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Effect of resveratrol on blood pressure: A systematic review and meta-analysis of randomized, controlled, clinical trials

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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; p=0.116; I²=62.1%], nor diastolic BP [WMD: −0.5 95% CI:(-2.2, 1.3) mmHg; p=0.613; I²=50.8], nor mean BP [MAP; WMD: −1.3 95% CI:(-2.8, 0.1) mmHg; p=0.070; I²=39.5%] nor pulse pressure [PP; WMD: −0.9 95% CI:(-3.1, 1.4) mmHg; p=0.449; I²=19.2%]. 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 p= 0.04) 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 p= 0.09) nor between baseline BMI and PP-lowering resveratrol activity (slope: 1.03; 95% CI: −1.33, 3.39; two-tailed p= 0.39). 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.
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Critical Reviews in Food Science and Nutrition
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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, SantAndrea 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 signicantly 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, signicant 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 inammation 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 prole of resveratrol is very high and
no clinically signicant 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
conicting 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,
SantOrsola-Malpighi University Hospital, U.O. Medicina Interna Borghi - Via Albertoni, 15, 40138 Bologna-Italy.
Color versions of one or more of the gures 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: (ResveratrolOR Vitis vinifera)
AND (Clinical trialAND Hemodynamic parametersOR
Blood pressureOR BPOR BPOR Systolic blood pres-
sureOR SBPOR SBPOR Diastolic blood pressureOR
DBPOR DBP). The wild-card term
was used to
increase the sensitivity of the search strategy. The reference lists
of identied 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 sufcient 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 sufcient 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) rst authors
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 unclearsuggested 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 subjectsnumber. (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 coefcient (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 xed- 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% condence interval (CI). Finally, sensitivity
analysis was executed in order to evaluate the inuence 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 xed-effect meta-regression using unrestricted
maximum likelihood model was performed to assess the
2F. FOGACCI ET AL.
association between the signicant 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 Beggs funnel plot asymmetry, Beggsrank
correlation test and Eggers weighted regression test. Duval
&Tweedietrim and llmethod 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 identied 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 specied, 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 identied 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 specied.
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
-3060 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 (2267)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)
-1870 years
-BMI 25 Kg/m
2
-at least one additional element of
MetS (excluding diabetes)
13 Placebo 43.5 (2169)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 (59.267.3)
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
-4070 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 liverat 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
-2060 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 brosis 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
-4570 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 (30.237.0)
NA 10 (100) 130 §12 83 §798.7§947§13.9
10 Placebo 47.5 §11.2 31.2 (27.439.3)
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
-3050 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
-3070 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
avonols, »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
avonols, »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
-1880 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
-2065 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 (dened
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
-4075 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
-3070 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
-3570 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 rst reading was discarded,
and the last two readings were averaged.
Risk of bias assessment
Almost all the included studies were characterized by suf-
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 signicantly
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
Signicant 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 signicant 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 conrmed by Eggers 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
intercept0.56; 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: intercept1.93; standard errorD0.95; 95% CI: ¡3.93,
0.06; tD2.04, dfD17; two-tailed pD0.06). In contrast, Beggs
rank correlation did not highlight any publication bias (SBP:
Kendalls Tau with continuity correction0.08; zD0.49;
two-tailed pD0.62; DBP: Kendalls Tau with continuity
correctionD0.12; zD0.70; two-tailed pD0.48; MAP: Kendalls
Tau with continuity correctionD0.07; zD0.42; two-tailed pD
Figure 2. Forest plot detailing weighted mean difference and 95% condence 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: Kendalls Tau with continuity correction0.05; zD
0.28; two-tailed pD0.78) (Figure 7). Correction of the asymme-
tries using Duval & Tweedie trim and llmethod yielded
potentially missing studies for SBP [1 missing study on the
right-side of the funnel plot, adjusted effect size1.82 (95%
CI: ¡4.97, 1.34) mmHg], MAP [2 missing studies on the left-
side of the funnel plot, adjusted effect size2.07 (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
size0.46 (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 stratied 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
CIDCondence Interval; NAFLDDNon-Alcoholic Fatty Liver Disease; WMDDWeighted Mean Difference.
Table 4. . Subgroup analyses stratied 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%
CIDCondence 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 rst 34 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 signicantly 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-analysisistherst one to comprehensively analyse evidences
from RCTs on the efcacy 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 signicant, 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 ndings 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
612 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 t 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
signicant 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 signicance 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 sufcient 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 efcacy (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 specic 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 ndings 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
conrm whether longer-term resveratrol supplementation
might signicantly 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
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14 F. FOGACCI ET AL.
... Epidemiological studies revealed that Mediterranean populations that intake red wine and/or polyphenol compounds suffer a lower incidence of coronary heart disease even though they consume a high-fat diet associated with unhealthy habits (23). This phenomenon is also known as "The French Paradox" (23), being the cardioprotective effect associated with polyphenol-stilbene compounds, like resveratrol (24), naturally found in many plants including berries, peanuts, grapes, and red wine (24,25). By contrast, the cardiovascular role of the alcohol (~10-12%) contained in red wine remains controversial and may be concentration-dependent (26)(27)(28). ...
... Epidemiological studies revealed that Mediterranean populations that intake red wine and/or polyphenol compounds suffer a lower incidence of coronary heart disease even though they consume a high-fat diet associated with unhealthy habits (23). This phenomenon is also known as "The French Paradox" (23), being the cardioprotective effect associated with polyphenol-stilbene compounds, like resveratrol (24), naturally found in many plants including berries, peanuts, grapes, and red wine (24,25). By contrast, the cardiovascular role of the alcohol (~10-12%) contained in red wine remains controversial and may be concentration-dependent (26)(27)(28). ...
... The long-term consumption of red wine (21,46) or dietary supplementation with polyphenol compounds (47,48) has been emerging as antihypertensive nutraceutical therapy (24). Here, we show that long-term treatment with red wine has an antihypertensive effect on diabetic (STZ) and hypertensive (SHR) rats, being this effect is not associated with the Figure 3. Endothelium-dependent relaxation is improved by red wine consumption. ...
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Aims: This raised the issue of whether in vivo long-term red wine treatment can act as a modulator of these targets. Main methods: We monitored SBP, glucose tolerance, oxidative stress, and cardiovascular function. Aortic and atrial tissues from normotensive-WKY, hypertensive-SHR, and diabetic-STZ animals, chronically exposed to red wine (3.715 ml/kg/v.o/day) or alcohol (12%) for 21-days, were used to measure contractile/relaxation responses by force transducers. Key findings: red wine, but not alcohol, prevented the increase of SBP and hyperglycemic peak. Additionally, was observed prevention of oxidative stress metabolites formation and an improvement in ROS scavenging antioxidant capacity of SHR. We also revealed that red wine intake enhances the endothelium-dependent relaxation, decreases the hypercontractile mediated by angiotensin-II in the aorta, and via β1-adrenoceptors in the atrium. Significance: The long-term consumption of red wine can improve oxidative stress and the functionality of angiotensin-II and β1-adrenoceptors, inspiring new pharmacologic and dietetic therapeutic approaches for the treatment of hypertension and diabetes.Abbreviation Acronyms and/or abbreviations: [Ca2+]cyt = Cytosolic Ca2+ Concentration; ACh = Acetylcholine; ANG II = Angiotensin II; AT1 = ANG II type 1 receptor; AUC = Area Under the Curve; Ca2+ = Calcium; Endo + = Endothelium Intact; Fen = Phenylephrine (1 μM); GTT = Glucose Tolerance Test; ISO = Isoprenaline (isoproterenol); KHN = Krebs-Henseleit Nutrient; LA = Left Atria; LH = Lipid Hydroperoxide; NO = Nitric Oxide; RA = Right Atria; RAS = Renin-Angiotensin System; ROS = Reactive Oxygen Species; SBP = Systolic Blood Pressure; SHR = Spontaneously Hypertensive Rats; STZ = Streptozotocin; WKY = Normotensive Wistar Kyoto Rats.
... It has been shown that pycnogenol has antioxidative and anti-inflammatory activity and inhibits platelet aggregation. There are studies indicating the beneficial effects of pycnogenol supplementation, such as the decrease of blood glucose levels, blood pressure, and the level of urinary albumin [32]. ...
... Resveratrol provided the least clinically important effect on blood pressure, both in SBP and DBP reduction, and the most clinically significant effects were observed only in research with a long-term follow-up or a high dosage administration. Fogacci et al. noticed that the favourable effect of resveratrol in order to prevent cardiovascular diseases is mostly when used in a daily dose of ≥300 mg/day [32], especially in people with diabetes. Resveratrol was also observed to be useful in metabolic parameter reduction and HDL increase, but still the effect depended on the high dosage (over 500 mg) or long-term intervention (over 10 weeks) [51]. ...
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Herbal supplements rich in phenolic compounds are evidenced to have a protective effect against cardiovascular diseases. Therefore, they are suggested to be included in diets for people with hypertension (HT). HT is a global health problem and is estimated to affect billions of people until the end of 2025. For this reason, every possible and effective solution preventing HT should be considered. The aim was to perform an updated meta-analysis and review of recently published studies to evaluate the effect of selected herbal supplements on blood pressure reduction. We searched the PubMed database with specified selection criteria, analysing the RCT studies from 2011 to 2021. A total of 31 studies were included in the analysis, and the meta-analysis was conducted on the data from 16 of them. The general effect size of all the supplements via placebo was d = 1.45, p < 0.05 for systolic blood pressure (SBP) and d = 0.31, p < 0.05 for diastolic blood pressure (DBP). The meta-analysis and review of the literature demonstrated that herbal supplements, such as resveratrol, cherry juice, beetroot juice, bergamot extracts, barberry, and pycnogenol, can be effective in blood pressure reduction and cardiovascular prevention, but attention should be paid to their appropriate dosage due to the possibility of side effects from the digestive system.
... Resveratrol from red wine has been considered promising in preventing human cardiovascular diseases [44] and as an antitumorigenic [45,46] and antiviral [47] compound, among other applications. It also modulates lipid metabolism and inhibits low-density The antioxidant/antimicrobial effects of chitosan and its derivatives can be explored in drug and cosmetic formulations due to their biocompatibility, non-toxic character, and effective human metabolization, enhancing the safety and shelf life of both pharmaceuticals and food products [42]. ...
... For example, chitosan nanoparticles modified through the formation of a Schiff base in the amino group, forming long-chain pyridinium radicals, exhibited increased antibacterial activity against the Gram-positive species Staphylococcus aureus and Bacillus cereus, as evaluated by MIC (minimum inhibitory concentration) and MIB (minimum bactericidal concentration), as well as mild antioxidant effects ( Figure 3) [56]. Resveratrol from red wine has been considered promising in preventing human cardiovascular diseases [44] and as an antitumorigenic [45,46] and antiviral [47] compound, among other applications. It also modulates lipid metabolism and inhibits low-density lipoprotein oxidation and platelet aggregation. ...
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Chitosan displays a dual function, acting as both an active ingredient and/or carrier for pharmaceutical bioactive molecules and metal ions. Its hydroxyl- and amino-reactive groups and acetylation degree can be used to adjust this biopolymer’s physicochemical and pharmacological properties in different forms, including scaffolds, nanoparticles, fibers, sponges, films, and hydrogels, among others. In terms of pharmacological purposes, chitosan association with different polymers and the immobilization or entrapment of bioactive agents are effective strategies to achieve desired biological responses. Chitosan biocompatibility, water entrapment within nanofibrils, antioxidant character, and antimicrobial and anti-inflammatory properties, whether enhanced by other active components or not, ensure skin moisturization, as well as protection against bacteria colonization and oxidative imbalance. Chitosan-based nanomaterials can maintain or reconstruct skin architecture through topical or systemic delivery of hydrophilic or hydrophobic pharmaceuticals at controlled rates to treat skin affections, such as acne, inflammatory manifestations, wounds, or even tumorigenesis, by coating chemotherapy drugs. Herein, chitosan obtention, physicochemical characteristics, chemical modifications, and interactions with bioactive agents are presented and discussed. Molecular mechanisms involved in chitosan skin protection and recovery are highlighted by overlapping the events orchestrated by the signaling molecules secreted by different cell types to reconstitute healthy skin tissue structures and components.
... However, there is some controversy regarding the effects of resveratrol on BP in humans. Nevertheless, the potential use of this phenolic compound as antihypertensive agent has been recently pointed out, mostly when administered at high daily dose (≥300 mg/day) and in diabetic patients (Fogacci et al. 2019). ...
... Wine lees (WL) are a great source of phenolic compounds and they have been used to obtain extracts with antioxidants effects (Romero-Díez et al. 2018; Jara-Palacios 2019). It has been evidenced that phenolic compounds identified in WL such as resveratrol, quercetin, GA, (+)-catechin, ( _ )-epicatechin or malvidin-3-glucoside exhibit antihypertensive effects in hypertensive animal and human models (Quiñones et al. 2015;Jin et al. 2017;Marunaka et al. 2017;Fogacci et al. 2019). Considering this evidence, together with the great antioxidant effect of WL extracts and the relationship between oxidative stress and HTN, WL could be a great alternative to manage HTN. ...
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Hypertension (HTN) is one of the leading causes of death in the world. Agri-food by-products are emerging as a novel source of natural antihypertensive agents allowing for their valorization and making food and agricultural industries more environmentally friendly. In this regard, wine making process generates large amounts of by-products rich in phenolic compounds that have shown potential to exert several beneficial effects including antihypertensive properties. The aim of this study was to review the blood pressure-lowering effects of winery by-products. In addition, molecular mechanisms involved in their bioactivity were also evaluated. Among the winery by-products, grape seed extracts have widely shown antihypertensive properties in both animal and human studies. Moreover, recent evidence suggests that grape stem, skin and pomace and wine lees may also have great potential to manage HTN, although more studies are needed in order to confirm their potential in humans. Improvement of endothelial dysfunction and reduction of oxidative stress associated with HTN are the main mechanisms involved in the blood pressure-lowering effects of these by-products.
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Resveratrol (RSV) is known as a natural polyphenolic compound that is known for its therapeutic activities but has limited bioavailability. The aim of our study was to explore various drug-delivering methods that are being employed to achieve target-oriented delivery and therapeutic performance of RSV. To improve the bioavailability and pharmacokinetic properties of RSV, efforts are being made by producing efficient formulations accompanying efficient drug delivery strategies. Several clinical trial studies have been conducted on RSV isomers, and the majority of studies indicated that trans-RSV had better clinical potential and therapeutic effectiveness in various types of complications such as colorectal cancer, metabolic syndrome, hypertension, obesity, neurodegenerative diseases, diabetes, hepatic disease, cardiac disorders, and breast cancer. However, multiple research studies enable us to understand various strategies that can enhance the systemic availability and efficacy of topical RSV formulations. In this article, we emphasize the hurdles of RSV delivery processes. We summarized that for delivering liquid and solid microparticles of RSV, the micro-particulate system works efficiently. Another technique in which particles are enclosed by a coating is called microencapsulation. This technique reduces the degradation of pharmaceutical compounds. Similarly, the cyclodextrin system is mainly used for poorly soluble drugs. On the other hand, the vesicular system is another micro-particulate system that can encapsulate hydrophilic and hydrophobic drugs. However, the RSV nanosponge formulations have advanced nanodrug delivery systems also make it possible to use RSV for its antioxidant potential.
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Resveratrol supplementation during pregnancy and lactation has been associated with a reduced risk of maternal obesity, gestational diabetes mellitus , and preeclampsia. In addition, emerging evidence has shown that maternal resveratrol supplementation diminishes cardio-metabolic disorders in offspring, highlighting its role in modulating adaptative responses involving phenotypical plasticity. Therefore, it is reasonable to infer that administration of resveratrol during pregnancy and lactation periods could be considered an important nutritional intervention to decrease the risk of maternal and offspring cardio-metabolic disorders. To highlight these new insights, this literature review will summarize the understanding emerging from experimental and clinical studies about resveratrol supplementation and its capacity to prevent or minimize maternal and offspring cardio-metabolic disorders.
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Background: Renovascular hypertension elicits cardiac damage and remodeling. Two-kidney, one-clip (2K1C) is an experimental model used to study hypertension pathophysiology. In this model, the renin-angiotensin-system (RAS) is overactive due to renal artery stenosis, leading to cardiac remodeling. Redox mechanisms underlying RAS activation mediate hypertension-induced cardiovascular damage. Preclinical studies and clinical trials demonstrated resveratrol's protective effects in cardiovascular diseases, mainly attributed to its antioxidant properties. We hypothesized resveratrol alone or in combination with an angiotensin-converting enzyme (ACE) inhibitor would be beneficial against cardiac damage caused by renovascular hypertension. Objective: We investigated the benefits of resveratrol against cardiac remodeling in 2K1C rats compared with captopril. Methods: Male Wistar rats underwent unilateral renal stenosis - 2K1C Goldblatt model of hypertension. Systolic Blood Pressure (SBP) was measured before and 6 weeks after surgery. Hypertensive 2K1C rats presented SBP≥160 mmHg. From the 6th week after the surgery, the animals received oral resveratrol (20 mg/kg), captopril (12 mg/kg), or their combination for 3 times per week for 3 weeks. Whole heart hypertrophy was evaluated. Histological assays assessed left ventricle hypertrophy and fibrosis. Results: Renovascular hypertension caused cardiac hypertrophy, accompanied by increased myocyte diameter and collagen deposition. Resveratrol reduced 2K1C rats' SBP and whole heart hypertrophy, independently of captopril. Resveratrol caused a higher reduction in ventricular hypertrophy than captopril. Collagen deposition was greater reduced by 2K1C treated only with resveratrol than with captopril alone or combined with resveratrol. Conclusion: Independent of captopril, resveratrol prompts cardioprotective effects on cardiomyocyte remodeling and fibrosis resulting from renovascular hypertension in 2K1C rats.
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Guidelines for the management of hypertension have been issued by different hypertension societies or organizations. Despite many similarities one can identify major differences in the diagnosis, management and treatment of the hypertensive patients among ESH/ESC, NICE, Canadian and NJC8 guidelines. Differences that can be identified are in the definition of hypertension in the elderly population, the optimal blood pressure targets in different hypertensive populations such as patients with diabetes and chronic kidney disease patients and the choose of the initial and appropriate antihypertensive agent depending on comorbidities of the treated population. Everyday clinical praxis physicians are confused by these differences and these incongruities contribute to doctor and patient inertia to reduce blood pressure levels at an optimal level. Community physicians cannot easily distinguish what recommendations are the best to be used for their patients. The critical view of these differences can also help the guidelines committees to make appropriate changes and finally to agree to a global view of recommendations for the management and treatment of hypertension.
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In recent years, there has been growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies, nutraceuticals might help patients obtain theraputic lipid goals and reduce cardiovascular residual risk. Some nutraceuticals have essential lipidlowering properties confirmed in studies; some might also have possible positive effects on nonlipid cardiovascular risk factors and have been shown to improve early markers of vascular health such as endothelial function and pulse wave velocity. However, the clinical evidence supporting the use of a single lipid-lowering nutraceutical or a combination of them is largely variable and, for many of the nutraceuticals, the evidence is very limited and, therefore, often debatable. The purpose of this position paper is to provide consensus-based recommendations for the optimal use of lipid-lowering nutraceuticals to manage dyslipidemia in patients who are still not on statin therapy, patients who are on statin or combination therapy but have not achieved lipid goals, and patients with statin intolerance. This statement is intended for physicians and other healthcare professionals engaged in the diagnosis and management of patients with lipid disorders, especially in the primary care setting. © The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved.
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On the basis of the available data, we would diagnose a normal blood pressure in elderly persons including those 75 years of age and older if the blood pressure was below 120/80 mmHg. We would diagnose hypertension in elderly persons including those aged 75 years and older if the systolic blood pressure was 130 mmHg and higher or if the diastolic blood pressure was 80 mmHg and higher. We would treat these elderly patients with hypertension to a blood pressure goal of less than 130/80 mmHg if the blood pressure was obtained by automated blood pressure monitoring in a quiet room. We would consider treating high-risk persons aged 75 years and older to a blood pressure goal of less than 120/80 mmHg if they were carefully monitored for serious adverse events. If the blood pressure is more than 20/10 mmHg above the goal blood pressure, we would initiate antihypertensive drug therapy with two antihypertensive drugs. The initial drug of choice for the treatment of hypertension in adults aged 75 years and older should be based on co-morbidities, co-incidental indications, tolerability, and cost.
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Although the regular consumption of resveratrol has been known to improve glucose homeostasis and reverse insulin resistance in type 2 diabetes mellitus (T2DM), the reported results are inconsistent. Thus, we aimed to assess the effects of resveratrol on glycemic control and insulin sensitivity among patients with T2DM. We searched for relevant articles published until June 2017 on PubMed-Medline, Embase, Cochrane Library, and Web of Science. Randomized controlled trials in T2DM patients administered with resveratrol as intervention were included. After study selection, quality assessment and data extraction were performed independently by two authors, and STATA and RevMan software were used for statistical analysis. Nine randomized controlled trials involving 283 participants were included. Meta-analysis showed that resveratrol significantly improved the fasting plasma glucose ( −0.29 mmol/l, 95% CI: −0.51, −0.06, p < 0.01) and insulin levels (−0.64 U/mL, 95% CI: −0.95, −0.32, p < 0.0001). The drug also reduced homeostasis model assessment of insulin resistance (HOMA-IR) index, systolic blood pressure, and diastolic blood pressure among participants with T2DM. The changes in hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were negligible. Subgroup analysis comparing the resveratrol supplementation doses of < 100 mg/d versus ≥ 100 mg/d revealed a significant difference in fasting plasma glucose. In particular, the latter dose presented more favorable results. This meta-analysis provides evidence that supplementation of resveratrol may benefit management of T2DM. Electronic supplementary material The online version of this article (10.1186/s12986-017-0217-z) contains supplementary material, which is available to authorized users.
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Background Results of previous clinical trials evaluating the effect of pistachio supplementation on endothelial reactivity (ER) are controversial. Aims We aimed to assess the impact of pistachio on ER through systematic review of literature and meta-analysis of available randomized, controlled-feeding clinical studies (RCTs). Methods The literature search included SCOPUS, PubMed-Medline, ISI Web of Science and Google Scholar databases up to 1st August 2017 to identify RCTs investigating the impact of pistachio on ER. Two independent reviewers extracted data on study characteristics, methods and outcomes. Overall, the impact of pistachio on ER was reported in 4 trials. Results The meta-analysis did not suggest a significant change in brachial artery flow-mediated dilatation (FMD) (WMD: +0.28%; 95%CI: −0.58, 1.13; p = 0.525) while brachial artery diameter (BAD) improved (WMD: +0.04%; 95%CI: 0.03, 0.06; p<0.001) following pistachios consumption. Conclusion The present meta-analysis suggests a significant effect of pistachios on ER, affecting BAD but not FMD.
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In recent years there has been a growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies nutraceuticals might help to obtain the theraputic lipid goals and reduce the cardiovascular residual risk. Some nutraceuticals have essential lipid lowering-properties confirmed in studies, some might have also possible positive effects on non-lipid cardiovascular risk factors and have proven to improve early markers of vascular health such as endothelial function and pulse wave velocity. However the clinical evidence supporting the use of single or a combination of lipid-lowering nutraceuticals is largely variable and for many of them very limitted and therefore often debatable. The purpose of this Position Paper is to provide consensus-based recommendations for optimal management of lipid-lowering nutraceuticals in patients with dyslipidemia still not being on statin therapy, on statin or combination therapy without lipid goals achieved, and for those with statin intolerance. This statement is intended for physicians and other health care professional that are engaged in the diagnosis and management of patients with lipid disorders, especially in the setting of primary care. Key words: dyslipidemia, lipid, nutraceuticals, position paper, recommendations.
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Resveratrol has been reported to have potent anti-atherosclerotic effects in animal studies. However, there are few interventional studies in human patients with atherosclerogenic diseases. The cardio-ankle vascular index (CAVI) reflects arterial stiffness and is a clinical surrogate marker of atherosclerosis. The aim of the present study was to investigate the effect of resveratrol on arterial stiffness assessed by CAVI in patients with type 2 diabetes mellitus (T2DM). In this double-blind, randomized, placebo-controlled study, 50 patients with T2DM received supplement of a 100mg resveratrol tablet (total resveratrol: oligo-stilbene 27.97 mg/100 mg/day) or placebo daily for 12 weeks. CAVI was assessed at baseline and the end of study. Body weight (BW), blood pressure (BP), glucose and lipid metabolic parameters, and diacron-reactive oxygen metabolites (d-ROMs; an oxidative stress marker) were also measured. Resveratrol supplementation decreased systolic BP (-5.5 ± 13.0 mmHg), d-ROMs (-25.6 ± 41.8 U.CARR), and CAVI (-0.4 ± 0.7) significantly (P < 0.05) and decreased BW (-0.8 ± 2.1 kg, P = 0.083) and body mass index (-0.5 ± 0.8 kg/m², P = 0.092) slightly compared to baseline, while there were no significant changes in the placebo group. Decreases in CAVI and d-ROMs were significantly greater in the resveratrol group than in the placebo group. Multivariate logistic regression analysis identified resveratrol supplementation as an independent predictor for a CAVI decrease of more than 0.5. In conclusion, 12-week resveratrol supplementation may improve arterial stiffness and reduce oxidative stress in patients with T2DM. Resveratrol may be beneficial in preventing the development of atherosclerosis induced by diabetes. However, a large-scale cohort study is required to validate the present findings.
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