. Macedo / Clinical Nutrition ESPEN 24 (2018) 14e2118

studies that showed a decrease in the fat mass after Ramadan found
a reduction of 1 kg and 3.6 kg [42,46], whereas the largest decrease
of fat mass was evidenced in the group of the Klempel et al. [8].
6. Cardiovascular outcome
Analysis of cardiovascular disease outcomes is paramount for a
better assessment of the lipid profile through IF. To this end, from a
total 448 patients in a study that evaluated the cardiovascular risk
potential, 122 patients periodically practiced religious fasting, and
there was a 54% reduction in the risk of coronary artery disease in
subjects who followed the periodic fasting, a value obtained after
multivariate adjustment for age, sex, body mass index, dyslipide-
mia, diabetes, smoking, and family history [47].
On the other hand, in a recent cross-sectional study with a large
sample (n ¼4052), the non-breakfast individuals had a higher risk
of atherosclerosis compared to those who ingested high-calorie for
breakfast (>20% of daily calorie intake). However, non-breakfast
patients, when compared to the high caloric intake group of
this meal, exhibited unfavorable parameters, such as: higher per-
centage of central obesity, body weight, body mass index, waist
circumference, dyslipidemia and glycemia; they were older, with a
higher percentage of women and smokers; ingested more daily
calories, animal protein, total fat, cholesterol, processed foods and
alcoholic beverage; and, they ate less dietary fiber, vegetables and
whole grains [48]. In the sight of this, it is hasty to say that food
deprivation at breakfast leads to cardiovascular events.
7. Clinical practice: strong points and limitations
Reviews that highlight IF as an effective method for lipid profile
control have not made explicit the value of lipid profile markers and
dietary data [7,49]. To avoid incomprehension and improve the
interpretation of this review: we standardized all units of the lipid
profile in mg/dL through classical equations [50], analyzed the loss
of body weight and feeding before and soon after the IF period;
since it is a consensus that weight loss, calorie deficit and dietary
quality interfere in the variation of the lipid profile [17,51,52].
Fig. 2. Proposed mechanisms for the decrease of the cho lesterol through intermittent fasting. Adapted from Shibata et al. [37]. SREPB-2, Sterol regulatory element-binding protein 2.
Table 2
Changes of body weight and body fat pre and post intermittent fasting.
Study Participants (n) Duration
(month)
Body fat pre
and post
intermittent
fasting (kg)
Body fat
change between
pre and
post intermittent
fasting
Used method for
analyzing body fat
Trepanowski et al., 2017 [10] 25yobese 6 38 /33.8* Y4.8 DXA
Moro et al., 2016 [9] 17 resistance-trained men 2 10.9 /9.3* Y1.62 DXA
Klempel et al., 2013 [8] 17 obese women 2 44.4 /39.0* Y5.4 DXA
Klempel et al., 2013 [8] 18 obese women 2 44.7 /39.5* Y4.2 DXA
Kassab et al., 2003 [46] 6 eutrophic women 1 34.9 /31.3* Y3.6 Bioelectrical impedance
Kassab et al., 2003 [46] 18 obese women 1 17.7 /17.5 Y0.2 Bioelectrical impedance
Ibrahim et al., 2008 [22] 14 (9 men e 4 women) health 1 21.7 /22.1 [0.4 Bioelectrical impedance
Mirzaei et al., 2012 [42] 14 athletes men 1 10.3 /9.3* Y1.0 Bioelectrical impedance
Sadiya et al., 2011 [43] 19 (14 women e 5 men)
metabolic syndrome
1 50.0 /49.5 Y0.5 Bioelectrical impedance
Hammouda et al., 2013 [24] 15 athletes men 1 10.8 /10.1 Y0.7 Bioelectrical impedance
*, statistical significance considered for p <0.05 before and after intermittent fasting as used in the original study; y, gender not specified after final sample; DXA, Dual-energy
X-ray absorptiometry; [, increased levels; Y, decreased levels.
H.O. Santos, R.C.O. Macedo / Clinical Nutrition ESPEN 24 (2018) 14e21 19

Furthermore, it is a consensus that women exhibit a more favorable
profile than men emainly the HDL e[53,54], and this review
provide the assessment of the lipid profile of both genders through
Table 1.
IF can improve the lipid profile in humans but is necessary to
consider the duration, gender and weight loss. Taken together, this
review included these considerations (Tables 1 and 2) in order to
provide better consciousness of physiological variations.
Importantly, one fact to be considered is the use of medicines,
especially lipid-lowering drugs. The majority of studies selected in
this review did not use drugs and most subjects were healthy. Only
the study by Akanji et al. analyzed IF in patients who were using the
lipid-lowering drug, such as statins and fibrates, since the patients
were dyslipidemic [30]. Akanji et al. did not find improvement in
the lipid profile in both men and women [30] (Table 1), therefore it
is hasty to consider IF as the main method for the dyslipidemia
control ethis should not be considered a treatment to substitute
the use of lipid-lowering drugs.
Analyzing the lipid profile after IF follow-up is essential to un-
derstand the repercussion of this dietary method in the lipid pro-
file. Of the few studies that verified the lipid profile after 1 month of
the IF period (Table 1), increased HDL levels remained the same
after 1 month of the Ramadan fasting by Aksungar et al. and
Adlouni et al. studies [39,55].
A limitation of this review is not to have amplified a specific
systematization for the inclusion of scientific articles.
8. Conclusion
IF may be a dietary method to aid in the improvement of the
lipid profile in healthy, obese and dyslipidemic men and women,
reducing total cholesterol, LDL, triglycerides and increasing HDL
levels. However, the majority of studies that analyze the IF impacts
on the lipid profile and body weight loss are observational and lack
detailed information about diet. Randomized clinical trials with a
larger sample size are needed to evaluate the IF effects mainly in
patients with dyslipidemia.
Statement of authorship
HOS wrote the manuscript and carried out the conception and
design of the study. RCOM participated in the interpretation of the
data, wrote, and contributed to the revision of the manuscript.
Conflict of interest
None.
Statement and funding sources
None.
Acknowledgements
None.
References
[1] Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applica-
tions. Cell Metabol 2014 Feb 4;19(2):181e92.
[2] Lima-Oliveira G, Volanski W, Lippi G, Picheth G, Guidi GC. Pre-analytical phase
management: a review of the procedures from patient preparation to labo-
ratory analysis. Scand J Clin Lab Investig 2017 May;77(3):153e63.
[3] Kackov S, Simundic A-M, Gatti-Drnic A. Are patients well informed about the
fasting requirements for laboratory blood testing? Biochem Med 2013 Oct
15;23(3):326e31.
[4] Stanga Z, Brunner A, Leuenberger M, Grimble RF, Shenkin A, Allison SP, et al.
Nutrition in clinical practice-the refeeding syndrome: illustrative cases and
guidelines for prevention and treatment. Eur J Clin Nutr 2008 Jun;62(6):
687e94.
[5] Ellis LM, Copeland EM, Souba WW. Perioperative nutritional support. Surg
Clin North Am 1991 Jun;71(3):493e507.
[6] Braga M, Ljungqvist O, Soeters P, Fearon K, Weimann A, Bozzetti F, et al. ESPEN
guidelines on parenteral nutrition: surgery. Clin Nutr Edinb Scotl 2009
Aug;28(4):378e86.
[7] Trepanowski JF, Bloomer RJ. The impact of religious fasting on human health.
Nutr J 2010 Nov 22;9:57.
[8] Klempel MC, Kroeger CM, Varady KA. Alternate day fasting increases LDL
particle size independently of dietary fat content in obese humans. Eur J Clin
Nutr 2013 Jul;67(7):783e5.
[9] Moro T, Tinsley G, Bianco A, Marcolin G, Pacelli QF, Battaglia G, et al. Effects of
eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal
strength, body composition, inflammation, and cardiovascular risk factors in
resistance-trained males. J Transl Med 2016 Oct 13;14:290.
[10] Trepanowski JF, Kroeger CM, Barnosky A, Klempel MC, Bhutani S, Hoddy KK,
et al. Effect of alternate-day fasting on weight loss, weight maintenance, and
cardioprotection among metabolically healthy obese adults: a randomized
clinical trial. JAMA Intern Med 2017 Jul 1;177(7):930e8.
[11] Martin B, Mattson MP, Maudsley S. Caloric restriction and intermittent fast-
ing: two potential diets for successful brain aging. Ageing Res Rev 2006
Aug;5(3):332e53.
[12] Patterson RE, Laughlin GA, LaCroix AZ, Hartman SJ, Natarajan L, Senger CM,
et al. Intermittent fasting and human metabolic health. J Acad Nutr Diet 2015
Aug;115(8):1203e12.
[13] Klop B, Elte JWF, Castro Cabezas M. Dyslipidemia in obesity: mechanisms and
potential targets. Nutrients 2013 Apr 12;5(4):1218e40.
[14] Longo VD, Panda S. Fasting, circadian rhythms, and time-restricted feeding in
healthy lifespan. Cell Metabol 2016 Jun 14;23(6):1048e59.
[15] Mattson MP. Challenging oneself intermittently to improve health. Dose
Response 2014 Oct 20;12(4):600e18.
[16] Fothergill E, Guo J, Howard L, Kerns JC, Knuth ND, Brychta R, et al. Persistent
metabolic adaptation 6 years after “The Biggest Loser”competition. Obesity
2016 Aug 1;24(8):1612e9.
[17] Alexander RW. President's address: common mechanisms of multiple dis-
eases: why vegetables and exercise are good for you. Trans Am Clin Climatol
Assoc 2010;121:1e20.
[18] Unalacak M, Kara IH, Baltaci D, Erdem O, Bucaktepe PGE. Effects of Ramadan
fasting on biochemical and hematological parameters and cytokines in
healthy and obese individuals. Metab Syndrome Relat Disord 2011 Apr;9(2):
157e61.
[19] Rosenson RS, Brewer HB, Ansell BJ, Barter P, Chapman MJ, Heinecke JW, et al.
Dysfunctional HDL and atherosclerotic cardiovascular disease. Nat Rev Cardiol
2016 Jan;13(1):48e60.
[20] Lüscher TF, Landmesser U, von Eckardstein A, Fogelman AM. High-density
lipoprotein: vascular protective effects, dysfunction, and potential as thera-
peutic target. Circ Res 2014 Jan 3;114(1):171e82.
[21] Krauss RM. Dietary and genetic probes of atherogenic dyslipidemia. Arte-
rioscler Thromb Vasc Biol 2005 Nov 1;25(11):2265e72.
[22] Ibrahim WH, Habib HM, Jarrar AH, Al Baz SA. Effect of Ramadan fasting on
markers of oxidative stress and serum biochemical markers of cellular dam-
age in healthy subjects. Ann Nutr Metab 2008;53(3e4):175e81.
[23] Adlouni A, Ghalim N, Saïle R, Hda N, Parra HJ, Benslimane A. Beneficial effect
on serum apo AI, apo B and Lp AI levels of Ramadan fasting. Clin Chim Acta Int
J Clin Chem 1998 Mar 23;271(2):179e89.
[24] Hammouda O, Chtourou H, Aloui A, Chahed H, Kallel C, Miled A, et al.
Concomitant effects of Ramadan fasting and time-of-day on apolipoprotein AI,
B, Lp-a and homocysteine responses during aerobic exercise in tunisian soccer
players. PLoS One 2013 Nov 11;8(11) [Internet]. Available from: https://www.
ncbi.nlm.nih.gov/pmc/articles/PMC3823586/.
[25] Kingwell BA, Chapman MJ. Future of high-density lipoprotein infusion ther-
apies: potential for clinical management of vascular disease. Circulation 2013
Sep 3;128(10):1112e21.
[26] Wang Y-X. PPARs: diverse regulators in energy metabolism and metabolic
diseases. Cell Res 2010 Feb;20(2):124e37.
[27] Maislos M, Khamaysi N, Assali A, Abou-Rabiah Y, Zvili I, Shany S. Marked
increase in plasma high-density-lipoprotein cholesterol after prolonged fast-
ing during Ramadan. Am J Clin Nutr 1993 May;57(5):640e2.
[28] Jacobson TA. Lipoprotein(a), cardiovascular disease, and contemporary man-
agement. Mayo Clin Proc 2013 Nov;88(11):1294e311.
[29] Maislos M, Abou-Rabiah Y, Zuili I, Iordash S, Shany S. Gorging and plasma HDL-
cholesterolethe Ramadan model. Eur J Clin Nutr 1998 Feb;52(2):127e30.
[30] Akanji AO, Mojiminiyi OA, Abdella N. Beneficial changes in serum apo A-1 and
its ratio to apo B and HDL in stable hyperlipidaemic subjects after Ramadan
fasting in Kuwait. Eur J Clin Nutr 2000 Jun;54(6):508e13.
[31] Siri-Tarino PW, Chiu S, Bergeron N, Krauss RM. Saturated fats versus poly-
unsaturated fats versus carbohydrates for cardiovascular disease prevention
and treatment. Annu Rev Nutr 2015;35:517e43.
[32] Jiang ZG, Robson SC, Yao Z. Lipoprotein metabolism in nonalcoholic fatty liver
disease. J Biomed Res 2013 Jan;27(1):1e13.
[33] Ebenbichler CF, Laimer M, Kaser S, Ritsch A, Sandhofer A, Weiss H, et al.
Relationship between cholesteryl ester transfer protein and atherogenic
H.O. Santos, R.C.O. Macedo / Clinical Nutrition ESPEN 24 (2018) 14e2120

lipoprotein profile in morbidly obese women. Arterioscler Thromb Vasc Biol
2002 Sep 1;22(9):1465e9.
[34] Shinkai H. Cholesteryl ester transfer-protein modulator and inhibitors and
their potential for the treatment of cardiovascular diseases. Vasc Health Risk
Manag 2012;8:323e31.
[35] Haas JT, Staels B. Cholesteryl-ester transfer protein (CETP): a Kupffer cell
marker linking hepatic inflammation with atherogenic dyslipidemia? Hep-
atology 2015 Dec 1;62(6):1659e61.
[36] Horton JD, Bashmakov Y, Shimomura I, Shimano H. Regulation of sterol reg-
ulatory element binding proteins in livers of fasted and refed mice. Proc Natl
Acad Sci U S A 1998 May 26;95(11):5987e92.
[37] Shibata N, Jishage K, Arita M, Watanabe M, Kawase Y, Nishikawa K, et al.
Regulation of hepatic cholesterol synthesis by a novel protein (SPF) that ac-
celerates cholesterol biosynthesis. FASEB J Off Publ Fed Am Soc Exp Biol 2006
Dec;20(14):2642e4.
[38] Tao R, Xiong X, DePinho RA, Deng C-X, Dong XC. Hepatic SREBP-2 and
cholesterol biosynthesis are regulated by FoxO3 and Sirt6. J Lipid Res 2013
Oct;54(10):2745e53.
[39] Adlouni A, Ghalim N, Benslimane A, Lecerf JM, Saïle R. Fasting during
Ramadan induces a marked increase in high-density lipoprotein cholesterol
and decrease in low-density lipoprotein cholesterol. Ann Nutr Metab
1997;41(4):242e9.
[40] Afrasiabi A, Hassanzadeh S, Sattarivand R, Mahboob S. Effects of Ramadan
fasting on serum lipid profiles on 2 hyperlipidemic groups with or without
diet pattern. Saudi Med J 2003 Jan;24(1):23e6.
[41] Ara T, Jahan N, Sultana N, Choudhury R, Yeasmin T. Effect of Ramadan fasting
on total cholesterol (TC) low density lipoprotein cholesterol (LDL-C) and high
density lipoprotein cholesterol (HDL-C) in healthy adult male. J Bangladesh
Soc Physiol 2016 Mar 31;10(2):46e50.
[42] Mirzaei B, Rahmani-Nia F, Moghadam MG, Ziyaolhagh SJ, Rezaei A. The effect
of Ramadan fasting on biochemical and performance parameters in collegiate
wrestlers. Iran J Basic Med Sci 2012 Nov;15(6):1215e20.
[43] Sadiya A, Ahmed S, Siddieg HH, Babas IJ, Carlsson M. Effect of Ramadan fasting
on metabolic markers, body composition, and dietary intake in Emiratis of
Ajman (UAE) with metabolic syndrome. Diabetes Metab Syndrome Obes
Targets Ther 2011 Dec 15;4:409e16.
[44] Salehi M, Neghab M. Effects of fasting and a medium calorie balanced diet
during the holy month Ramadan on weight, BMI and some blood parameters
of overweight males. Pak J Biol Sci PJBS 2007 Mar 15;10(6):968e71.
[45] Ziaee V, Razaei M, Ahmadinejad Z, Shaikh H, YousefiR, Yarmohammadi L,
et al. The changes of metabolic profile and weight during Ramadan fasting.
Singap Med J 2006 May;47(5):409e14.
[46] Kassab SE, Abdul-Ghaffar T, Nagalla DS, Sachdeva U, Nayar U. Serum leptin
and insulin levels during chronic diurnal fasting. Asia Pac J Clin Nutr
2003;12(4):483e7.
[47] Horne BD, Muhlestein JB, Anderson JL. Health effects of intermittent fasting:
hormesis or harm? A systematic review. Am J Clin Nutr 2015 Aug;102(2):
464e70.
[48] Uzhova I, Fuster V, Fern
andez-Ortiz A, Ordov
as JM, Sanz J, Fern
andez-Friera L,
et al. The importance of breakfast in atherosclerosis disease: insights from the
PESA study. J Am Coll Cardiol 2017 Oct 2;70(15):1833e42.
[49] Mazidi M, Rezaie P, Chaudhri O, Karimi E, Nematy M. The effect of Ramadan
fasting on cardiometabolic risk factors and anthropometrics parameters: a
systematic review. Pak J Med Sci 2015;31(5):1250e5.
[50] Rugge B, Balshem H, Sehgal R, Relevo R, Gorman P, Helfand M. Lipid con-
version factors [Internet]. US: Agency for Healthcare Research and Quality;
2011 [cited 2017 Oct 10]. Available from: https://www.ncbi.nlm.nih.gov/
books/NBK83505/.
[51] Medina-Rem
on A, Casas R, Tressserra-Rimbau A, Ros E, Martínez-
Gonz
alez MA, Fit
o M, et al. Polyphenol intake from a Mediterranean diet
decreases inflammatory biomarkers related to atherosclerosis: a substudy of
the PREDIMED trial. Br J Clin Pharmacol 2017 Jan;83(1):114e28.
[52] Ros E, Hu FB. Consumption of plant seeds and cardiovascular health: epide-
miological and clinical trial evidence. Circulation 2013 Jul 30;128(5):553e65.
[53] Kolovou GD, Anagnostopoulou KK, Damaskos DS, Bilianou HI, Mihas C,
Milionis HJ, et al. Gender differences in the lipid profile of dyslipidemic sub-
jects. Eur J Intern Med 2009 Mar;20(2):145e51.
[54] Wang X, Magkos F, Mittendorfer B. Sex differences in lipid and lipoprotein
metabolism: it's not just about sex hormones. J Clin Endocrinol Metab 2011
Apr;96(4):885e93.
[55] Aksungar FB, Eren A, Ure S, Teskin O, Ates G. Effects of intermittent fasting on
serum lipid levels, coagulation status and plasma homocysteine levels. Ann
Nutr Metab 2005 Apr;49(2):77e82.
[56] Akaberi A, Golshan A, Moojdekanloo M, Hashemian M. Does fasting in
Ramadan ameliorate lipid profile? A prospective observational study. Pak J
Med Sci 2014;30(4):708e11.
[57] Bilto YY. Effects of Ramadan fastingonbodyweightandthebiochemical
and haematological parameters of the blood. Arab Gulf J Sci Res 1998;16(1):
1e14.
[58] Fakhrzadeh H, Larijani B, Sanjari M, Baradar-Jalili R, Amini MR. Effect of
Ramadan fasting on clinical and biochemical parameters in healthy adults.
Ann Saudi Med 2003 Jul;23(3e4):223e6.
[59] Gur E, Turan G, Ince O, Karadeniz M, Tatar S, Kasap E, et al. Effect of Ramadan
fasting on metabolic markers, dietary intake and abdominal fat distribution in
pregnancy. Hippokratia 2015;19(4):298e303.
[60] Attarzadeh Hosseini SR, Hejazi K. The effects of Ramadan fasting and physical
activity on blood hematological-biochemical parameters. Iran J Basic Med Sci
2013 Jul;16(7):845e9.
[61] Nematy M, Alinezhad-Namaghi M, Rashed MM, Mozhdehifard M, Sajjadi SS,
Akhlaghi S, et al. Effects of Ramadan fasting on cardiovascular risk factors: a
prospective observational study. Nutr J 2012 Sep 10;11:69.
[62] Ramadan J, Telahoun G, Al-Zaid NS, Barac-Nieto M. Responses to exercise,
fluid, and energy balances during Ramadan in sedentary and active males.
Nutrition 1999 Oct 1;15(10):735e9.
[63] Temizhan A, Tandogan I, D€
onderici
€
O, Demirbas B. The effects of Ramadan
fasting on blood lipid levels. Am J Med 2000 Sep 1;109(4):341.
H.O. Santos, R.C.O. Macedo / Clinical Nutrition ESPEN 24 (2018) 14e21 21