Clinical Nutrition xxx (2014) 1e8
Contents lists available at ScienceDirect
Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu
Meta-analyses
Effect of resveratrol on blood pressure: A meta-analysis of randomized controlled trials Yanxia Liu a, d, Wanqiang Ma b, d, Po Zhang c, Shunchuan He a, Daifa Huang a, * a
The Second Cadres Ward, General Hospital of Shenyang Military Area Command, Shenyang City, Liaoning Province 110840, China The 210th Hospital of PLA, Dalian City, Liaoning Province 116000, China c Department of Congenital Heart Disease, Cardiovascular Research Institute of PLA, General Hospital of Shenyang Military Area Command, Shenyang City, Liaoning Province 110840, China b
a r t i c l e i n f o
s u m m a r y
Article history: Received 27 January 2014 Accepted 22 March 2014
Background & aims: The results of human clinical trials that have investigated the effects of resveratrol on blood pressure are inconsistent. We aimed to quantitatively evaluate the effects of resveratrol on systolic blood pressure (SBP) and diastolic blood pressure (DBP). Methods: We conducted a strategic literature search of PubMed, EMBASE, MEDLINE, and the Cochrane Library (updated to January, 2014) for randomized controlled trials that evaluate the effects of resveratrol on SBP and DBP. Study quality was assessed using the Jadad scale. Weighted mean differences were calculated for net changes in SBP and DBP using fixed-effects or random-effects models. We performed pre-specified subgroup, sensitivity and meta-regression analyses to evaluate potential the heterogeneity. Dose effects of resveratrol on SBP and DBP were estimated using meta-regression analyses. Results: Six studies comprising a total of 247 subjects were included in our meta-analysis. The overall outcome of the meta-analysis indicates that resveratrol consumption can not significantly reduce SBP and DBP. Subgroup analyses indicated that higher-dose of resveratrol consumption (150 mg/d) significantly reduces SBP of 11.90 mmHg (95% CI: 20.99, 2.81 mmHg, P ¼ 0.01), whereas lower dose of resveratrol did not show a significant lowering effect on SBP. The meta-regression analyses did not indicate dose effects of resveratrol on SBP or DBP. Conclusions: The present meta-analysis indicates that resveratrol consumption significantly decreases the SBP level at the higher dose, while resveratrol has no significant effects on DBP levels. Additional high-quality studies are needed to further evaluate the causal conclusions. Ó 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: Resveratrol Systolic blood pressure Diastolic blood pressure Meta-analysis
1. Introduction Cardiovascular disease (CVD) is one of the major disease burdens worldwide, and even becomes a bigger health concern faced by developing world. CVD also remains the leading causes of death in the world, accounting for 17.3 million deaths per year, a number that is projected to rise to >23.6 million by 2030.1,2 High blood
Abbreviations: BMI, body mass index; CVD, cardiovascular disease; DBP, diastolic blood pressure; GE, grape extract; GE-RES, grape extract containing resveratrol; RCTs, randomized controlled trials; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus. * Corresponding author. The Second Cadres Ward, General Hospital of Shenyang Military Area Command, No. 83 Wenhua Road, Shenhe District, Shenyang City, Liaoning Province 110840, China. Tel./fax: þ86 2428851186. E-mail address: [email protected] (D. Huang). d Yanxia Liu and Wanqiang Ma contributed equally to this article.
pressure has been shown to be a major risk factor of CVD,3e6 and each increment of blood pressure by 20/10 mmHg above 115/ 75 mmHg can double the risk of CVD for people aged 40 to 70.7 Accumulating evidence suggests that dietary modification can decrease the blood pressure, which in turn reduce the risk of hypertension and CVD.8,9 Therefore, specific recommendations of healthy diet become more and more important for adults with higher risk of CVD. It has been demonstrated that grapes, containing a wide variety of polyphenol compounds, have the beneficial effects on cardiovascular health.10 Resveratrol and proanthocyanidin are the major polyphenol compounds in grapes, which mainly present in the grape skin and seeds, respectively. Feringa et al.11 have found that grape seeds extract can lower systolic blood pressure (SBP) based on the data of 5 randomized controlled trials (RCT).12e16 On the other hand, resveratrol has also been reported to reduce systolic blood pressure (SBP) in several animal models. In addition,
http://dx.doi.org/10.1016/j.clnu.2014.03.009 0261-5614/Ó 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Please cite this article in press as: Liu Y, et al., Effect of resveratrol on blood pressure: A meta-analysis of randomized controlled trials, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.03.009
2
Y. Liu et al. / Clinical Nutrition xxx (2014) 1e8
We searched PubMed (up to January 2014; http://www.ncbi. nlm.nih.gov/pubmed/), Embase, MEDLINE (1980 to January 2014; http://www.embase.com/), and Cochrane Library (1985 to January 2014; http://www.cochrane.org/) using the following terms in the title and abstract: resveratrol OR resveratrols. The search was limited to clinical trials in humans. Additionally, we hand-searched the reference list and reviews to further identify RCTs examining the effects of resveratrol on SBP and DBP in humans.
net changes in SBP or DBP values. The statistical heterogeneity was estimated using Cochran’s test (P < 0.1). The I2 statistic was calculated, and I2 > 50% indicated significant heterogeneity across studies.21 We used a random-effects model if significant heterogeneity was observed among studies. Otherwise, we used a fixedeffects model. Percent changes in mean and SD values were excluded when we extracted SD values for an outcome. SD values were calculated from standard errors, P values, 95% CIs, or t-statistics if they were not directly available. In addition, as suggested by Follmann et al., we assumed a correlation coefficient of 0.5 between the baseline and endpoint values.22 Funnel plots and the Egger’s regression test were used to assess publication bias. Additionally, pre-specified subgroup analyses that included resveratrol dose, duration, and BMI were conducted to evaluate possible sources of heterogeneity within the included studies. Meanwhile, we conducted meta-regression analyses to investigate the potential explanations for heterogeneity among the RCTs, and detect dose-effect relationship between resveratrol and SBP or DBP. Furthermore, we performed sensitivity analyses according to the Handbook for Systematic Review of Interventions of Cochrane software (Version 5.0.2; The Cochrane Collaboration, Oxford, United Kingdom).
2.2. Study selection
3. Results
Studies were included for analysis if they met the following criteria: 1) participants ingested resveratrol for 2 weeks; 2) the study was a RCT in humans with either a crossover or parallel design; 3) the baseline and endpoint values for SBP or DBP (or their differences) with SD, SEM, or 95% CI were available for each group in the trial; 4) resveratrol was not given as part of a multicomponent supplement, such as grape, wine or grape juice in the study; 5) the study used a concurrent control group for the resveratrol treatment group, and the difference between the intervention and control group was resveratrol.
3.1. Results of the literature search
previous studies demonstrated that resveratrol can increase nitric oxide (NO) concentrations, and reduce oxidative stress, angiotensin II and ET-1, all of which protect against increasing SBP.17e19 Therefore, we hypothesized that resveratrol would have a favorable effect on the prevention and control of hypertension by regulating blood pressure. However, the results of human clinical trials investigating the effect of resveratrol on blood pressure were inconsistent. Thus, we conducted a meta-analysis of all published RCTs to quantitatively assess the effect of resveratrol on SBP and diastolic blood pressure (DBP) based on PRISMA guidelines. 2. Methods 2.1. Search strategy
2.3. Quality assessment We estimated the quality of the studies using the following criteria: 1) randomization; 2) double blinding (participant masking and researcher masking); 3) reporting of the number of withdrawal and reasons for dropouts; 4) allocation concealment; and 5) generation of random numbers. RCTs scored one point for each area addressed in the study design for a possible score between 0 and 5 (highest level of quality).20 A score 4 indicated a higher-quality trial, whereas a score < 4 indicated a lower-quality trial.
Figure 1 shows the detailed process of study selection. In summary, 132 articles were initially identified, and 108 articles were excluded, either because of duplication or because they were deemed irrelevant to this meta-analysis after careful review of the titles and abstracts. Additionally, among the 24 trials that remained, an additional 18 articles were excluded for various reasons: 10 articles were excluded because they did not contain data on SBP or DBP, 6 studies were discarded because resveratrol was given as part of a multi-component supplement, 1 study was excluded because the duration of resveratrol treatment was less than 2 weeks, and 1 study was excluded because of inappropriate study design. Thus, 6 articles were ultimately selected for inclusion in the meta-analysis.23e28
2.4. Data extraction The data was collected using to a pilot-tested data extraction form that included the following: 1) study characteristics, including region, authors, publication year, sample size, study design, type of intervention, dose, treatment duration, and type of diet; 2) population information, including age, baseline health status and body mass index (BMI); 3) mean differences in changes of SBP or DBP. If outcomes were reported multiple times at different stages of the studies, only the final posttreatment outcomes were selected in our meta-analysis. 2.5. Statistical analysis We performed the meta-analysis using the STATA program (Version 11; StataCorp, College Station, TX). Treatment effects were defined as weighted mean differences and 95% CIs calculated for
Fig. 1. Flow diagram of the study selection process showing the number of eligible articles included in this meta-analysis.
Please cite this article in press as: Liu Y, et al., Effect of resveratrol on blood pressure: A meta-analysis of randomized controlled trials, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.03.009
Y. Liu et al. / Clinical Nutrition xxx (2014) 1e8
3
Table 1 Characteristics of the 6 randomized controlled trials included in the analysis. Author, publication year, country
No. of Study subjects design
Movahed, 2013, Iran
66
Bhatt, 2012, India
57
Yoshino, 2012, USA
29
Carneiro, 2012, Spain 50 Fujitaka, 2011, Japan
34
Timmers, 2011, Netherlands
11
Population duration
T2DM, 52.4 6.18 years of age Parallel T2DM, 56.67 8.91 years of age Parallel Healthy, 58.2 4.0 years of age Parallel CVD, 62 9 years of age Parallel Metabolic syndrome, 63 9 years of age Crossover Obese, 52.5 2.1 years of age
Parallel
BMI Resveratrol group (kg/m2) 45 d
>25
3 mo
Contents lists available at ScienceDirect
Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu
Meta-analyses
Effect of resveratrol on blood pressure: A meta-analysis of randomized controlled trials Yanxia Liu a, d, Wanqiang Ma b, d, Po Zhang c, Shunchuan He a, Daifa Huang a, * a
The Second Cadres Ward, General Hospital of Shenyang Military Area Command, Shenyang City, Liaoning Province 110840, China The 210th Hospital of PLA, Dalian City, Liaoning Province 116000, China c Department of Congenital Heart Disease, Cardiovascular Research Institute of PLA, General Hospital of Shenyang Military Area Command, Shenyang City, Liaoning Province 110840, China b
a r t i c l e i n f o
s u m m a r y
Article history: Received 27 January 2014 Accepted 22 March 2014
Background & aims: The results of human clinical trials that have investigated the effects of resveratrol on blood pressure are inconsistent. We aimed to quantitatively evaluate the effects of resveratrol on systolic blood pressure (SBP) and diastolic blood pressure (DBP). Methods: We conducted a strategic literature search of PubMed, EMBASE, MEDLINE, and the Cochrane Library (updated to January, 2014) for randomized controlled trials that evaluate the effects of resveratrol on SBP and DBP. Study quality was assessed using the Jadad scale. Weighted mean differences were calculated for net changes in SBP and DBP using fixed-effects or random-effects models. We performed pre-specified subgroup, sensitivity and meta-regression analyses to evaluate potential the heterogeneity. Dose effects of resveratrol on SBP and DBP were estimated using meta-regression analyses. Results: Six studies comprising a total of 247 subjects were included in our meta-analysis. The overall outcome of the meta-analysis indicates that resveratrol consumption can not significantly reduce SBP and DBP. Subgroup analyses indicated that higher-dose of resveratrol consumption (150 mg/d) significantly reduces SBP of 11.90 mmHg (95% CI: 20.99, 2.81 mmHg, P ¼ 0.01), whereas lower dose of resveratrol did not show a significant lowering effect on SBP. The meta-regression analyses did not indicate dose effects of resveratrol on SBP or DBP. Conclusions: The present meta-analysis indicates that resveratrol consumption significantly decreases the SBP level at the higher dose, while resveratrol has no significant effects on DBP levels. Additional high-quality studies are needed to further evaluate the causal conclusions. Ó 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: Resveratrol Systolic blood pressure Diastolic blood pressure Meta-analysis
1. Introduction Cardiovascular disease (CVD) is one of the major disease burdens worldwide, and even becomes a bigger health concern faced by developing world. CVD also remains the leading causes of death in the world, accounting for 17.3 million deaths per year, a number that is projected to rise to >23.6 million by 2030.1,2 High blood
Abbreviations: BMI, body mass index; CVD, cardiovascular disease; DBP, diastolic blood pressure; GE, grape extract; GE-RES, grape extract containing resveratrol; RCTs, randomized controlled trials; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus. * Corresponding author. The Second Cadres Ward, General Hospital of Shenyang Military Area Command, No. 83 Wenhua Road, Shenhe District, Shenyang City, Liaoning Province 110840, China. Tel./fax: þ86 2428851186. E-mail address: [email protected] (D. Huang). d Yanxia Liu and Wanqiang Ma contributed equally to this article.
pressure has been shown to be a major risk factor of CVD,3e6 and each increment of blood pressure by 20/10 mmHg above 115/ 75 mmHg can double the risk of CVD for people aged 40 to 70.7 Accumulating evidence suggests that dietary modification can decrease the blood pressure, which in turn reduce the risk of hypertension and CVD.8,9 Therefore, specific recommendations of healthy diet become more and more important for adults with higher risk of CVD. It has been demonstrated that grapes, containing a wide variety of polyphenol compounds, have the beneficial effects on cardiovascular health.10 Resveratrol and proanthocyanidin are the major polyphenol compounds in grapes, which mainly present in the grape skin and seeds, respectively. Feringa et al.11 have found that grape seeds extract can lower systolic blood pressure (SBP) based on the data of 5 randomized controlled trials (RCT).12e16 On the other hand, resveratrol has also been reported to reduce systolic blood pressure (SBP) in several animal models. In addition,
http://dx.doi.org/10.1016/j.clnu.2014.03.009 0261-5614/Ó 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Please cite this article in press as: Liu Y, et al., Effect of resveratrol on blood pressure: A meta-analysis of randomized controlled trials, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.03.009
2
Y. Liu et al. / Clinical Nutrition xxx (2014) 1e8
We searched PubMed (up to January 2014; http://www.ncbi. nlm.nih.gov/pubmed/), Embase, MEDLINE (1980 to January 2014; http://www.embase.com/), and Cochrane Library (1985 to January 2014; http://www.cochrane.org/) using the following terms in the title and abstract: resveratrol OR resveratrols. The search was limited to clinical trials in humans. Additionally, we hand-searched the reference list and reviews to further identify RCTs examining the effects of resveratrol on SBP and DBP in humans.
net changes in SBP or DBP values. The statistical heterogeneity was estimated using Cochran’s test (P < 0.1). The I2 statistic was calculated, and I2 > 50% indicated significant heterogeneity across studies.21 We used a random-effects model if significant heterogeneity was observed among studies. Otherwise, we used a fixedeffects model. Percent changes in mean and SD values were excluded when we extracted SD values for an outcome. SD values were calculated from standard errors, P values, 95% CIs, or t-statistics if they were not directly available. In addition, as suggested by Follmann et al., we assumed a correlation coefficient of 0.5 between the baseline and endpoint values.22 Funnel plots and the Egger’s regression test were used to assess publication bias. Additionally, pre-specified subgroup analyses that included resveratrol dose, duration, and BMI were conducted to evaluate possible sources of heterogeneity within the included studies. Meanwhile, we conducted meta-regression analyses to investigate the potential explanations for heterogeneity among the RCTs, and detect dose-effect relationship between resveratrol and SBP or DBP. Furthermore, we performed sensitivity analyses according to the Handbook for Systematic Review of Interventions of Cochrane software (Version 5.0.2; The Cochrane Collaboration, Oxford, United Kingdom).
2.2. Study selection
3. Results
Studies were included for analysis if they met the following criteria: 1) participants ingested resveratrol for 2 weeks; 2) the study was a RCT in humans with either a crossover or parallel design; 3) the baseline and endpoint values for SBP or DBP (or their differences) with SD, SEM, or 95% CI were available for each group in the trial; 4) resveratrol was not given as part of a multicomponent supplement, such as grape, wine or grape juice in the study; 5) the study used a concurrent control group for the resveratrol treatment group, and the difference between the intervention and control group was resveratrol.
3.1. Results of the literature search
previous studies demonstrated that resveratrol can increase nitric oxide (NO) concentrations, and reduce oxidative stress, angiotensin II and ET-1, all of which protect against increasing SBP.17e19 Therefore, we hypothesized that resveratrol would have a favorable effect on the prevention and control of hypertension by regulating blood pressure. However, the results of human clinical trials investigating the effect of resveratrol on blood pressure were inconsistent. Thus, we conducted a meta-analysis of all published RCTs to quantitatively assess the effect of resveratrol on SBP and diastolic blood pressure (DBP) based on PRISMA guidelines. 2. Methods 2.1. Search strategy
2.3. Quality assessment We estimated the quality of the studies using the following criteria: 1) randomization; 2) double blinding (participant masking and researcher masking); 3) reporting of the number of withdrawal and reasons for dropouts; 4) allocation concealment; and 5) generation of random numbers. RCTs scored one point for each area addressed in the study design for a possible score between 0 and 5 (highest level of quality).20 A score 4 indicated a higher-quality trial, whereas a score < 4 indicated a lower-quality trial.
Figure 1 shows the detailed process of study selection. In summary, 132 articles were initially identified, and 108 articles were excluded, either because of duplication or because they were deemed irrelevant to this meta-analysis after careful review of the titles and abstracts. Additionally, among the 24 trials that remained, an additional 18 articles were excluded for various reasons: 10 articles were excluded because they did not contain data on SBP or DBP, 6 studies were discarded because resveratrol was given as part of a multi-component supplement, 1 study was excluded because the duration of resveratrol treatment was less than 2 weeks, and 1 study was excluded because of inappropriate study design. Thus, 6 articles were ultimately selected for inclusion in the meta-analysis.23e28
2.4. Data extraction The data was collected using to a pilot-tested data extraction form that included the following: 1) study characteristics, including region, authors, publication year, sample size, study design, type of intervention, dose, treatment duration, and type of diet; 2) population information, including age, baseline health status and body mass index (BMI); 3) mean differences in changes of SBP or DBP. If outcomes were reported multiple times at different stages of the studies, only the final posttreatment outcomes were selected in our meta-analysis. 2.5. Statistical analysis We performed the meta-analysis using the STATA program (Version 11; StataCorp, College Station, TX). Treatment effects were defined as weighted mean differences and 95% CIs calculated for
Fig. 1. Flow diagram of the study selection process showing the number of eligible articles included in this meta-analysis.
Please cite this article in press as: Liu Y, et al., Effect of resveratrol on blood pressure: A meta-analysis of randomized controlled trials, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.03.009
Y. Liu et al. / Clinical Nutrition xxx (2014) 1e8
3
Table 1 Characteristics of the 6 randomized controlled trials included in the analysis. Author, publication year, country
No. of Study subjects design
Movahed, 2013, Iran
66
Bhatt, 2012, India
57
Yoshino, 2012, USA
29
Carneiro, 2012, Spain 50 Fujitaka, 2011, Japan
34
Timmers, 2011, Netherlands
11
Population duration
T2DM, 52.4 6.18 years of age Parallel T2DM, 56.67 8.91 years of age Parallel Healthy, 58.2 4.0 years of age Parallel CVD, 62 9 years of age Parallel Metabolic syndrome, 63 9 years of age Crossover Obese, 52.5 2.1 years of age
Parallel
BMI Resveratrol group (kg/m2) 45 d
>25
3 mo
