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Critical Reviews in Food Science and Nutrition
ISSN: 1040-8398 (Print) 1549-7852 (Online) Journal homepage: https://www.tandfonline.com/loi/bfsn20
The effects of quercetin supplementation on
lipid profiles and inflammatory markers among
patients with metabolic syndrome and related
disorders: A systematic review and meta-analysis
of randomized controlled trials
Reza Tabrizi, Omid Reza Tamtaji, Naghmeh Mirhosseini, Kamran B.
Lankarani, Maryam Akbari, Seyed Taghi Heydari, Ehsan Dadgostar &
Zatollah Asemi
To cite this article: Reza Tabrizi, Omid Reza Tamtaji, Naghmeh Mirhosseini, Kamran B.
Lankarani, Maryam Akbari, Seyed Taghi Heydari, Ehsan Dadgostar & Zatollah Asemi (2019):
The effects of quercetin supplementation on lipid profiles and inflammatory markers among
patients with metabolic syndrome and related disorders: A systematic review and meta-
analysis of randomized controlled trials, Critical Reviews in Food Science and Nutrition, DOI:
10.1080/10408398.2019.1604491
To link to this article: https://doi.org/10.1080/10408398.2019.1604491
Published online: 24 Apr 2019.
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REVIEW
The effects of quercetin supplementation on lipid profiles and inflammatory
markers among patients with metabolic syndrome and related disorders:
A systematic review and meta-analysis of randomized controlled trials
Reza Tabrizi
a
, Omid Reza Tamtaji
b
, Naghmeh Mirhosseini
c
, Kamran B. Lankarani
d
, Maryam Akbari
a
,
Seyed Taghi Heydari
d
, Ehsan Dadgostar
e
, and Zatollah Asemi
b
a
Health Policy Research Center, Institute of Health, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran;
b
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran;
c
School of
Public Health, University of Saskatchewan, Saskatoon, SK, Canada;
d
Health Policy Research Center, Shiraz University of Medical Sciences,
Shiraz, Iran;
e
Halal Research Center of IRI, FDA, Tehran, Iran
ABSTRACT
Aims: This systematic review and meta-analysis of randomized controlled trials (RCTs) was per-
formed to determine the effect of quercetin administration on lipid profiles and inflammatory
markers among patients with metabolic syndrome (MetS) and related disorders.
Methods: We searched systematically online databases including Cochrane Library, EMBASE,
MEDLINE, and Web of Science to identify the relevant RCTs until November 2018. Q-test and I
2
statistics were applied to assess heterogeneity among included studies. Data were combined using
fixed- or random-effects model and presented as standardized mean difference (SMD) with 95%
confidence interval (CI).
Results: Out of 591 citations, 16 RCTs were included in the meta-analysis. The pooled findings
showed that quercetin consumption significantly decreased total-cholesterol (SMD ¼0.98; 95%
CI, 1.48, 0.49; p<0.001; I
2
: 94.0), LDL-cholesterol (SMD ¼0.88; 95% CI, 1.35, 0.41;
p<0.001; I
2
: 92.7) and C-reactive protein (CRP) levels (0.64; 95% CI, 1.03, 0.25; p¼0.001; I
2
:
90.2). While, quercetin supplementation did not significantly affect triglycerides (TG) (SMD ¼0.32;
95% CI, 0.68, 0.04; p¼0.08; I
2
: 84.8), HDL-cholesterol (SMD ¼0.20; 95% CI, 0.20, 0.24; p¼0.84;
I
2
: 70.6), interleukin 6 (IL-6) (SMD ¼0.69; 95% CI, 1.69, 0.31; p¼0.17; I
2
: 94.5) and tumor necrosis
factor-alpha (TNF-a) levels (SMD ¼0.06; 95% CI, 0.25, 0.14; p¼0.58; I
2
: 35.6)
Conclusions: In summary, the current meta-analysis demonstrated that quercetin supplementation
significantly reduced total-cholesterol, LDL-cholesterol, and CRP levels, yet did not affect triglycer-
ides, HDL-cholesterol, IL-6 and TNF-aamong patients with MetS and related disorders.
KEYWORDS
Quercetin; metabolic
syndrome; lipid profiles;
inflammatory markers;
meta-analysis
Introduction
Dyslipidemia, defined as elevated levels of triglycerides and
cholesterol (particularly LDL-cholesterol), and reduced levels
of HDL-cholesterol, has been introduced as a strong risk
factor for the commencement and progression of athero-
sclerosis, which in turn results in cardiovascular disease
(CVD) (Stokes et al. 2002; Stapleton et al. 2010). In add-
ition, hypercholesterolemia is correlated with overproduction
of free radicals, reactive oxygen species (ROS) and inflam-
matory markers which subsequently leads to increased oxi-
dative damage (Yildirim, Senchenkova, and Granger 2016;
Mollazadeh et al. 2018). On the other hand, increased circu-
lating markers of inflammation, including C-reactive protein
(CRP), interleukin-6 (IL-6) and tumor necrosis factor alpha
(TNF-a) are consistently linked to the risk of hypertension,
type 2 diabetes mellitus (T2DM), metabolic syndrome
(MetS) and CVD (Shai et al. 2005; Ridker 2009).
Among bioflavonoids, quercetin is known to have the
highest antioxidative properties (Morel et al. 1993).
Quercetin belongs to flavonols that exists amply in apples,
berries, onions, red wine, cabbage and nuts (Naderi et al.
2003). An extensive variety of quercetin activities has been
claimed, including anti-inflammatory, antioxidative, antia-
therosclerotic and anticarcinogenic effects (Lotito and Frei
2006; Mamani-Matsuda et al. 2006). In a study conducted
by Lu et al. (2015), consumption of quercetin-enriched
onion juice for 8 weeks significantly attenuated total-, LDL-
and HDL-cholesterol levels in healthy individuals with mild
hypercholesterolemia. Furthermore, consuming quercetin-
rich foods in obese post-menopausal women upregulated
LDL receptor expression and decreased the levels of LDL-
cholesterol (Arai et al. 2000). The results of a meta-analysis
consisting of seven randomized controlled trials (RCTs)
indicated a significant reduction of circulating CRP concen-
trations in both healthy and ill individuals following
CONTACT Zatollah Asemi asemi_r@yahoo.com Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical
Sciences, Kashan, Iran; Seyed Taghi Heydari heidaryt@sums.ac.ir Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/bfsn.
ß2019 Taylor & Francis Group, LLC
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
https://doi.org/10.1080/10408398.2019.1604491
quercetin supplementation (Mohammadi-Sartang et al.
2017). While, quercetin administration at a dosage of
250 mg/day for 8 weeks did not influence glycemic control
and lipid profiles among patients with T2DM (Mazloom
et al. 2014). In another study, 500 mg/day quercetin supple-
mentation for 10 weeks significantly reduced systolic blood
pressure, but had no impact on other cardiovascular risk
factors and inflammatory cytokines in diabetic patients
(Zahedi et al. 2013). The differences in study design, popula-
tion characteristics, the dosage of quercetin utilized, and the
duration of intervention might explain the discrepancies
among the results of published trials.
To our best knowledge, there is no published systematic
review or meta-analysis assessing the effect of quercetin
administration on lipid profiles and inflammatory markers
in human. Thus, the current meta-analysis was carried out
to summarize the present evidence of RCTs regarding the
effects of quercetin administration on lipid profiles and
inflammatory markers among patients with meta-
bolic disorders.
Materials and methods
Search strategy and study selection
We searched systematically online databases including
Cochrane Library, EMBASE, MEDLINE, and Web of
Science until November 2018 to identify the relevant RCTs
investigating the effects of quercetin supplementation on
lipid profiles and inflammatory markers. Literature reviews
were conducted using the following MeSH and text words:
patients [“metabolic disease”OR “Mets”OR “diabetes”OR
“T2DM”OR “overweight”OR “obese”OR “polycystic ovary
syndrome (PCOS)”OR “hypertension”OR “blood pressure
(BP)”OR “coronary heart disease (CHD)”OR “chronic kid-
ney disease (CKD)”OR “non-alcoholic fatty liver disease
(NAFLD)”OR “hypercholesterolemia”], intervention
[“quercetin”AND “intake”OR “supplementation”], and out-
comes [“triglycerides (TG)”OR “total cholesterol”OR
“LDL-cholesterol”OR “HDL-cholesterol”OR “CRP”OR
“IL-6”OR “TNF-a”]. To reduce the chance of missing any
relevant study, we searched manually the reference lists of
included articles. Also we searched for the findings of
ongoing RCTs in the following databases: International
Standard Randomized Controlled Trial Number Register
and Meta-register for RCTs. There were no limitations for
the date and the language of the publications when searches
were conducted. The search and selection of RCTs were per-
formed by two independent reviewers (R.T. and E.D.). Any
disagreements resolved through the discussion with a third
reviewer (Z.A.).
Inclusion criteria
Clinical trials that met the following inclusion criteria were
included in the meta-analysis: original human studies with a
RCT design (either parallel or cross-over), treatment and
control groups were administered quercetin supplement and
placebo, respectively, and clinical trial reported means, SDs,
standard error of the mean (SEMs), or related 95% confi-
dence intervals (CIs) for intervention and placebo groups at
baseline and end of the intervention for triglycerides, total-,
LDL-, HDL-cholesterol, CRP, TNF-a, and IL-6 levels among
patients with MetS and related disorders. Animal experi-
ments, in vitro studies, case reports, case series, observa-
tional studies, trial protocols or abstracts without findings,
and clinical trials did not have a control group were
excluded from the meta-analysis.
Data extraction and quality assessment
The authors used the Cochrane Collaboration risk of bias
tool to evaluate the quality of the included RCTs, using the
following risk of bias items: ‘randomization generation, allo-
cation concealment, blinding of participants and outcome
assessors, incomplete outcome data, and selective outcome
reporting, and the other sources of bias’. Data were
extracted, using a standard excel form, included: first
author’s name, publication year, location of the study, age,
study design, number of subjects (in both intervention and
placebo groups), type of intervention, dosage and duration
of the supplementation, type of disease, the mean (SD)
changes of lipid profiles and inflammatory markers between
intervention and control groups. If studies outcomes were
reported by various strata of variables such as dose, type,
and duration of intervention, each strata was considered as
a separate trial in the current meta-analysis.
Data synthesis and statistical analysis
All statistical analyses were performed using STATA version
12.0 (Stata Corp., College Station, TX) and RevMan V.5.3
software (Cochrane Collaboration, Oxford, UK). Pooled
effect size was defined as the standardized mean difference
(SMD) with 95% CI calculated using fixed- or random-
effects model. Heterogeneity among included studies was
statistically assessed using Cochran’sQand I
2
tests. The
source of heterogeneity was explored using subgroup analy-
ses according to some of the potential moderator variables
including type of intervention (quercetin enriched onion
juice vs. quercetin plus other nutrients vs. quercetin), dosage
of intervention (<100 mg/day vs. 101–250 mg/day vs.
>250 mg/day), duration of intervention (8 vs. >8 weeks),
type of disease (hypercholesterolemic vs. obese or over-
weight vs. other disease), and type of study (parallel vs.
cross-over design). Sensitivity analyses were used to examine
the influence of each trial on the validity of the pooled
SMDs. Egger’s regression test was applied to identify evi-
dence of possible publication bias among included trials.
pValues less than 0.05 were considered statistically significant.
Results
Out of 591 potential reports, after checking titles and
abstracts and removing duplicates or irrelevant articles, 16
articles (or 24 effect sizes) were eligible to be included in the
2 R. TABRIZI ET AL.
current meta-analysis. The flowchart of step by step process
of RCTs identification and selection is illustrated in
Figure 1.
Sixteen studies were randomized, placebo-controlled trial,
of them eight studies were conducted using parallel design
and other eight cross-over. Considering 24 trials included in
the meta-analysis, the overall number of subjects was 1575,
of which 790 subjects were in intervention group and 785
control group. Eighteen trials determined the effects of quer-
cetin supplementation on triglyceride (Clifton 2004;
Edwards et al. 2007; Egert et al. 2010; Qureshi et al. 2013;
Zahedi et al. 2013; Mazloom et al. 2014; Lu et al. 2015;
Chekalina et al. 2016; Cialdella-Kam et al. 2016; Cicero et al.
2016;Br
€
ull et al. 2017a), twenty-one on total cholesterol
(Clifton 2004; Edwards et al. 2007; Egert et al. 2009; Egert
et al. 2010; Qureshi et al. 2013; Zahedi et al. 2013; Mazloom
et al. 2014;Br
€
ull et al. 2015; Lu et al. 2015; Chekalina et al.
2016; Cialdella-Kam et al. 2016; Cicero et al. 2016;Br
€
ull
et al. 2017a; Nieman et al. 2017), twenty on LDL- and HDL-
cholesterol (Clifton 2004; Edwards et al. 2007; Egert et al.
2009; Egert et al. 2010; Qureshi et al. 2013; Zahedi et al.
2013; Mazloom et al. 2014;Br
€
ull et al. 2015; Lu et al. 2015;
Chekalina et al. 2016; Cialdella-Kam et al. 2016; Cicero et al.
2016;Br
€
ull et al. 2017b), fifteen on CRP (Egert et al. 2009;
Egert et al. 2010; Qureshi et al. 2013; Zahedi et al. 2013;
Br€
ull et al. 2015; Cialdella-Kam et al. 2016;Ciceroetal.
2016;Br
€
ull et al. 2017b; Nedoborenko et al. 2017;Nieman
et al. 2017), five on IL-6 (Zahedi et al. 2013; Cialdella-
Kam et al. 2016; Nedoborenko et al. 2017;Niemanetal.
2017), and seven on TNF-alevels (Egert et al. 2009;Egert
et al. 2010;Zahedietal.2013; Chekalina et al. 2016;
Cialdella-Kam et al. 2016;Br
€
ull et al. 2017b). The dosage
of quercetin varied from 3.12 to 3000 mg/day, and the
duration of intervention with quercetin supplements
ranged from a few hours to 12 weeks. Eight trials were
performed among patients with hypercholesterolemia,
eleven obese or overweight individuals, and six partici-
pants with other diseases. Table 1 shows the characteris-
tics of included RCTs.
Main outcomes
Pooled effects of quercetin on lipid profiles
The forest plots indicating the effect of quercetin supple-
mentation on lipid profiles are illustrated in Figure 2.We
found that quercetin consumption significantly decreased
total (SMD ¼0.98; 95% CI, 1.48, 0.49; p<0.001; I
2
:
94.0) and LDL-cholesterol levels (SMD ¼0.88; 95% CI,
1.35, 0.41; p<0.001; I
2
: 92.7). However, the pooled
Articles screened by title and
abstract (n=119)
Full text articles assessed for
eligibility (n=43)
Studies included in this study
(n=16)
Articles excluded (n=472) due to duplicate
articles, not randomized controlled trials,
review and not human
Excluded non-relevant articles (n=76)
Articles excluded (n=27):
1. Data presentation inappropriate for meta-
analysis (n=5)
2. Not placebo (n=22)
Articles identified through
electronic database search (n=591)
Figure 1. Literature search and review flowchart for selection of studies.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 3
Table 1. Characteristics of included studies.
References
Publication
year
Sample size
(control/
intervention) Country/population
Intervention/
daily dose Duration Presented data
Age (y) (control,
intervention)
Chekalina
et al. (2016)
2016 33/30 Ukraine/CVD Quercetin/3000 mg 8 weeks TG, TC, LDL-C, HDL-
C, TNF-a
Aged (48–72)
Cialdella-Kam
et al. (2016)
2016 24/24 USA/obese Quercetin plus
other
nutrients/
1000 mg
10 weeks TG, TC, LDL-C, HDL-
C, CRP, TNF-a,
and IL-6
55.3 ± 7.3, 56.9 ± 9.3
Cicero et al. (2016) 2016 13/12 Italy/HCH Quercetin plus
other
nutrients/50 mg
4 weeks TG, TC, LDL-C, HDL-
C, and CRP
53.65 ± 8.67,
52.78 ± 8.33
Lu et al. (2015) (a) 2015 12/12 China/HCH Quercetin rich
onion
juice/3.12 mg
2 weeks TG, TC, LDL-C,
HDL-C
Aged (35–55)
Lu et al. (2015) (b) 2015 12/12 China/HCH Quercetin rich
onion
juice/3.12 mg
6 weeks TG, TC, LDL-C,
HDL-C
Aged (35–55)
Lu et al. (2015) (c) 2015 12/12 China/HCH Quercetin rich
onion
juice/3.12 mg
8 weeks TG, TC, LDL-C,
HDL-C
Aged (35–55)
Lu et al. (2015) (d) 2015 12/12 China/HCH Quercetin rich
onion
juice/3.12 mg
10 weeks TG, TC, LDL-C,
HDL-C
Aged (35–55)
Mazloom
et al. (2014)
2014 21/26 Iran/T2DM Quercetin/250 mg 8 weeks TG, TC, LDL-C,
HDL-C
51.5 ± 8.6, 52.9 ± 7.0
Nedoborenko
et al. (2017)
2017 15/15 Ukraine/obese Quercetin plus
other
nutrients/4 mg
3 days ± 60th CRP and IL-6 40.3 ± 7.59
Nieman et al.
(2017) (a)
2017 52/51 USA/obese Quercetin plus
other
nutrients/104 mg
12 weeks TC, CRP, and IL-6 50.3 ± 1.6, 50.3 ± 2.0
Nieman et al.
(2017) (b)
2017 52/51 USA/obese Quercetin plus
other
nutrients/104 mg
4 weeks CRP and IL-6 50.3 ± 1.6, 50.3 ± 2.0
Zahedi et al. (2013) 2013 28/34 Iran/T2DM Quercetin/500 mg 10 weeks TG, TC, LDL-C, HDL-
C, CRP, TNF-a,
and IL-6
46.4 ± 4.5
Br€
ull et al. (2015) 2015 68/68 Germany/obese and
(pre-HTN)
Quercetin/162 mg 6 weeks TC, LDL-C, HDL-C,
and CRP
474±105
Br€
ull et al.
(2017a) (b)
2017 68/68 Germany/obese and
(pre-HTN)
Quercetin/162 mg 6 weeks CRP and TNF-a, 47.4 ± 10.5
Br€
ull et al.
(2017b) (a)
2017 22/22 Germany/obese
and (HTN)
Quercetin/54 mg 2 h postprandial TG, TC, LDL-C, HDL-
C, and CRP
48.1 ± 10.9
Br€
ull et al.
(2017b) (b)
2017 22/22 Germany/obese
and (HTN)
Quercetin/54 mg 4 h postprandial TG, TC, LDL-C, HDL-
C, and CRP
48.1 ± 10.9
Clifton (2004) 2004 35/35 Australia/HCH
or HTN
Quercetin plus
other
nutrients/
1000 mg
12 weeks TG, TC, LDL-C, and
HDL-C
58
Edwards et al.
(2007) (a)
2007 22/22 USA/HTN Quercetin/730 mg 12 weeks TG, TC, LDL, and
HDL-C
49.2 ± 2.9
Edwards et al.
(2007) (b)
2007 19/19 USA/pre-HTN Quercetin/730 mg 12 weeks TG, TC, LDL, and
HDL-C
47.8 ± 3.5
Egert et al.
(2009) (b)
2009 93/93 Germany/
overweight
Quercetin/150 mg 6 weeks TC, LDL-C, HDL-C,
CRP, and TNF-a
451±1053
Egert et al.
(2010) (a)
2010 60/60 Germany/over-
weight with
apoE3
phenotypes
Quercetin/150 mg 6 weeks TG, TC, LDL-C, HDL-
C, CRP, and
TNF-a
45 ± 10.5
Egert et al.
(2010) (b)
2010 26/26 Germany/over-
weight with
apoE4
phenotypes
Quercetin/150 mg 6 weeks TG, TC, LDL-C, HDL-
C, CRP, and
TNF-a
45 ± 10.5
Qureshi et al.
2013) (a)
2013 32/32 Pakistan/(sub-
group c)
Quercetin plus
other
nutrients/50 mg
6 weeks TG, TC, LDL-C, HDL-
C, and CRP
58.15 ± 0.77
Qureshi et al.
(2013) (b)
2013 32/32 Pakistan/HCH (sub-
group D)
Quercetin plus
other
nutrients/50 mg
6 weeks TG, TC, LDL-C, HDL-
C, and CRP
57.14 ± 1.33
CAD, coronary artery disease; HCH, hypercholesterolemic; T2DM, type 2 diabetes mellitus; pre-HTN, pre-hypertension; TG, triglycerides; TC, total cholesterol;
HDL-C, high density lipoprotein-cholesterol; LDL-C, low density lipoprotein-cholesterol; CRP, C-reactive protein; IL-6, interlokin-6; TNF-a, tumor necrosis fac-
tor alpha.
4 R. TABRIZI ET AL.
Figure 2. Meta-analysis lipid profiles and inflammatory markers standardized mean differences estimates for (A) triglycerides, (B) total-, (C) LDL-, (D) HDL-choles-
terol, (E) CRP, (F) IL-6, and (G) TNF-alevels in quercetin and control groups (CI ¼95%).
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 5
findings showed no significant effect of quercetin supple-
mentation on triglycerides (SMD ¼0.32; 95% CI, 0.68,
0.04; p¼0.08; I
2
: 84.8) and HDL-cholesterol levels (SMD ¼
0.20; 95% CI, 0.20, 0.24; p¼0.84; I
2
: 70.6). Because of the
evidence of significant heterogeneity across included trials
for lipid profiles, random-effects model was used to pool
data. Estimation of the influences of quercetin consumption
on the studied markers in both intervention and placebo
Figure 2. Continued.
6 R. TABRIZI ET AL.
groups (SMD) at baseline and end of intervention are pre-
sented in Table 2.
For total-, LDL-, and HDL-cholesterol levels, findings
of sensitivity analyses remained consistent after excluding
each trial. For triglyceride, after excluding Edwards
et al.
(a)
study (Edwards et al. 2007) the pooled effect size
significantly changed to SMD ¼0.38; 95% CI,
0.74, 0.02.
Pooled effects of quercetin on inflammatory markers
The pooled effect of quercetin consumption on CRP levels
was estimated using fifteen trials. There was a significant
reduction in CRP levels (SMD ¼0.64; 95% CI, 1.03,
0.25; p¼0.001; I
2
: 90.2) among patients supplemented
with quercetin compared to placebo groups. However, we
found that quercetin supplementation did not statistically
Figure 2. Continued.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 7
affect IL-6 (SMD ¼0.69; 95% CI, 1.69, 0.31; p¼0.17;
I
2
:94.5)andTNF-alevels (SMD ¼0.06; 95% CI, 0.25,
0.14; p¼0.58; I
2
:35.6)(Figure 2).Duetotheheterogeneity
existing across included trials, random-effects model was
used to pool the data showing the effect of quercetin sup-
plementation on inflammatory markers. Sensitivity analyses
indicated no change in the pooled effect of inflammatory
markers, expect for IL-6, which changed significantly after
excluding Nieman et al.
(b)
study (Nieman et al. 2017)
(SMD ¼1.06; 95% CI, 1.82, 0.29). The lower and
higher pooled SMD for lipid profiles and inflammatory
markers in post-sensitivity analysis are summarized in
Table 3.
Subgroup analyses for lipid profiles and
inflammatory markers
Subgroup analyses for lipid profiles and inflammatory
markers were done based on potential moderator variables
including type of intervention, dosage and duration of sup-
plementation, type of disease, and type of study design.
The findings of subgroup analyses did not indicate any
statistically significant subgroup-effect interaction for tri-
glycerides, HDL-cholesterol, and TNF-a. However, type
and dosage of intervention for total-, LDL-cholesterol, and
CRP, duration of intervention for total-, LDL-cholesterol,
and IL-6, also type of disease for total- and LDL-
Figure 2. Continued.
Table 2. Estimation of the effects of quercetin supplementation on lipid profiles and inflammatory markers with confidence interval 95% between the inter-
vention and control groups.
Parameter
Number of
study
Standardized
mean difference 95% CI
Heterogeneity
I
2
(%) Qp-value
Triglyceride Intervention group (after vs. before) 17 0.30 0.71, 0.71 88.4 137.75 <0.001
Placebo group (after vs. before) 17 0.06 0.23, 0.35 76.2 67.25 <0.001
Intervention vs. placebo group 18 0.32 0.68, 0.04 84.8 111.90 <0.001
Total cholesterol Intervention group (after vs. before) 20 1.00 1.50, 0.51 93.7 303.22 <0.001
Placebo group (after vs. before) 20 0.31 0.69, 0.07 90.2 193.60 <0.001
Intervention vs. placebo group 21 0.98 1.48, 0.49 94.0 331.05 <0.001
LDL-cholesterol Intervention group (after vs. before) 19 0.83 1.31 , 0.36 92.8 248.75 <0.001
Placebo group (after vs. before) 19 0.24 0.58, 0.09 86.8 136.07 <0.001
Intervention vs. placebo group 20 0.88 1.35, 0.41 92.7 261.72 <0.001
HDL-cholesterol Intervention group (after vs. before) 19 0.19 0.19, 0.58 89.7 175.28 <0.001
Placebo group (after vs. before) 19 0.12 0.13, 0.36 76.1 75.46 <0.001
Intervention vs. placebo group 20 0.20 0.20, 0.24 70.6 64.67 <0.001
CRP Intervention group (after vs. before) 14 0.45 0.91, 0.01 92.8 180.13 <0.001
Placebo group (after vs. before) 14 0.11 0.05, 0.27 47.2 24.60 0.02
Intervention vs. placebo group 15 0.64 1.03, 0.25 90.2 142.68 <0.001
IL-6 Intervention group (after vs. before) 5 0.67 2.06 , 0.73 96.9 130.23 <0.001
Placebo group (after vs. before) 5 0.28 1.57, 1.01 0.00 112.99 <0.001
Intervention vs. placebo group 5 0.69 1.69, 0.31 94.5 72.72 <0.001
TNF-aIntervention group (after vs. before) 7 0.61 1.21, 0.01 92.5 79.91 <0.001
Placebo group (after vs. before) 7 0.39 0.90, 0.11 89.5 57.25 <0.001
Intervention vs. placebo group 7 0.06 0.25, 0.14 35.6 9.32 0.01
8 R. TABRIZI ET AL.
cholesterol was significantly affected by subgroup-effect
interactions (Table 4).
Publication bias and risk of bias assessment
There was no evidence of publication bias for assessing the
effects of quercetin consumption on triglycerides (B¼
2.99, p¼0.27), HDL-cholesterol (B¼1.44, p¼0.30), IL-6
(B¼7.95, p¼0.40), TNF-alevels (B¼0.70, p¼2.02)
using Egger’s regression test in current meta-analyses.
However, the existence of publication biases was deter-
mined using Egger’s linear regression for total-cholesterol
(B¼6.93, p¼0.001), LDL-cholesterol (B¼7.07,
p<0.001), and CRP levels (B¼5.79, p¼0.01). The
authors used non parametric method (Duval and Tweedie)
to estimate the results of censored trials for parameters
with publication bias. Findings showed that the overall
pooled SMDs for theses parameters did not significantly
change between pre- and post-included censored trials.
Details of the methodological quality assessment of all
included trials based on authors’judgments are presented
in Figure 3.
Discussion
To our best knowledge, this is the first meta-analysis of
RCTs assessing the effect of quercetin supplementation on
lipid profiles and inflammatory markers in patients with
MetS and related disorders. The current meta-analysis dem-
onstrated that quercetin supplementation significantly
reduced total-, LDL-cholesterol, and CRP levels, yet did not
affect other lipid profiles and inflammatory markers in
these patients.
Effects on lipid profiles
Existing evidence are promising regarding the effect of
quercetin on total- and LDL-cholesterol levels, yet triglycer-
ides and HDL-cholesterol levels might not be influenced by
quercetin among patients with MetS and related disorders.
Hypolipidemic effects of quercetin intake in human clinical
studies have been controversial. Supplements with quer-
cetin-rich onion powder in hyperlipidemic patients (Lee
et al. 2008), grape juice in both hemodialysis patients and
healthy subjects (Castilla et al. 2006), and grape powder in
pre- and postmenopausal women (Zern et al. 2005) have
demonstrated beneficial effects on lipid profiles in human
studies. Besides current evidence of controlled clinical stud-
ies, epidemiological evidence has indicated that consump-
tion of dietary quercetin is negatively correlated with
circulating levels of LDL-cholesterol (Arai et al. 2000). Lu
et al. (2015) demonstrated that taking quercetin-rich onion
juice for 8 weeks by healthy subjects with mild hypercholes-
terolemia significantly attenuated total-, LDL- and HDL-
cholesterol levels. In addition, consuming quercetin-rich
food in obese post-menopausal women upregulated LDL
receptor expression and decreased LDL-cholesterol levels
(Arai et al. 2000). A 10-week supplementation of 100 mg/
day quercetin in healthy smoker males could significantly
improve the components of lipid profiles, except triglycer-
ides (Lee et al. 2011). However, daily supplementation with
250 mg quercetin for 8 weeks did not influence lipid profiles
among patients with T2DM (Mazloom et al. 2014).
Moreover, Egert et al. (2009) reported that 150 mg/day
quercetin supplementation for 6 weeks resulted in no sig-
nificant alterations in lipid profiles among overweight
healthy subjects with high cardiovascular risk phenotype.
The difference in dosages of quercetin used, the route of
supplementation and the type of quercetin used (only
Table 3. The effects of quercetin supplementation on lipid profiles and inflammatory markers based on sensitivity analysis.
Variables
Pre-sensitivity analysis
Upper and lower of
effect size
Post-sensitivity analysis
No. of
studies included
Pooled SMD
(random effect) 95% CI
Pooled SMD
(random effect) 95% CI Excluded studies
Triglycerides 18 0.32 0.68, 0.04 Upper 0.17 0.46, 0.10 Qureshi et al.
(2013) (b)
Lower 0.38 0.74, 0.02 Edwards et al.
(2007) (a)
Total cholesterol 21 0.98 1.48, 0.49 Upper 0.65 1.07, 0.24 Qureshi et al.
(2013) (a)
Lower 1.07 1.58, 0.55 Zahedi (2013)
LDL-cholesterol 20 0.88 1.35, 0.41 Upper 0.53 0.89, 0.17 Qureshi et al.
(2013) (a)
Lower 0.97 1.47, 0.46 Br€
ull et al. (2015)
HDL-cholesterol 20 0.20 0.20, 0.24 Upper 0.04 0.18, 0.27 Edwards et al.
(2007) (b)
Lower 1.08 0.22, 0.01 Qureshi et al.
(2013) (a)
CRP 15 0.64 1.03, 0.25 Upper 0.33 0.55, 0.11 Qureshi et al.
(2013) (b)
Lower 0.70 1.13, 0.26 Egert et al. (2009)
IL-6 5 0.69 1.69, 0.31 Upper 0.32 1.25, 0.60 Zahedi et al. (2013)
Lower 1.06 1.82, 0.29 Nieman et al.
(2017) (a)
TNF-a70.06 0.25, 0.14 Upper 0.01 0.15, 0.16 Chekalina
et al. (2016)
Lower 0.10 0.27, 0.06 Zahedi et al. (2013)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 9
Table 4. The assess of quercetin supplementation on lipid profiles and inflammatory markers based on subgroup analysis.
Parameter Triglycerides Total-cholesterol LDL-cholesterol HDL-cholesterol CRP IL-6 TNF-a
Type of intervention
Quercetin rich onion juice
K66662——
SMD
(95% CI)
0.13
(0.42, 0.16)
0.32
(0.62, 0.01)
0.33
(0.63, 0.03)
0.00
(0.29, 0.29)
0.04
(0.38, 0.46)
——
p-value 0.379 0.043 0.033 0.993 0.845 ——
I
2
0.0 8.2 4.1 0.0 0.0 ——
Q1.99 5.44 5.21 0.07 0.00 ——
Quercetin plus other nutrients
K5655741
SMD
(95% CI)
0.61
(1.54, 0.33)
3.59
(5.62, 1.56)
4.31
(7.00, 1.62)
0.40
(0.54, 1.35)
1.44
(2.46, 0.42)
0.33
(1.26, 0.61)
0.10
(0.67, 0.46)
p-value 0.203 0.001 0.002 0.405 0.006 0.493 0.722
I
2
92.2 97.9 98.1 92.6 95.3 92.7 —
Q51.52 233.51 210.80 53.92 27.69 41.03 0.00
Quercetin
K7899616
SMD
(95% CI)
0.24
(0.83, 0.36)
0.08
(0.32, 0.15)
0.10
(0.34, 0.14)
0.13
(0.27, 0.02)
0.22
(0.37, 0.07)
2.17
(2.80, 1.54)
0.05
(0.28, 0.17)
p-value 0.435 0.491 0.411 0.081 0.004 <0.001 0.647
I
2
88.4 57.8 59.2 0.0 0.0 —46.1
Q111.90 18.98 19.61 3.96 3.03 72.72 9.28
Dosage of intervention
<100 mg/day
K999961—
SMD
(95% CI)
0.48
(1.06, 0.11)
2.31
(3.74, 0.88)
2.50
(3.95, 1.05)
0.24
(0.35, 0.83)
1.66
(3.11, 0.21)
0.80
(1.54, 0.05)
—
p-value 0.109 0.001 0.001 0.421 0.025 0.036 —
I
2
84.5 96.1 96.2 85.2 95.9 ——
Q51.58 206.71 209.49 54.19 122.35 0.00 —
101–250 mg/day
K3655724
SMD
(95% CI)
0.14
(0.12, 0.41)
0.43
(1.11, 0.25)
0.02
(0.14, 0.19)
0.14
(0.31, 0.03)
0.18
(0.32, 0.05)
0.18
(1.96, 1.61)
0.03
(0.21, 0.14)
p-value 0.286 0.216 0.781 0.097 0.009 0.845 0.723
I
2
0.0 94.1 0.0 0.0 0.0 97.4 0.0
Q0.92 84.34 0.517 0.83 0.49 38.47 0.63
>250 mg/day
K6666223
SMD
(95% CI)
0.34
(1.04, 0.36)
0.17
(0.59, 0.25)
0.22
(0.60, 0.16)
0.07
(0.29, 0.15)
0.41
(0.84, 0.02)
1.18
(3.11, 0.75)
0.10
(0.73, 0.53)
p-value 0.335 0.428 0.263 0.533 0.060 0.231 0.750
I
2
89.2 71.3 65.9 0.0 21.8 95.2 76.6
Q46.28 17.45 14.68 3.27 1.28 20.64 8.53
Duration of intervention
8
K121414141225
SMD
(95% CI)
0.27
(0.69, 0.15)
1.20
(1.83, 0.56)
1.21
(1.86, 0.56)
0.08
(0.23, 0.38)
0.76
(1.24, 0.27)
1.02
(1.38, 0.66)
0.11
(0.31, 0.09)
p-value 0.207 <0.001 <0.001 0.49 0.002 <0.001 0.277
I
2
83.4 94.5 94.7 78.8 92.2 0.0 27.1
Q66.40 237.91 245.05 61.21 140.63 0.45 5.49
>8
K6766332
SMD
(95% CI)
0.42
(1.16, 0.32)
0.62
(1.45, 0.21)
0.33
(0.77, 0.11)
0.06
(0.30, 0.17)
0.30
(0.57, 0.03)
0.53
(2.17, 1.10)
0.18
(0.34, 0.70)
p-value 0.266 0.142 0.141 0.54 0.031 0.524 0.500
I
2
88.7 93.1 69.9 0.0 1.3 96.5 47.6
Q44.40 7 16.68 3.35 2.03 57.86 1.91
Type of disease
Hypercholesterolemic
K77773——
SMD
(95% CI)
0.64
(1.36, 0.09)
3.07
(5.04, 1.11)
3.38
(5.39, 1.36)
0.32
(0.48, 1.12)
3.50
(6.26, 0.74)
——
p-value 0.085 0.002 0.001 0.435 0.013 ——
I
2
85.7 96.5 96.6 88.6 96.4 ——
Q41.95 171.96 174.89 52.60 56.10 ——
Obese or overweight
K58771145
SMD
(95% CI)
0.14
(0.08, 0.37)
0.31
(0.85, 0.23)
0.04
(0.12, 0.19)
0.13
(0.29, 0.02)
0.15
(0.28, 0.03)
0.33
(1.26, 0.61)
0.04
(0.21, 0.13)
p-value 0.210 0.265 0.654 0.091 0.015 0.493 0.657
I
2
0.0 91.9 0.0 0.0 0.0 92.7 0.0
Q0.73 86.11 2.34 0.97 1.87 41.03 0.69
(continued)
10 R. TABRIZI ET AL.
quercetin or combined quercetin with other nutrients),
study design, and characteristics of study populations are
some of the possible reasons explaining discrepant results
regarding the effect of quercetin on lipid profiles among
these studies. Quercetin intake may activate AMP-activated
protein kinase (AMPK) and prevent lipid accumulation in
the liver (Zang et al. 2006). AMPK subsequently inhibits
the activity of Acetyl-CoA carboxylase and carbohydrate
response element-binding protein, and the gene expression
of sterol regulatory element-binding transcription factor 1c
(Browning and Horton 2004). In addition, quercetin intake
may increase the gene expression of peroxisome prolifer-
ator-activated receptor-gamma (PPAR-c) (Beekmann et al.
2015). PPAR-cplays main functions in the metabolism of
lipid and insulin (Beekmann et al. 2015).
Effects on inflammatory markers
The current meta-analysis demonstrated that quercetin sup-
plementation significantly reduced CRP levels, but did not
affect IL-6 and TNF-aamong patients with MetS and
related disorders. Increased circulating inflammatory
markers have been recognized as a strong predictor of car-
diovascular disease (Venugopal, Devaraj, and Jialal 2005)
which plays main functions in atherosclerotic progression
(Pasceri, Willerson, and Yeh 2000). The potential role of
quercetin intake in decreasing inflammation in animal (Das
et al. 2013) and human (Askari et al. 2012) models, reinfor-
ces the hypothesis that quercetin supplementation may
reduce CVD incidence and protect against atherosclerotic
progression by decreasing the CRP levels. In a meta-ana-
lysis conducted by Mohammadi-Sartang et al. (2017), quer-
cetin supplementation resulted in a significant reduction in
the circulating CRP concentrations in both healthy and dis-
eased individuals. The observed beneficial effect of quer-
cetin intake on circulating CRP concentrations in the
current meta-analysis was confirmed by previous
experimental (Bhaskar et al. 2013) and RCTs findings
(Zahedi et al. 2013). However, anti-inflammatory effects of
quercetin intake are different in humans and animals
(Rivera et al. 2008) which may be the result of diverse con-
centrations of inflammatory markers or physiological dis-
similarities between animals and humans. The mechanisms
by which quercetin may reduce CRP levels are not clear.
Several mechanisms were claimed for the anti-inflammatory
and potential CRP-lowering role of quercetin. Inhibiting
nuclear factor-kB (NF-jB) signaling pathways, the reduc-
tion of leukotriene B4 formation in leukocytes (Loke et al.
2008) and suppression of nitric oxide production
(Kumazawa, Kawaguchi, and Takimoto 2006) are some of
the hypotheses that have been tested in experimental stud-
ies and RCTs. Quercetin and its metabolites at physiological
levels can suppress the expression of key molecules
involved in monocyte recruitment such as vascular cell
adhesion molecule 1, intercellular adhesion molecule 1 and
monocyte chemoattractant protein-1 gene expression
(Tribolo et al. 2008; Panicker et al. 2010; Chen et al. 2012).
In addition, antioxidant properties of quercetin could be
responsible for its anti-inflammatory effects. Quercetin was
documented to suppress IjB kinase and C-Jun kinase
which subsequently could result in the suppression of NF-
jB activation (Peet and Li 1999; Yoshizumi et al. 2002).
Quercetin has also significant effect on the attenuation of
inflammatory processes initiated by the oxidized low-dens-
ity lipoprotein and this effect is through regulating the
Toll-like receptors-NF-jB signaling pathway (Bhaskar,
Sudhakaran, and Helen 2016).
This meta-analysis had few limitations. There were few
eligible RCTs and a modest number of participants to be
included in the meta-analysis. Diverse range of doses of
quercetin were administered for intervention in the included
studies. Substantial heterogeneity was seen across studies,
which was expected considering differences in participants’
characteristics (e.g. gender, geographic region, genetic
Table 4. Continued.
Parameter Triglycerides Total-cholesterol LDL-cholesterol HDL-cholesterol CRP IL-6 TNF-a
Other diseases
K6666112
SMD
(95% CI)
0.37
(1.06, 0.32)
0.18
(0.60, 0.24)
0.25
(0.63, 0.14)
0.05
(0.27, 0.17)
0.62
(1.13, 0.10)
2.17
(2.80, 1.54)
0.10
(1.15, 0.96)
p-value 0.294 0.400 0.205 0.661 0.018 <0.001 0.849
I
2
88.9 71.4 66.1 0.0 ——88.3
Q45.07 17.51 14.74 3.26 0.00 0.00 8.53
Type of study
Parallel design
K 9 10 9 9 6 5 3
SMD
(95% CI)
0.26
(0.65, 0.12)
0.67
(1.34, 0.01)
0.47
(0.89, 0.05)
0.02
(0.20, 0.23)
0.34
(0.65, 0.04)
0.69
(1.69, 0.31)
0.10
(0.73, 0.53)
p-value 0.180 0.047 0.027 0.887 0.028 0.174 0.750
I
2
66.2 90.4 70.8 0.0 49.7 94.5 76.6
Q23.64 93.68 27.39 0.89 9.93 72.72 8.53
Cross-over design
K 9 11 11 11 9 —4
SMD
(95% CI)
0.38
(0.98, 0.22)
1.31
(2.05, 0.58)
1.29
(2.04, 0.55)
0.04
(0.32, 0.40)
0.87
(1.48, 0.27)
0.03
(0.21, 0.14)
p-value 0.209 <0.001 0.001 0.823 0.005 —0.723
I
2
90.9 95.6 95.7 84.3 94.0 —0.0
Q88.17 229.50 233.69 63.54 132.71 –0.63
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 11
background, and gene-environment interactions), duration
of study and dosage of quercetin used.
Conclusions
In summary, the current meta-analysis demonstrated that
quercetin supplementation significantly improved lipid pro-
file and inflammatory status by reducing total-, LDL-choles-
terol, and CRP levels. Yet it did not affect other lipid
profiles and inflammatory markers among patients with
MetS and related disorders.
Abbreviations
CAD coronary artery disease
CRP C-reactive protein
HCH hypercholesterolemic
HDL-C high density lipoprotein-cholesterol
IL-6 interlokin-6
LDL-C low density lipoprotein-cholesterol
pre-HTN pre-hypertension
T2DM type 2 diabetes mellitus
TC total cholesterol
TG triglycerides
TNF-atumor necrosis factor alpha
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
Research reported in this publication was supported by Elite
Researcher Grant Committee under award number (977483) from the
National Institutes for Medical Research Development (NIMAD),
Tehran, Iran.
Author contributions
RT, O-RT, NM, K-BL, MA, S-TH, and ED contributed into the con-
ception, design, statistical analysis and drafting of the manuscript. ZA
supervised the study. All authors confirmed the final version
for submission.
ORCID
Kamran B. Lankarani http://orcid.org/0000-0002-7524-9017
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