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Critical Reviews in Food Science and Nutrition
ISSN: 1040-8398 (Print) 1549-7852 (Online) Journal homepage: http://www.tandfonline.com/loi/bfsn20
Effect of resveratrol on blood pressure: A
systematic review and meta-analysis of
randomized, controlled, clinical trials
Federica Fogacci, Giuliano Tocci, Vivianne Presta, Andrea Fratter, Claudio
Borghi & Arrigo F. G. Cicero
To cite this article: Federica Fogacci, Giuliano Tocci, Vivianne Presta, Andrea Fratter, Claudio
Borghi & Arrigo F. G. Cicero (2018): Effect of resveratrol on blood pressure: A systematic review
and meta-analysis of randomized, controlled, clinical trials, Critical Reviews in Food Science and
Nutrition, DOI: 10.1080/10408398.2017.1422480
To link to this article: https://doi.org/10.1080/10408398.2017.1422480
Published online: 23 Jan 2018.
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Effect of resveratrol on blood pressure: A systematic review and meta-analysis
of randomized, controlled, clinical trials
Federica Fogacci
a
, Giuliano Tocci
b
, Vivianne Presta
b
, Andrea Fratter
c
, Claudio Borghi
a
,
*,
and Arrigo F. G. Cicero
a
*
a
Medical and Surgical Sciences Dept., University of Bologna, Italy;
b
Division of Cardiology, Department of Clinical and Molecular Medicine, Faculty
of Medicine and Psychology, University of Rome Sapienza, Sant’Andrea Hospital, Rome, and IRCCS Neuromed, Pozzilli (IS), Italy;
c
Labomar R&D, Istrana,
Italy
ABSTRACT
Introduction: Results of previous clinical trials evaluating the effect of resveratrol supplementation on
blood pressure (BP) are controversial.
Purpose: We aimed to assess the impact of resveratrol on BP through systematic review of literature and
meta-analysis of available randomized, controlled clinical trials (RCTs).
Methods: Literature search included SCOPUS, PubMed-Medline, ISI Web of Science and Google Scholar
databases up to 17th October 2017 to identify RCTs investigating the impact of resveratrol on BP. Two
review authors independently extracted data on study characteristics, methods and outcomes. Overall, the
impact of resveratrol on BP was reported in 17 trials.
Results: Administration of resveratrol did not significantly affect neither systolic BP [weighted mean difference
(WMD): ¡2.5 95% CI:(-5.5, 0.6) mmHg; pD0.116; I
2
D62.1%], nor diastolic BP [WMD: ¡0.5 95% CI:(-2.2, 1.3)
mmHg; pD0.613; I
2
D50.8], nor mean BP [MAP;WMD:¡1.3 95% CI:(-2.8, 0.1) mmHg; pD0.070; I
2
D39.5%] nor
pulse pressure [PP;WMD:¡0.9 95% CI:(-3.1, 1.4) mmHg; pD0.449; I
2
D19.2%]. However, significant WMDs
were detected in subsets of studies categorized according to high resveratrol daily dosage (300 mg/day)
and presence of diabetes. Meta-regression analysis revealed a positive association between systolic BP-
lowering resveratrol activity (slope: 1.99; 95% CI: 0.05, 3.93; two-tailed pD0.04) and Body Mass Index (BMI) at
baseline, while no association was detected neither between baseline BMI and MAP-lowering resveratrol
activity (slope: 1.35; 95% CI: ¡0.22, 2.91; two-tailed pD0.09) nor between baseline BMI and PP-lowering
resveratrol activity (slope: 1.03; 95% CI: ¡1.33, 3.39; two-tailed pD0.39). Resveratrol was fairly well-tolerated
and no serious adverse events occurred among most of the eligible trials.
Conclusion: The favourable effect of resveratrol emerging from the current meta-analysis suggests the
possible use of this nutraceutical as active compound in order to promote cardiovascular health, mostly
when used in high daily dose (300 mg/day) and in diabetic patients.
KEYWORDS
Resveratrol; blood pressure;
meta-analysis;
metaregression; type 2
diabetes
Introduction
During the last decade a growing interested has been observed
as it regards the effect of natural compounds on cardiovascular
health (Sonoswka et al. 2017).
Resveratrol (3,5,40-trihydroxystilbene) belongs to a family
of polyphenolic compounds known as stilbenes, particularly
concentrated in grape and red wine. Many studies have
shown the antihypertensive effects of resveratrol in different
preclinical models of hypertension, through a multitude of
mechanisms mostly including its antioxidant properties, the
stimulation of endothelial nitride oxide production, the
inhibition of vascular inflammation and the prevention of
platelet aggregation (Borghi and Cicero 2017;Ciceroetal.
2017;Lietal.2012). Moreover, resveratrol effects on vascu-
lar health could be increased by its parallel improving
action on plasma lipids (Cicero et al. 2017b), All these
effects may promote blood pressure (BP) reductions and
improve BP control in hypertensive patients in a setting of
clinical practice.
In this regard, several randomized clinical trials (RCTs) have
demonstrated resveratrol produces systolic/diastolic BP reduc-
tions. Even if the results are relatively variable in different trials,
the tolerability and safety profile of resveratrol is very high and
no clinically significant pharmacological interaction of this
nutraceutical with conventional drugs is known (Cicero and
Colletti 2015; Sirtori et al. 2015). Moreover, the low bioavail-
ability of resveratrol could be at least partly improved by the
application of modern pharmaceutical technologies.
Today, available studies are few and explorative and yield
conflicting data. Therefore, we aimed to assess the impact of
resveratrol on BP through a systematic review of literature and
meta-analysis of available randomized clinical trials (RCTs).
CONTACT Arrigo F. G. Cicero, MD, PhD arrigo.cicero@unibo.it Atherosclerosis and Hypertension Research Group, Medical and Surgical Sciences Department,
Sant’Orsola-Malpighi University Hospital, U.O. Medicina Interna Borghi - Via Albertoni, 15, 40138 Bologna-Italy.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/bfsn.
*Claudio Borghi and Arrigo Cicero are co-last authors.
© 2018 Taylor & Francis Group, LLC
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
https://doi.org/10.1080/10408398.2017.1422480
Methods
Search strategy
The study was designed according to guidelines of the 2009
preferred reporting items for systematic reviews and meta-
analysis (PRISMA) statement (Moher et al. 2009). PubMed-
Medline, Researchgate, SCOPUS, Google Scholar and ISI Web
of Science databases were searched using the following search
items in titles and abstracts: (“Resveratrol”OR “Vitis vinifera”)
AND (“Clinical trial”AND “Hemodynamic parameters”OR
“Blood pressure”OR “BP”OR “BP”OR “Systolic blood pres-
sure”OR “SBP”OR “SBP”OR “Diastolic blood pressure”OR
“DBP”OR “DBP”). The wild-card term “
”was used to
increase the sensitivity of the search strategy. The reference lists
of identified papers were checked manually for additional rele-
vant article. No language restriction was used in literature
search. The search was limited to studied in human. The litera-
ture was searched from inception to October 17, 2017.
Study selection
Original studies were included if they met the following
inclusion criteria: (i) being a randomized trial with either
parallel or cross-over design, (ii) investigating the impact of
chronic resveratrol supplementation on systolic BP (SBP)
and diastolic BP (DBP), (iii) providing sufficient informa-
tion on BP at baseline and at the end of follow-up in each
group, (iv) having an appropriate controlled design, e.g., if
resveratrol was administered as an adjunct to another drug/
supplement, the control group had to receive the same
drug/supplement. Exclusion criteria were: (i) lack of a con-
trol group for resveratrol supplementation, (ii) testing acute
effect of resveratrol intake, and (iii) lack of sufficient infor-
mation on baseline or follow-up SBP or DBP, (iv) use of
daily resveratrol doses <50 mg. Two authors independently
reviewed all articles. Then, a third author arbitrated any
discrepancies in including the studies in the meta-analysis.
Data extraction
Data abstracted from the eligible studies were: (i) first author’s
name; (ii) year of publication; (iii) study location; (iv) study
design; (v) inclusion criteria and underlying disease; vi) dose
and duration of resveratrol supplementation; (vii) number of
participants in the active and control group; (viii) age, gender,
body mass index (BMI) and waist circumference (WC) of study
participants; and (ix) baseline SBP and DBP measurements at
rest.
Quality assessment
A systematic assessment of bias in the included study was per-
formed using the Cochrane criteria. (Higgins and Green 2010).
The items applied for each study assessment were the following
ones: adequacy of sequence generation, allocation concealment,
blinding addressing of dropouts (incomplete outcome data),
selective outcome reporting, and other probable sources of bias
(Sahebkar et al. 2017). Based on the recommendations of the
Cochrane Handbook, risk of bias was judged to be high or low.
Labelling an item as “unclear”suggested an unclear or
unknown risk of bias.
Quantitative data synthesis
Mean pulse pressure (PP) was calculated as the difference
between SBP and DBP (PPDSBP - DBP). PP standard devia-
tion (SD) was estimated as follows: SD
PP
Dsquare root (SD
SBP2
CSD
DBP2
). Mean arterial pressure (MAP) was obtained by
adding one-third of PP to DBP (MAPD
1
/
3
PP CDBP). SD
MAP
value resulted from the following formula: SD
MAP
Dsquare root
(
1
/
3
SD
PP2
CSD
DBP2
). If the outcome measures were reported in
mean and variation range or mean and inter-quartile range,
SDs were calculated as described by Hozo et al. (Hozo et al.
2005). Where standard error of the mean (SEM) was only
reported, SD was estimated as follows: SDDSEM 0square
root (n), being nthe subjects’number. (Sahebkar et al. 2016).
Meta-analysis was entirely conducted using Comprehensive
Meta-Analysis (CMA) V3 software (Biostat, NJ) (Borenstein
et al. 2005). Net changes in SBP, DBP, PP and MAP (change
scores) were calculated by subtracting the value at baseline
from that after intervention in the active-treated groups and in
the control ones. SDs of the mean difference were obtained as
follows:
SD Dsquare root [(SD
pre-treatment
)
2
C(SD
post-treatment
)
2
–(2R 0SD
pre-treatment
0SD
post-treatment
)],
assuming a correlation coefficient (R) D0.5 for both pre-test /
post-test (parallel groups) and crossover designed studies (Foll-
mann et al. 1992)
When results were presented in multiple time points, only
data relating to the longest duration of treatment were consid-
ered. Moreover, in order to avoid double-counting problem, in
trials comparing multiple treatment arms versus a single control
group, the number of subjects in the control group was divided
by the number of the treatment arms. Results of the selected
studies were combined using the generic inverse variance method
and a fixed- or random-effects model, depending respectively on
the presence of low-to-moderate (<50%) or high (50%) het-
erogeneity, which was quantitatively assessed using Higgins index
(I
2
). Effect sizes were expressed as weighted mean difference
(WMD) and 95% confidence interval (CI). Finally, sensitivity
analysis was executed in order to evaluate the influence of each
single study on the overall effect size (Table 3). A leave-one-out
method was used (i.e. one study was removed at a time and the
analysis repeated). (Fogacci et al. 2017).
Additional analysis
Subgroups analyses were performed to explore the impact on
resveratrol BP-lowering activity of type 2 diabetes or non-alco-
holic fatty liver disease (NAFLD) (listed among the inclusion
criteria), administered daily dose (>or the median dosage)
and duration of treatment (>or 3 months).
Meta-regression analysis
A weighted fixed-effect meta-regression using unrestricted
maximum likelihood model was performed to assess the
2F. FOGACCI ET AL.
association between the significant estimated effect sizes with
potential moderator variables including resveratrol daily dosage
and BMI at baseline.
Publication bias
Potential publication biases were explored using visual
inspection of Begg’s funnel plot asymmetry, Begg’srank
correlation test and Egger’s weighted regression test. Duval
&Tweedie“trim and fill”method was used to adjust the
analysis for the effects of publication biases (Duval and
Tweedie 2000).
Results
Flow and characteristics of the included study
After database searches according to inclusion and exclusion
criteria, 297 published studies were identified and the abstracts
reviewed. Of these, 93 were non-original article and were
excluded. Then, other 175 studies were eliminated because they
did not meet the inclusion criteria. Thus, 29 full text articles
were careful assessed and reviewed. After assessment, 12 studies
were excluded because: testing different phytochemicals in
combination (nD2), testing acute effect of resveratrol intake
(nD1), and reporting incomplete data (nD9). Finally, 17 studies
were eligible and included in the present systematic review and
meta-analysis. (Kjær et al. 2017; Imamura et al. 2017; Heebøll
et al. 2016; Timmers et al. 2016; Chen et al. 2015; Faghihzadeh
et al. 2015; van der Made et al. 2015; Anton et al. 2014;
Chachay et al. 2014;M
endez-del Villar et al. 2014; Kumar and
Joghee 2013; Tom
e-Carneiro et al. 2013; Movahde et al. 2013;
Wong et al. 2013; Bhatt et al. 2012; Yoshino et al. 2012;
Timmers et al. 2011). The study selection process is shown in
Figure 1.
Data were pooled from 17 RCTs comprising 36 treatment
arms, which included 681 subjects, with 407 in the resveratrol
arm and 375 in the control one (the sum is higher than the total
because patients enrolled in cross-over trials were treated both
with resveratrol and placebo). Included studies were published
between 2011 and 2017, and were conducted in the Nether-
lands (3), Denmark (2), Spain, US of America (2), Mexico, Aus-
tralia (2), India (2), Iran (2), China (1) and Japan (1).
Intervention periods ranged between 30 days and 6 months
and several dosage resveratrol forms were tested. Selected trials
were designed cross-over, (Timmers et al. 2016; van der Made
et al. 2015; Wong et al. 2013; Timmers et al. 2011). or per paral-
lel groups. (Kjær et al. 2017; Imamura et al. 2017; Heebøll et al.
2016; Chen et al. 2015; Faghihzadeh et al. 2015; Anton et al.
2014; Chachay et al. 2014;M
endez-del Villar et al. 2014; Kumar
and Joghee 2013; Tom
e-Carneiro et al. 2013; Movahde et al.
2013; Bhatt et al. 2012; Yoshino et al. 2012) .Enrolled subjects
were overweight or slightly obese individuals without any
major disease (van der Made et al. 2015; Anton et al. 2014;
Wong et al. 2013; Yoshino et al. 2012; Timmers et al. 2011). or
individuals affected by MetS, (Kjær et al. 2017;M
endez-del Vil-
lar et al. 2014). well controlled T2DM, [Imamura et al. 2017;
Timmers et al. 2016; Kumar and Joghee 2013; Movahde et al.
2013; Bhatt et al. 2012], NAFLD, (Heebøll et al. 2016; Chen
et al. 2015; Faghihzadeh et al. 2015; Chachay et al. 2014) stable
angina or acute coronary syndrome. (Tom
e-Carneiro et al.
2013). Anthropometric and hemodynamic characteristics of
the evaluated studies are presented in Table 1.
BP measurements methods
Not all the included studies reported BP assessment methods.
When specified, BP was always assessed from the brachial
artery, according to standardized protocols by the use of mer-
cury sphygmomanometers. Subjects were seated at rest for at
Figure 1. Flow chart of the number of studies identified and included into the meta-analysis.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 3
Table 1. Baseline characteristics of the studies included in the meta-analysis. Data are reported as mean §standard deviation, unless otherwise specified.
First author
(year) Study location Design
Main inclusion
criteria for the studies
Resveratrol
treatment
duration Participants (n) Study group Age (years) BMI (Kg/m
2
) WC (cm) Male (n,%)
SBP
(mmHg)
DBP
(mmHg)
MAP
(mmHg)
PP
(mmHg)
Kjær, TN (2017) Denmark Randomized, double-blind,
placebo-controlled, parallel
group clinical study
-Male sex 16 weeks 21 Resveratrol 1000 mg/day
(standardization to trans-
resveratrol not reported)
51.9 §633.8§3.2 114 §9.6 21 (100) 146 §10.5 89.3 §7.8 108.2 §8.8 56.7 §13.1
-30–60 years
-MetS diagnosis (according to the
International Diabetes Federation
criteria for MetS) but otherwise
healthy
21 Resveratrol 150 mg/day
(standardization to trans-
resveratrol not reported)
49.1 §6.9 33.4 §4.1 116 §8.7 21 (100) 140 §10.5 86.9 §6.9 104.6 §8.3 53.1 §12.6
24 Placebo 47.8 §6.4 34.1 §3.9 116 §10.3 24 (100) 150 §16.7 91.3 §10.3 110.9 §12.8 58.7 §19.6
Imamura, H (2017) Japan Randomized, double-blind,
placebo-controlled, parallel
group clinical study
-T2DM (HbA1c >7.0%) 12 weeks 25 Resveratrol 100 mg/day
(standardized in resveratrol-e)
57.4 §10.6 26.1 §4.2 NA 15 (60) 137.1 §18.7 82 §9.5 100.4 §13.3 55.1 §21
25 Placebo 58.2 §10.1 24.1 §4 NA 11(44) 137.1 §25 80.8 §11.5 99.6 §17.2 56.3 §27.5
Heebøll, S (2016) Denmark Randomized, double-blind,
placebo-controlled, parallel
group clinical study
-Elevated serum ALT (>70 U/L for
men and >45 for women)
6 months 13 Resveratrol 1500 mg/day
(standardization to trans-
resveratrol not reported)
43.2 (22–67)x32.1 §3.1 NA 9 (69) 142 §15 89 §8 106.7 §10.8 53 §17
-NAFLD (diagnosed by the
presence of steatosis at US
examination)
-18–70 years
-BMI 25 Kg/m
2
-at least one additional element of
MetS (excluding diabetes)
13 Placebo 43.5 (21–69)x32 §5.4 8 (62) 136 §15 79 §898§10.8 57 §17
Timmers, S (2016) The Netherlands Randomized, double-blind,
placebo-controlled, crossover
clinical study
-Well-controlled T2DM (HbA1c
<8.0%)
30 days 17 Resveratrol 150 mg/day (99.9%
trans-resveratrol)
64 (59.2–67.3)
30.5 §2.3 NA 17 (100) 139 §17.3 85 §11.1 103 §13.5 54 §20.6
17 Placebo 30.5 §2.5 NA 17 (100) 142 §16.1 87 §11.1 105.3 §13 55 §19.6-male sex
-40–70 years
-BMI 27 Kg/m
2
and 35 Kg/m
2
Chen, S (2015) China Randomized, double-blind,
placebo-controlled, parallel
group clinical study
-NAFLD (diagnosed by the presence
of “bright liver”at US examination
in absence of known aetiologies of
chronic liver disease)
3 months 30 Resveratrol 600 mg/day (98%
trans-resveratrol)
45.2 §10 25.3 §2.1 88.4 §7 22 (73) 124.1 §13.1 80.6 §8.8 95.1 §10.4 43.5 §15.8
30 Placebo 43.5 §11 26.2 §3.1 88.2 §7.1 20 (67) 131.7 §21.7 84.5 §14.4 100.2 §17 47.2 §25.9
-20–60 years
-BMI >20 -Kg/m
2
and <30 Kg/m
2
-FPG <140 mg/dL
Faghihzadeh, F
(2015)
Iran Randomized, double-blind,
placebo-controlled, parallel
group clinical study
-Persistent elevated serum ALT
(>30 U/L for men and >19 for
women) for 6 months
12 weeks 24 Resveratrol 500 mg/day (pure
trans-resveratrol)
44 §10.128.4 §3.5 95.5 §7.8 18 (72)119 §13.8 79.7 §8.4 92.8 §10.5 39.3 §16.2
-NAFLD (diagnosed by the presence
of steatosis on both US
examinations and fibrosis on
FibroScan)
24 Placebo 46.3 §9.528.8 §3.5 96.2 §7.8 17 (68)116.4 §14 78 §8.4 90.8 §10.6 38.4 §16.3
Van der Made, SM
(2015)
The Netherlands Randomized, double-blind,
placebo-controlled, crossover
clinical study
-Non-smoking 4 weeks 45 Resveratrol 150 mg/day (99%
trans-resveratrol)
60 §728.8§3.2 NA 25 (56) 136 §17 88 §9 104 §12.3 48 §19.2
-45–70 years
-TC <309.4 mg/dL
-HDL-C <46.8 mg/dL for men and
<59.2 for women
45 Placebo
-FPG <126 mg/dL
-BMI 25 Kg/m
2
and 35 Kg/m
2
-mean alcohol consumption <20
units/week for men and <14
units/week for women
4F. FOGACCI ET AL.
Anton, SD (2014) US of America Randomized, placebo-controlled,
parallel group clinical pilot
study
-Non-smoking 90 days 10 Resveratrol 1000 mg/day
(standardization to trans-
resveratrol not reported)
73.6 §2.5 29 §147.6§5.8 5 (50) 132.1 §5.5 73.5 §3.7 93 §4.4 58.6 §6.6
-BMI 25 Kg/m
2
and 34.9 Kg/m
2
-sedentary lifestyle (physical
exercising <120 min per week) 12 Resveratrol 300 mg/day
(standardization to trans-
resveratrol not reported)
73.2 §2.1 29.8 §0.6 42.6 §1.5 6 (50) 125.5 §3.2 71.5 §2.8 89.5 §2.9 54 §4.3
-self-reported ability to walk 1 mile
10 Placebo 73.3 §2.1 29.7 §0.6 46.8 §4.8 5 (50) 136.1 §3.4 77.2 §2.9 96.8 §3.1 58.9 §4.5
Chachay, VS (2014) Australia Randomized, double-blind,
placebo-controlled, parallel
group clinical study
-NAFLD (diagnosed by the presence of
steatosis at US examinations in
absence of known aetiologies of
chronic liver disease)
8 weeks 10 Resveratrol 3000 mg/day (s
standardization to trans-
resveratrol not reported )
48.8 §12.2 31.8 (30.2–37.0)
NA 10 (100) 130 §12 83 §798.7§947§13.9
10 Placebo 47.5 §11.2 31.2 (27.4–39.3)
10 (100) 130 §10 82 §698§75.6 48 §11.7
-male sex
-BMI >25 Kg/m
2
-WC >90 cm
-mean alcohol consumption <40 g/
day
M
endez-del Villar,
M(2014)
Mexico Randomized,double-blind,
placebo-controlled, parallel
group clinical study
-MetS diagnosis (according to the
International Diabetes Federation
criteria for MetS)
90 days 11 Resveratrol 1500 mg/day (pure
trans-resveratrol)
39.8 §5.4 35.6 §3.2 109 §9 1 (9) 120 §13 78 §892§9.9 42 §15.3
10 Placebo 40.3 §5.4 33.7 §3.7 104 §8 5 (50) 116 §13 77 §890§9.9 39 §15.3
-non-smoking
-30–50 years
Kumar, BJ (2013) India Prospective, open-label,
randomized, controlled,
parallel group clinical study
-T2DM (minimum 3 years duration of
the disease)
6 months 28 Resveratrol 250 mg/day
(standardization to trans-
resveratrol not reported)
NA 24.7 §3.6 NA 12 (43) 139.7 §16.1 81.4 §9.6 100.8 §12.2 58.3 §18.7
-30–70 years
–minimum of 6 months of ongoing
oral hypoglycaemic treatment
or combination therapy
(metformin and/or
glibenclamide)
29 Placebo 24.9 §3.1 9 (31) 134.5 §14.6 78.6 §10.9 97.2 §12.3 55.9 §18.2
Tom
e-Carneiro, J
(2013)
Spain Randomized, double-blind,
placebo-controlled, parallel
group clinical study
-Stable angina or acute coronary
syndrome for at least 6 months
before the inclusion in the study
6 months 25 Resveratrol 350 mg/day
(standardization to trans-
resveratrol not reported)and
grape extract (»25 mg
anthocyanins, »1mg
flavonols, »40 mg
procyanidins, and »0.8 mg
hydroxycinnamic acids)
60 §12 29.7 §5.1 NA 24 (96) 126 §16 71 §989.3§11.8 55 §18.4
-left ventricular ejection fraction
45%
-NYHA functional class I-II 25 Grape extract (»25 mg
anthocyanins, »1mg
flavonols, »40 mg
procyanidins, and »0.8 mg
hydroxycinnamic acids)
59 §10 30.8 §4.6 NA 19 (76) 124 §18 73 §10 90 §13.2 51 §20.6
-18–80 years
-more than 3 months of ongoing
pharmacological therapy
according to ESC guidelines
Movahed, A (2013) Iran Randomized, double-blind,
placebo-controlled, parallel
group clinical study
-T2DM 45 days 33 Resveratrol 1000 mg/day (99%
trans-resveratrol)
52.5 §6.2 27.1 §3.1 NA 16 (47) 129 §15.0 76.9 §19.5 94.3 §18.1 52.1 §24.6
-20–65 years
–minimum of 6 months of ongoing
oral hypoglycaemic treatment
or combination therapy
31 Placebo 51.8 §7.0 27.8 §4.2 NA 17 (55) 129.3 §15.2 78.6 §15.4 95.5 §15.3 50.7 §21.6
Wong, RHX (2013) Australia Randomized, double-blind,
placebo-controlled, crossover
clinical study
-Male sex or women in
postmenopausal status (defined
on the basis of self-reported
cassation of menses for at least
12 months)
6 weeks 28 Resveratrol 75 mg/day (99% trans-
resveratrol)
61 §6.9 33.3 §3.2 NA 12 (43) 127.4 §12.7 73.3 §6.9 91.3 §9.2 54.1 §14.5
-40–75 years
–BMI 30 Kg/m
2
and 45 Kg/m
2
28 Placebo
(Continued on next page)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 5
Table 1. (Continued).
First author
(year) Study location Design
Main inclusion
criteria for the studies
Resveratrol
treatment
duration Participants (n) Study group Age (years) BMI (Kg/m
2
) WC (cm) Male (n,%)
SBP
(mmHg)
DBP
(mmHg)
MAP
(mmHg)
PP
(mmHg)
Bhatt, JK (2012) India Prospective, open-label,
randomized, controlled,
parallel group clinical study
-T2DM (minimum 3 years duration of
the disease)
3 months 28 Resveratrol 250 mg/day (pure
trans-resveratrol)
56.7 §8.9 24.7 §3.6 212.8 §64.5 12 (43) 139.7 §16.1 81.4 §9.6 100.8 §12.2 58.3 §18.7
-30–70 years
-minimum of 6 months of ongoing
oral hypoglycaemic treatment
(metformin and/or
glibenclamide)
29 No treatment 57.8 §8.7 24.9 §3.1 182 §46.22 9 (31) 134.5 §14.6 78.6 §10.9 97.2 §12.3 55.9 §18.2
Yoshino, J (2012)
[16]
US of America Randomized, double-blind,
placebo-controlled, parallel
group clinical study
-Female sex 12 weeks 15 Resveratrol 75 mg/day (99.7%
trans-resveratrol)
58.2 §424.2§2.8 NA 0 (0) 118 §16 67 §11 84 §12.9 51 §19.4
-post-menopausal status (at least
1 year since last spontaneous
menstrual bleeding)
14 Placebo 59.8 §4.3 24.3 §2.7 NA 0 (0) 123 §15 65 §10 84.3 §11.9 58 §18
-35–70 years
-BMI 20 Kg/m
2
and 30 Kg/m
2
-mean alcohol consumption >20 g/
day
Timmers, S (2011) The Netherlands Randomized, double-blind,
placebo-controlled, crossover
clinical study
-Male sex 30 days 11 Resveratrol 150 mg/day (99%
trans-resveratrol)
52.5 §7 31.45 §2.7 NA 11 (100) 132 §9.9 83 §8.6 99.3 §9.1 49 §13.1
-obesity
-good health 11 Placebo 52.5 §7 31.59 §2.5 NA 11 (100) 131 §10.3 82 §8.3 98.3 §949§11.1
values calculated by the inclusion in the analysis of the patients who dropped out (nD1 in the active treated group and in the placebo treated one)
expressed as median and 95% CI
xexpressed as mean and variation range
ALTDALanine aminoTransferase; BMIDBody Mass Index; DBPDDiastolic Blood Pressure; ESCDEuropean Society of Cardiology; FPGDFasting Plasma Glucose; HbA1cDHaemoglobin A1c; HDL-CDHigh Density Lipoprotein Choles-
terol; MAPDMean Arterial Pressure; MetSDMetabolic Syndrome; MMSEDMini Mental State Examination; nDsubjects; NADNot Available; NAFLDDNon-Alcoholic Fatty Liver Disease; NYHADNew York Heart Association; PPD
Pulse Pressure; SBPDSystolic Blood Pressure; T2DDType 2 Diabetes; TCDTotal Cholesterol; USDUnited States; WCDWaist Circumference.
6F. FOGACCI ET AL.
least 10 minutes in a quiet room, and three readings were taken
at intervals of at least 1-minute. The first reading was discarded,
and the last two readings were averaged.
Risk of bias assessment
Almost all the included studies were characterized by suffi-
cient information regarding sequence generation, allocation
concealment and personnel and outcome assessments, and
showed low risk of bias because of incomplete outcome
data and selective outcome reporting. Details of the quality
of bias assessment are reported in Table 2.
Effect of resveratrol on BP
The effect of resveratrol on BP was reported in 19 treat-
ment arms. Resveratrol intervention did not significantly
affect neither SBP [SBP: WMD: -2.5 95% CI:(-5.5, 0.6)
mmHg; pD0.116; I
2
D62.1%] nor DBP [DBPDWMD: -0.5
95% CI:(-2.2, 1.3) mmHg; pD0.613; I
2
D50.8] nor MAP
[MAPDWMD: -1.3 95% CI:(-2.8, 0.1) mmHg; pD0.070;
I
2
D39.5%] nor PP [PPDWMD: -0.9 95% CI:(-3.1, 1.4)
mmHg; pD0.449; I
2
D19.2%] (Figure 2). These results were
robust in the leave-one-out sensitivity analysis (Figure 3).
When the studies were categorized according to resvera-
trol administered dose, there was a comparable DBP-lower-
ing resveratrol effect between the subsets of studies with
<300 mg/day and 300 mg/day (Table 3). Moreover,
changes in mean SBP, MAP and PP were comparable in
subsetsoftrialswithandwithoutdiabetesasinclusioncri-
terion (Table 3).
Additional analysis
Significant WMDs were detected in subsets of studies catego-
rized according to resveratrol daily dosage (<or 300 mg/day)
and presence of diabetes or NAFLD as inclusion criteria
(Table 4). With respect to treatment duration (<or
3 months), no significant change in BP was observed between
subsets of trials lasting less than 3 months or more (Table 4).
Meta-regression analysis
Meta-regression analysis was conducted to evaluate the associa-
tion between changes in BP with either resveratrol daily dosage
and BMI at baseline. Considering diabetes, results revealed a
positive association between SBP-lowering resveratrol activity
(slope: 1.99; 95% CI: 0.05, 3.93; two-tailed pD0.04) and BMI at
baseline, while no association was detected neither between
baseline BMI and MAP-lowering resveratrol activity (slope:
1.35; 95% CI: ¡0.22, 2.91; two-tailed pD0.09) nor between
baseline BMI and PP-lowering resveratrol activity (slope: 1.03;
95% CI: ¡1.33, 3.39; two-tailed pD0.39) (Figure 4). Resveratrol
daily dosage was not associated neither with SBP- (slope:
¡0.002; 95% CI: ¡0.01, 0.01; two-tailed pD0.73) nor MAP-
(slope: ¡0.001; 95% CI: ¡0.01, 0.01; two-tailed pD0.84) nor
PP- (slope: ¡0.003; 95% CI: ¡0.02, 0.01; two-tailed pD0.68)
lowering effects (Figure 5).
In the subset of studies characterized by the presence of
NAFLD as inclusion criterion, meta-regression analysis did
not reveal any association between DBP-lowering resveratrol
activity and BMI at baseline (slope: ¡0.31; 95% CI: ¡1.54, 0.91;
two-tailed pD0.62) or resveratrol daily dosage (slope: 0.001;
95% CI: ¡0.002, 0.004; two-tailed pD0.49) (Figure 6).
Publication biases
The funnel plots of standard error by effect size (WMD) were
asymmetric (Figure 7), suggesting potential publication biases
in the meta-analysis of resveratrol effect on all the considered
hemodynamic parameters. The presence of publication biases
was confirmed by Egger’s linear regression only for PP (SBP:
Table 2. Quality of bias assessment of the included studies according to Cochrane guidelines.
AUTHOR
SEQUENCE
GENERATION
ALLOCATION
CONCEALMENT
BLINDING OF PARTICIPANTS,
PERSONNEL AND OUTCOME
ASSESSMENT
INCOMPLETE
OUTCOME DATA
SELECTIVE
OUTCOME
REPORTING
OTHER POTENTIAL
THREATS TO VALIDITY
Kjær, TN (2017)L L L L L U
Imamura, H (2017)L U L L L L
Heebøll, S (2016)L L L L L L
Timmers, S (2016)L U L L U U
Chen, S (2015)L L U L L L
Faghihzadeh, F
(2015)
LU L L L H
Van der Made, SM
(2015)
LL L L L L
Anton, SD (2014)L L L L L L
Chachay, VS (2014)L U U L L L
M
endez-del Villar,
M(2014)
LL L L L L
Kumar, BJ (2013)L L H L L L
Tom
e-Carneiro, J
(2013)
LU U L L U
Movahed, A (2013)L L L L L L
Wong, RHX (2013)L L L L L L
Bhatt, JK (2012)L L H L L L
Yoshino, J (2012)L U U L U U
Timmers, S (2011)L U L L U L
LDlow risk of bias; HDhigh risk of bias; UDunclear risk of bias.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 7
interceptD¡0.56; standard errorD1.47; 95% CI: ¡3.66, 2.54;
tD0.38, dfD17; two-tailed pD0.71; DBP: interceptD0.91;
standard errorD1.25; 95% CI: ¡1.73, 3.56; tD0.73, dfD17;
two-tailed pD0.48; MAP: interceptD0.37; standard errorD
1.22; 95% CI: ¡2.20, 2.95; tD0.31, dfD17; two-tailed pD0.76;
PP: interceptD¡1.93; standard errorD0.95; 95% CI: ¡3.93,
0.06; tD2.04, dfD17; two-tailed pD0.06). In contrast, Begg’s
rank correlation did not highlight any publication bias (SBP:
Kendall’s Tau with continuity correctionD¡0.08; zD0.49;
two-tailed pD0.62; DBP: Kendall’s Tau with continuity
correctionD0.12; zD0.70; two-tailed pD0.48; MAP: Kendall’s
Tau with continuity correctionD0.07; zD0.42; two-tailed pD
Figure 2. Forest plot detailing weighted mean difference and 95% confidence intervals for the studies included in the meta-analysis.
Figure 3. Plot showing leave-one-out sensitivity analysis.
8F. FOGACCI ET AL.
0.67; PP: Kendall’s Tau with continuity correctionD¡0.05; zD
0.28; two-tailed pD0.78) (Figure 7). Correction of the asymme-
tries using Duval & Tweedie “trim and fill”method yielded
potentially missing studies for SBP [1 missing study on the
right-side of the funnel plot, adjusted effect sizeD¡1.82 (95%
CI: ¡4.97, 1.34) mmHg], MAP [2 missing studies on the left-
side of the funnel plot, adjusted effect sizeD¡2.07 (95% CI:
¡3.48, ¡0.66) mmHg] and PP [7 missing studies on the right-
side of the funnel plot, adjusted effect sizeD2.31 (95% CI: 0.38,
4.23) mmHg] and no missing studies for DBP [adjusted effect
sizeD¡0.46 (95% CI: ¡2.25, 1.33) mmHg].
Tolerability and safety of resveratrol consumption
Resveratrol was fairly well-tolerated and no serious adverse
events (AEs) occurred among most of the eligible trials. 4 RCTs
(Chachay et al. 2014; Anton et al. 2014; Heebøll et al. 2016;
Kjær et al. 2017; Ornstrup et al. 2014). reported mild com-
Table 3. P-values referring to WMDs between subgroups of studies stratified by resveratrol daily dose (>or the median dosage), duration of treatment (>or
3 months), and presence of type 2 diabetes or non-alcoholic fatty liver disease as inclusion criteria.
SISTOLIC BLOOD PRESSURE DIASTOLIC BLOOD PRESSURE MEAN ARTERIAL PRESSURE PULSE PRESSURE
Type 2 diabetes 0.006 0.276 0.043 0.007
NAFLD 0.616 0.087 0.182 0.833
Daily dosage>300 mg 0.707 0.013 0.690 0.350
Treatment period>3 months 0.783 0.389 0.271 0.355
CIDConfidence Interval; NAFLDDNon-Alcoholic Fatty Liver Disease; WMDDWeighted Mean Difference.
Table 4. . Subgroup analyses stratified by resveratrol daily dose (>or the median dosage), duration of treatment (>or 3 months), and presence of type 2 diabetes or
non-alcoholic fatty liver disease as inclusion criteria.
SISTOLIC BLOOD PRESSURE DIASTOLIC BLOOD PRESSURE MEAN ARTERIAL PRESSURE PULSE PRESSURE
Type 2 diabetes
YES Number of considered studies: 5 5 5 5
WMD ¡8.8 mmHg ¡2 mmHg ¡4.2 mmHg ¡6.5 mmHg
95% CI (¡12.5, ¡5) mmHg (¡4.7, 0.7) mmHg (¡7.4, ¡1.1) mmHg (¡11.2, ¡1.8) mmHg
p-value <0.001 0.152 0.008 0.006
I
2
31.3% 0% 0% 0%
NO Number of considered studies: 12 12 12 12
WMD ¡0.5 mmHg ¡0.03 mmHg ¡0.6 mmHg 0.8 mmHg
95% CI (¡3.6, 2.6) mmHg (¡2.3, 2.2) mmHg (¡2.2, 1.1) mmHg (¡1.7, 3.3) mmHg
p-value 0.754 0.982 0.508 0.547
I
2
50.4% 59.8% 40.4% 2.9%
NAFLD
YES Number of considered studies: 4 4 4 4
WMD ¡4.2 mmHg ¡3.3 mmHg ¡3.7 mmHg ¡1.4 mmHg
95% CI (¡11.6, 3.3) mmHg (¡6.3, ¡0.3) mmHg (¡7.3, 0.04) mmHg (¡7, 4.2) mmHg
p-value 0.271 0.034 0.052 0.623
I
2
56.9% 26.5% 27.6% 0%
NO Number of considered studies: 13 13 13 13
WMD ¡2.1 mmHg 0.2 mmHg ¡0.9 mmHg ¡0.8 mmHg
95% CI (¡5.5, 1.4) mmHg (¡1.8, 2.2) mmHg (¡2.5, 0.7) mmHg (¡3.2, 1.7) mmHg
p-value 0.239 0.825 0.257 0.539
I
2
64.6% 51.8% 41.3% 28%
Daily dosage300 mg
YES Number of considered studies: 9 9 9 9
WMD ¡2.5 mmHg ¡2.2 mmHg ¡2.4 mmHg 0.1 mmHg
95% CI (¡4.9, ¡0.04) mmHg (¡4, ¡0.5) mmHg (¡4.4, ¡0.4) mmHg (¡2.9, 3.2) mmHg
p-value 0.047 0.012 0.021 0.933
I
2
46.1% 45.3% 0% 31.7%
NO Number of considered studies: 9 9 9 9
WMD ¡1.7 mmHg 0.8 mmHg ¡0.2 mmHg ¡2 mmHg
95% CI (¡7.2, 3.8) mmHg (¡0.8, 2.5) mmHg (¡3.5, 3.2) mmHg (¡5.2, 1.3) mmHg
p-value 0.541 0.328 0.924 0.230
I
2
74% 42.6% 58% 2.9%
Treatment period3 months
YES Number of considered studies: 10 10 10 10
WMD ¡2.1 mmHg ¡0.9 mmHg ¡1.4 mmHg ¡0.01 mmHg
95% CI (¡6.4, 2.1) mmHg (¡3.7, 1.8) mmHg (¡4.3, 1.5) mmHg (¡2.9, 2.8) mmHg
p-value 0.327 0.510 0.332 0.993
I
2
65.9% 65.2% 53.7% 28.7%
NO Number of considered studies: 7 7 7 7
WMD ¡3 mmHg 0.5 mmHg ¡0.7 mmHg ¡2.1 mmHg
95% CI (¡7.6, ¡1.6) mmHg (¡1.3, 2.4) mmHg (¡3, 1.6) mmHg (¡5.7, 1.4) mmHg
p-value 0.200 0.573 0.568 0.232
I
2
59.7% 0% 0% 0%
CIDConfidence Interval; NAFLDDNon-Alcoholic Fatty Liver Disease; WMDDWeighted Mean Difference.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 9
plaints of the gastrointestinal tract, which were described as an
increased frequency of bowel movements and loose stools,
especially occurring during the first 3–4 weeks of treatment.
(Chachay et al. 2014; Ornstrup et al. 2014). One month after
randomization, one patient receiving resveratrol at high dose
(1000 mg daily) developed a transient itchy skin rash which
resolved 14 days after having stop taking it. (Ornstrup et al.
2014). Other AEs were rare and unlikely related with
resveratrol treatment. A serious case of febrile leukopenia and
thrombocytopenia after 10 days of supplementation was
reported in one study. (Heebøll et al. 2016). The trial conducted
by Anton et al. found that participants receiving the higher
dose of resveratrol (1000 mg/day) had slightly lower haemoglo-
bin levels, lower mean corpuscular haemoglobin concentration
levels and higher alkaline phosphatase levels than baseline.
(Anton et al. 2014). However, lower doses of resveratrol did
Figure 4. Meta-regression bubble plots of the association between mean changes
in SBP, MAP and PP and mean baseline BMI in subset of trials with diabetes as
inclusion criterion. The size of each circle is inversely proportional to the variance
of change.
Figure 5. Meta-regression bubble plots of the association between mean changes
in SBP, MAP and PP and resveratrol daily dose in subset of trials with diabetes as
inclusion criterion. The size of each circle is inversely proportional to the variance
of change.
10 F. FOGACCI ET AL.
not significantly result in similar alterations of these haemato-
chemical parameters, as previously found by Yoshino et al.
(Yoshino et al. 2012)
Discussion
At the best of our knowledge, the current systematic review and
meta-analysisisthefirst one to comprehensively analyse evidences
from RCTs on the efficacy of supplementation with resveratrol on
BP. In particular, a previous meta-analysis of Liu et al. (Liu et al.
2015). included only six trials for a total of 247 subjects, while we
included 17 trials with 681 subjects. The one of Sahbekar et al.
(Sahebkar et al. 2015). was more comprehensive compared with
the one of Liu et al. but focused on trials reporting the effect of res-
veratrol on hsCRP, thus excluding the ones reporting data on BP
but without hsCRP, otherwise included in our meta-analysis.
Moreover, both meta-analyses meta-analysed data on SBP and
DBP, but not on MAP and PP, as we did. Indeed, the present anal-
ysis provides several items to be discussed.
First, it demonstrates favourable, though not significant, BP
lowering effects of resveratrol on SBP, MAP and PP, whilst no
relevant effect was observed with regard to DBP. This may
have at least, in part, potentially important clinical
implications, since recent sets of International guidelines have
strengthened the need of achieving the recommended thera-
peutic BP targets, mostly for SBP (140 mmHg) in order to
reduce hypertension-related morbidity and mortality (Antza
et al. 2017). Despite the availability of different pharmacologi-
cal drugs and molecules, observational studies have showed
persistently low rates of BP control, mostly in Western coun-
tries, thus highlighting the need of using other and integrated
approach to reduce BP levels and achieve effective BP control.
These considerations may promote a more extended use of res-
veratrol in hypertensive patients for ameliorating the effective-
ness of a given antihypertensive strategy.
Secondly, our data show a more pronounced BP lowering
effect in those patients at high cardiovascular risk, such as those
with diabetes and metabolic abnormalities or obesity. In view of
the high prevalence of these conditions in general hypertensive
populations and in view of the detrimental role in enhancing
the risk of coronary events and stroke in diabetic patients with
high BP levels (Newmann et al. 2017), our findings may suggest
a potential way to improve BP control rates and reduce the risk
of hypertension-related complications in hypertensive patients
with diabetes. Moreover, the insulin-sensitivity improving
effect of resveratrol, that contribute to its blood pressure
improving effect, could also have a positive impact on diabetes
control (Zhu et al. 2017).
Thirdly, considerations on tolerability of the resveratrol
administration may also have important clinical implications,
since it is well known that hypertension is an asymptomatic
clinical condition in which adherence and persistence on pre-
scribed antihypertensive medications is relatively low after
6–12 months (Burnier 2017). Discontinuation rates may be
even higher in presence of adverse events or drug reactions,
(Burnier 2017). so that the lack of any clinical relevant side
effects with resveratrol, also when used at high or very high
dosages, can be of potential clinical usefulness.
Finally, the clinical effectiveness of resveratrol-based therapy
in lowering systolic BP levels has been observed across a wide
spectrum of age classes included in the selected RCTs. This
aspect should be taken in consideration, mostly when treating
elderly or very elderly patients with isolated systolic hyperten-
sion, which is commonly observed in the clinical practice, espe-
cially in view of the recently increased average life expectancy,
worldwide. (Rochlani et al. 2017). Resveratrol might be used
both in fit elderly patients for improving stricter BP control, as
recommended by current guidelines, as well as in frail elderly,
in whom conservative BP control has been proposed for the
frequent concomitant presence of additional clinical conditions
and comorbidities.
It is then noteworthy that similar effects on BP have been
observed also with other natural antioxidant compounds as
quercetin (Serban et al. 2016): it would be interesting in the
next future to investigate if the contemporary use of resveratrol
and other similar natural molecules could further improve its
effect on BP.
Potential limitations
Certainly, our meta-analysis has some limitations. Firstly,
among the eligible RCTs was found a moderate and marginally
Figure 6. Meta-regression bubble plots of the association between mean changes
in SBP and mean baseline BMI (above) and resveratrol daily dosage (below) in sub-
set of trials with presence of NAFLD as inclusion criterion. The size of each circle is
inversely proportional to the variance of change.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 11
significant heterogeneity which may be due to differences in the
intervention duration, sample size and daily dose of resveratrol.
For this reason, we performed the random effects analysis,
which is a suitable method in the presence of heterogeneity
studies. Remarkably, the significance of estimated pooled effect
size on SBP was not biased by any single study overall.
Then, since no dose-escalation study has yet been carried
out to determine the optimal dose of resveratrol to improve
DBP, it is unclear if the doses used in the included trials
are sufficient to elicit a sizable effect in DBP in clinical set-
ting, even if they are clearly enough to improve SBP. More-
over, the resveratrol bioavailability after oral administration
is usually poor in humans, because of the massive biotrans-
formation phenomena occurring in the liver microsomes
and intestine and the relative metabolites are much less
active or completely inactive (Walle et al. 2004;Walle
2011). On the other side, the development of new drug
delivery systems intended to enhance its bioavailability
could dramatically increase its plasma level and, presum-
ably, its efficacy (Amri et al. 2012;Sergidesetal.2016).
However, since no direct comparison between different res-
veratrol formulation has been yet carried out, it was impos-
sible to carry out a specific subanalysis to understand if
these approach are more effective than the use of standard
resveratrol.
Another potential limitation is the methodology applied for
measuring BP levels in the selected RCTs, which was mostly
based on the use of mercury sphygmomanometer. Since the
accuracy of this method in detecting systolic/diastolic BP levels
is lower than other oscillometric devices, further clinical studies
based on proper assessment of clinic BP levels are needed to
support the main findings of our analysis.
Conclusions
In conclusion, the favourable effect of resveratrol emerging
from the current meta-analysis suggests the possible use of this
nutraceutical as active compound in order to promote cardio-
vascular health, mostly when used in high dose and in diabetic
patients. However, further well-designed trials are needed to
confirm whether longer-term resveratrol supplementation
might significantly improve BP by decreasing DBP other than
SBP.
ORCID
Federica Fogacci http://orcid.org/0000-0001-7853-0042
Giuliano Tocci http://orcid.org/0000-0002-0635-4921
Claudio Borghi http://orcid.org/0000-0001-8039-8781
Arrigo F. G. Cicero http://orcid.org/0000-0002-4367-3884
References
Anton, S. D., C. Embry, M. Marsiske, X. Lu, H. Doss, C. Leeuwenburgh,
and T. M. Manini. 2014. Safety and metabolic outcomes of resveratrol
supplementation in older adults: results of a twelve-week, placebo-con-
trolled pilot study. Experimental Gerontology 57:181–7.
Antza, C., I. Doundoulakis, S. Stabouli, and V. Kotsis. 2017. Comparison
among recommendations for the management of arterial hypertension
issued by last US, Canadian, British and European Guidelines. High
Blood Pressure & Cardiovascular Prevention 2017 Nov 1. doi: 10.1007/
s40292-017-0236-x. [Epub ahead of print]
Amri, A., J. C. Chaumeil, S. Sfar, and C. Charrueau. 2012. Administration
of resveratrol: What formulation solutions to bioavailability limi-
tations? Journal of Controlled Release 158:182–93;
Bhatt, J. K., S. Thomas, and M. J. Nanjan. 2012. Resveratrol supplementa-
tion improves glycemic control in type 2 diabetes mellitus. Nutrition
Research 32:537–41.
Borenstein, M., L. Hedges, J. Higgins, and H. Rothstein. 2005. Comprehen-
sive meta-analysis version 3. Englewood, NJ. Biostatistics 2005:104.
Borghi, C., and A. F. Cicero. 2017. Nutraceuticals with a clinically detect-
able blood pressure-lowering effect: A review of available randomized
clinical trials and their meta-analyses. British Journal of Clinical Phar-
macology 83:163–171.
Burnier, M. 2017. Drug adherence in hypertension. Pharmacological
Research 125:142–149.
Chachay, V. S., G. A. Macdonald, J. H. Martin, J. P. Whitehead,
T. M. O’Moore-Sullivan, P. Lee, M. Franklin, K. Klein, P. J. Taylor,
Figure 7. Funnel plot detailing publication biases in the studies included in the meta-analysis.
12 F. FOGACCI ET AL.
M. Ferguson, et al. 2014. Resveratrol does not benefit patients with
nonalcoholic fatty liver disease. Clinical Gastroenterology and Hepatol-
ogy 12:2092–103.e1–6.
Chen, S., X. Zhao, L. Ran, J. Wan, X. Wang, Y. Qin, F. Shu, Y. Gao, L.
Yuan, Q. Zhang, and M. Mi. 2015. Resveratrol improves insulin resis-
tance, glucose and lipid metabolism in patients with non-alcoholic fatty
liver disease: a randomized controlled trial. Digestive and Liver Disease
47:226–32.
Cicero, A. F., F. Fogacci, and A. Colletti. 2017a. Food and plant bioactives
for reducing cardiometabolic disease risk: an evidence based approach.
Food and Function 8:2076–2088.
Cicero, A. F., A. Colletti, G. Bajraktari, O. Descamps, D. M. Djuric, M.
Ezhov, Z. Fras, N. Katsiki, M. Langlois, G. Latkovskis, et al. 2017b.
Lipid lowering nutraceuticals in clinical practice: position paper from
an International Lipid Expert Panel. Archives of Medical Science 13:
965–1005.
Cicero, A. F., and A. Colletti. 2015. Nutraceuticals and blood pressure con-
trol: results from clinical trials and meta-analyses. High Blood Pressure
and Cardiovascular Prevention 22:203–13.
Duval, S., and R. Tweedie. 2000. Trim and fill: a simple funnelplot–based
method of testing and adjusting for publication bias in metaanalysis.
Biometrics 56:455–63.
Faghihzadeh, F., P. Adibi, and A. Hekmatdoost. 2015. The effects of resver-
atrol supplementation on cardiovascular risk factors in patients with
non-alcoholic fatty liver disease: a randomised, double-blind, placebo-
controlled study. British Journal of Nutrition 114:796–803.
Fogacci, F., A. F. G. Cicero, G. Derosa, M. Rizzo, M. Veronesi, and C. Bor-
ghi. 2017. Effect of pistachio on brachial artery diameter and flow-
mediated dilatation: a systematic review and meta-analysis of random-
ized, controlled-feeding clinical studies. Critical Reviews in Food Science
and Nutrition 30:0.
Follmann, D., P. Elliott, I. Suh, and J. Cutler. 1992. Variance imputation for
overviews of clinical trials with continuous response. Journal of Clinical
Epidemiology 45:769–73.
Heebøll, S., M. Kreuzfeldt, S. Hamilton-Dutoit, M. Kjær Poulsen, H. Stødkilde-
Jørgensen, H. J. Møller, N. Jessen, K. Thorsen, Y. Kristina Hellberg, S.
Bønløkke Pedersen, et al. 2016. Placebo-controlled, randomised clinical
trial: high-dose resveratrol treatment for non-alcoholic fatty liver disease.
Scandinavian Journal of Gastroenterology 51:456–64.
Higgins, J., S. Green. 2010. Cochrane Handbook for Systematic Reviews of
Interventions. Version 5.0. 2. 2009. Chichester, UK, John Wiley and
Sons Ltd.
Hozo, S. P., B. Djulbegovic, and I. Hozo. 2005. Estimating the mean and
variance from the median, range, and the size of a sample. BMC Medi-
cal Research Methodology 5:13.
Imamura, H., T. Yamaguchi, D. Nagayama, A. Saiki, K. Shirai, and I. Tat-
suno. 2017. Resveratrol ameliorates arterial stiffness assessed by cardio-
ankle vascular index in patients with Type 2 diabetes mellitus. Interna-
tional Heart Journal 58:577–583.
Kumar, B. J., and N. M. Joghee. 2013. Resveratrol supplementation in
patients with type 2 diabetes mellitus: a prospective, open label, ran-
domized controlled trial. International Research Journal of Pharmacy
4:245–249.
Kjær, T. N., M. J. Ornstrup, M. M. Poulsen, H. Stødkilde-Jørgensen, N. Jes-
sen, J. O. L. Jørgensen, B. Richelsen, and S. B. Pedersen. 2017. No bene-
ficial effects of resveratrol on the metabolic syndrome: a randomized
placebo-controlled clinical trial. The Journal of Clinical Endocrinology
and Metabolism 102:1642–1651.
Li, H., N. Xia, and U. F€
orstermann. 2012. Cardiovascular effects and
molecular targets of resveratrol. Nitric oxide 26:102–10.
Liu, Y., W. Ma, P. Zhang, S. He, and D. Huang. 2015. Effect of resveratrol
on blood pressure: a meta-analysis of randomized controlled trials.
Clinical Nutrition 34: 27–34.
M
endez-del Villar, M., M. Gonz
alez-Ortiz, E. Mart
ınez-Abundis, K. G.
P
erez-Rubio, and R. Liz
arraga-Valdez. 2014. Effect of resveratrol
administration on metabolic syndrome, insulin sensitivity, and insulin
secretion. Metabolic Syndrome and Related Disorders 12:497–501.
Moher, D., A. Liberati, J. Tetzlaff, and D. G. Altman, P. R. I. S. M. A.
Group. 2009. Preferred reporting items for systematic reviews and
meta-analyses: the PRISMA statement. The BMJ 339:b2535.
Movahed, A., I. Nabipour, X. Lieben Louis, S. J. Thandapilly, L. Yu, M.
Kalantarhormozi, S. J. Rekabpour, and T. Netticadan. 2013. Antihyper-
glycemic effects of short term resveratrol supplementation in type 2
diabetic patients. Evidence-Based Complementary and Alternative Med-
icine 2013:851267.
Newman, J. D., A. Z. Schwartzbard, H. S. Weintraub, I. J. Goldberg, and
J. S. Berger. 2017. Primary prevention of cardiovascular disease in
diabetes mellitus. Journal of the American College of Cardiology
70:883–893.
Ornstrup, M. J., T. Harsløf, T. N. Kjær, B. L. Langdahl, and S. B. Pedersen.
2014. Resveratrol increases bone mineral density and bone alkaline
phosphatase in obese men: a randomized placebo-controlled trial. The
Journal of Clinical Endocrinology and Metabolism 99:4720–9.
Rochlani, Y., M. H. Khan, and W. S. Aronow. 2017. Managing hyperten-
sion in patients aged 75 years and older. Current Hypertension Reports
19:88.
Sahebkar, A., M. Pirro, M. Banach, D. P. Mikhailidis, S. L. Atkin, and A. F.
G. Cicero. 2017. Lipid-lowering activity of artichoke extracts: A system-
atic review and meta-analysis. Critical Reviews in Food Science and
Nutrition 13:1–8.
Sahebkar, A.,
Z. Reiner, L. E. Simental-Mend
ıa, G. Ferretti, and A. F. Cic-
ero. 2016. Effect of extended-release niacin on plasma lipoprotein(a)
levels: A systematic review and meta-analysis of randomized placebo-
controlled trials. Metabolism 65:1664–1678.
Sahebkar, A., C. Serban, S. Ursoniu, N. D. Wong, P. Muntner, I. M. Gra-
ham, D. P. Mikhailidis, M. Rizzo, J. Rysz, L. S. Sperling, G. Y. Lip, and
M. Banach, Lipid and Blood Pressure Meta-analysis Collaboration
Group. 2015. Lack of efficacy of resveratrol on C-reactive protein and
selected cardiovascular risk factors–Results from a systematic review
and meta-analysis of randomized controlled trials. International Jour-
nal of Cardiology 189: 47–55.
Serban, M. C., A. Sahebkar, A. Zanchetti, D. P. Mikhailidis, G. Howard, D.
Antal, F. Andrica, A. Ahmed, W. S. Aronow, P. Muntner, G. Y. Lip, I.
Graham, N. Wong, J. Rysz, and M. Banach, Lipid and Blood Pressure
Metaanalysis Collaboration (LBPMC) Group. 2016. Effects of querce-
tin on blood pressure: a systematic review and meta-analysis of ran-
domized controlled trials. Journal of the American Heart Association 5:
pii: e002713.
Sergides, C., M. Chiril
a, L. Silvestro, D. Pitta, and A. Pittas. 2016. Bioavail-
ability and safety study of resveratrol 500 mg tablets in healthy male
and female volunteers. Experimental and Therapeutic Medicine
11:164–170.
Sirtori, C. R., A. Arnoldi, and A. F. Cicero. 2015. Nutraceuticals for blood
pressure control. Annals of Medicine 47:447–56.
Sosnowska, B., P. Penson, and M. Banach. The role of nutraceuticals in the
prevention of cardiovascular disease. 2017. Cardiovascular Diagnosis
and Therapy 7(Suppl 1):S21–S31.
Tom
e-Carneiro, J., M. Gonz
alvez, M. Larrosa, M. J. Y
a~
nez-Gasc
on, F. J.
Garc
ıa-Almagro, J. A. Ruiz-Ros, F. A. Tom
as-Barber
an, M. T. Garc
ıa-
Conesa, and J. C. Esp
ın. 2013. Grape resveratrol increases serum adipo-
nectin and downregulates inflammatory genes in peripheral blood
mononuclear cells: a triple-blind, placebo-controlled, one-year clinical
trial in patients with stable coronary artery disease. Cardiovascular
Drugs and Therapy 27:37–48.
Timmers, S., M. de Ligt, E. Phielix, T. van de Weijer, J. Hansen, E.
Moonen-Kornips, G. Schaart, I. Kunz, M. K. Hesselink, V. B. Schrau-
wen-Hinderling, et al. 2016. Resveratrol as add-on therapy in subjects
with well-controlled type 2 diabetes: a randomized controlled trial.
Diabetes Care 39:2211–2217.
Timmers, S., E. Konings, L. Bilet, R. H. Houtkooper, T. van de Weijer, G.
H. Goossens, J. Hoeks, S. van der Krieken, D. Ryu, S. Kersten, et al.
2011. Calorie restriction-like effects of 30 days of resveratrol supple-
mentation on energy metabolism and metabolic profile in obese
humans. Cell Metabolism 14:612–22.
van der Made, S. M., J. Plat, and R. P. Mensink. 2015. Resveratrol does not
influence metabolic risk markers related to cardiovascular health in
overweight and slightly obese subjects: a randomized, placebo-con-
trolled crossover trial. PLoS One 10:e0118393.
Walle,T.,F.Hsieh,M.H.DeLegge,J.E.OatisJr,andU.K.Walle.
2004. High absorption but very low bioavailability of oral
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 13
resveratrol in humans. Drug Metabolism and Disposition 32:1377–
82. Epub 2004 Aug 27;
Walle, T. 2011. Bioavailability of resveratrol. Annals of the New York Acad-
emy of Sciences 2011;1215:9–15.
Wong, R. H., N. M. Berry, A. M. Coates, J. D. Buckley, J. Bryan, I. Kunz,
and P. R. Howe. 2013. Chronic resveratrol consumption improves bra-
chial flow-mediated dilatation in healthy obese adults. Journal of
Hypertension 31:1819–27.
Yoshino, J., C. Conte, L. Fontana, B. Mittendorfer, S. Imai, K. B. Schecht-
man, C. Gu, I. Kunz, F. Rossi Fanelli, B. W. Patterson, et al. 2012. Res-
veratrol supplementation does not improve metabolic function in
nonobese women with normal glucose tolerance. Cell Metabolism
16:658–64.
Zhu, X., C. Wu, S. Qiu, X. Yuan, and L. Li. 2017. Effects of resveratrol on
glucose control and insulin sensitivity in subjects with type 2 diabetes:
systematic review and meta-analysis. Nutrition and Metabolism 14:60.
14 F. FOGACCI ET AL.
