The effect of hesperidin supplementation on inflammatory markers in human adults: A systematic review and meta-analysis of randomized controlled clinical trials

Chemico-Biological Interactions 307 (2019) 8–15

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The effect of hesperidin supplementation on inflammatory markers in human adults: A systematic review and meta-analysis of randomized controlled clinical trials

T

Elnaz Lorzadeha,b, Nahid Ramezani-Jolfaiea,b, Mohammad Mohammadia,b, Yadollah Khoshbakhta,b, Amin Salehi-Abargoueia,b,* a b

Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

ARTICLE INFO

ABSTRACT

Keywords: Hesperidin Citrus flavonoid Inflammatory markers Systematic review Meta-analysis

Background: Hesperidin (a flavanone found in citrus fruits) supplementation is suggested to inversely affect inflammation; however, clinical trials have led to inconsistent results. Objective: To examine the effect of hesperidin supplementation on inflammatory markers using systematic review and meta-analysis of randomized controlled clinical trials (RCTs). Patient and methods: Online databases including PubMed, Scopus, ISI Web of Science, and Google Scholar were searched up to December 2018. A random-effects model was used to compare the mean changes in the inflammatory markers between hesperidin supplemented and control subjects. Results: Six eligible RCTs with 296 participants were included in the systematic review. The meta-analysis revealed that hesperidin significantly reduces Vascular Cell Adhesion Molecule 1 (VCAM-1) levels [weighted mean difference (WMD) = −22.81 ng/L, P = 0.041, n = 3]. No considerable changes was observed for serum C-reactive protein (CRP) levels (WMD = −0.69 mg/L, P = 0.079, n = 5); the subgroup analysis showed a significant reduction in studies with a parallel design (WMD = −0.72 mg/L, P = 0.024, n = 3), and studies with more than 4 weeks of follow-up (WMD = −0.76 mg/L, P = 0.020, n = 2). Hesperidin supplementation had no signification effect on circulating E-selectin, interleukin 6, and Intercellular Adhesion Molecule 1 (ICAM-1) levels. Conclusion: The present study suggests that although hesperidin supplementation significantly improves VCAM1 levels; however, other inflammatory markers might not be affected. Further high-quality systematic reviews exploring the effect of hesperidin particularly on VCAM-1, ICAM-1, E-selectin, and interleukin 6 are still needed to confirm these results.

1. Introduction Chronic systemic inflammation destroys the balance between body systems including cardiovascular/respiratory, endocrine, central nervous, and digestive systems [1]. High levels of inflammatory cytokines might result in inducing beta-cell apoptosis, increase adipocyte inflammation and result in secretory dysfunction [2]. Indeed, if the inflammation becomes chronic, it could be followed by some life-threatening diseases such as cardiovascular diseases (CVDs) [3], and also a variety of cancers [4]. The induction in inflammation is mitigated by healthy dietary habits which are also associated with the lower circulating concentration of inflammatory markers [5]. Epidemiological studies and meta-

*

analyses suggest that consumption of diets rich in plant polyphenols might offer some protection against chronic inflammatory diseases including CVDs and cancers [6]. Several polyphenols, such as quercetin [7], isoflavones [8], lignans [9], flavanones [10], ellagic acid [11], resveratrol [12], and curcumin [13] have been suggested to have protective effects against inflammation in humans, and also in in vitro and in vivo models, although their mechanisms of action are not the same [14]. Hesperidin is a flavanone originally found in citrus fruits such as clementine, lemons, mandarins, grapefruit, and oranges [15]. It is suggested that hesperidin might be effective against inflammation, oxidative stress, hypertension, nitric oxide synthase inhibition, apoptosis, and infection [16]. It was recently reported that hesperidin attenuates

Corresponding author. Department of Nutrition, School of Public Health, Sahid Sadoughi University of Medical Sciences, Yazd, Iran. E-mail addresses: [email protected], [email protected] (A. Salehi-Abargouei).

https://doi.org/10.1016/j.cbi.2019.04.016 Received 27 January 2019; Received in revised form 30 March 2019; Accepted 12 April 2019 Available online 13 April 2019 0009-2797/ © 2019 Elsevier B.V. All rights reserved.

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hyperglycemia, mediates oxidative stress and pro-inflammatory cytokine production in type 2 diabetic rats [17]. However, the results of a recent meta-analysis demonstrated that hesperidin might not have a significant effect on lipid profile and blood pressure [18]. Hesperidin is highly found in red orange juice which was shown to reduce circulating C-reactive protein (CRP) [19] and E-selectin [20] concentrations. A number of studies also reported that the levels of inflammatory cytokines [i.e, interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α)] were reduced after consuming hesperidin and redfleshed orange juice [19,21]. However, ambivalent results were found regarding the effect of hesperidin supplementation on inflammatory factors; for instance, no significant effects were observed in multiple studies [22,23]. To our knowledge, there is no systematic review and meta-analysis considering the possible effect of hesperidin supplementation on the markers of systemic inflammation. The aim of the present study was to summarize the available data provided by randomized controlled trials (RCTs) regarding the effect of hesperidin supplementation compared to placebo or no intervention on different inflammatory markers in adults.

2.4. Risk of bias assessment

2. Methods

2.5. Statistical analysis

The current systematic review and meta-analysis followed preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [24] during every stage of its processing, analysis, and reporting. The study protocol is registered in the prospective register of systematic reviews (PROSPERO) [protocol code: CRD42017059923].

The estimated effect size was the difference in mean changes ± standard error (SE) of inflammatory markers (change in the treatment group/period minus the change in the control group/period) in each of the included studies. If there was no report of the change values, P values or estimated correlation coefficient for baseline and follow-up values were used to calculate the SE for mean changes. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for net changes by using the random-effects model which takes the between-study heterogeneity into account. The between-study heterogeneity was assessed using Cochrane Q test; furthermore, To calculate the percentage of total variation explained by the between-study heterogeneity, the I2 statistic (which is an estimate ranging from 0 to 100% with lower values indicating less heterogeneity) was used [26]. Substantial heterogeneity exists when I2 exceeds 50% or P value was less than 0.05 [27]. Subgroups analyses were also used to detect potential sources of between-study heterogeneity. Sensitivity analyses were planned to assess the robustness of the overall results [28]. Potential publication bias was investigated by visual inspection of the funnel plots [29]. The statistical analyses of the present meta-analysis were performed by using STATA version 11.2 (StataCorp, College Station, TX). Two-tailed P values equal or less than 0.05 were considered as statistically significant.

A systematic assessment of risk of bias in the included studies was fulfilled using Cochrane Collaboration's tool [25]; and by using the following criteria: 1) random sequence generation (selection bias); 2) allocation concealment (selection bias); 3) blinding of participants and personnel (performance bias); 4) blinding of outcome assessment (detection bias); 5) incomplete outcome data (attrition bias); and 6) selective outcome reporting (reporting bias). According to the recommendations of the Cochrane Handbook, a judgment of “low risk of bias”, “high risk of bias” or “unclear risk of bias” was made in each domain. The last category indicates either lack of information or uncertainty over the potential for bias. Additionally, by identifying the six domains as the most important ones (‘key domains’), each RCT was assigned an overall risk of bias in terms of low risk (low for all key domains), high risk (high for one or more key domains.), and unclear risk (unclear for one or more key domains). The quality assessment was conducted by NRJ and EL independently and was discussed with ASA in case of inconsistencies.

2.1. Search strategy Relevant articles from the earliest available online indexing year to December 2018 were identified through searches of the literature in PubMed/MEDLINE, Scopus, ISI Web of Science, and Google Scholar, without language or any other restriction. The keywords used to search the online databases are provided in the Supplementary Table 1. The reference lists of the relevant literature were also checked manually for any missing related study. 2.2. Eligibility criteria Screening the titles and abstracts, followed by the full texts assessment of the eligible articles were done by two independent investigators (MM and NRJ). All published controlled clinical trials that reported the effect of hesperidin supplementation on all possible circulating inflammatory markers [such as C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and other markers], were included for further consideration. If the studies were conducted among children and adolescents aged below 18 years, and also if they had no control group or outcomes of interest, we excluded them from the review. In the case of multiple publications from the same trial, we selected only the most recent or informative one.

3. Results 3.1. Study selection We initially identified 3912 potentially relevant studies from the bibliographic database search. Among them, 26 potentially relevant full texts were assessed according to inclusion and exclusion criteria and the following studies were excluded: nine studies supplemented components besides hesperidin in the intervention group, so hesperidin supplementation was not the only difference between the intervention and the control groups/periods [30–38], and eleven studies did not have any reports on the relevant outcomes [39–49]. Therefore, six eligible randomized controlled studies were included (Fig. 1). These included RCTs which enrolled a total of 296 participants, assessed the effect of hesperidin supplementation on the systemic inflammatory markers; five studies reported data on CRP, four on IL-6, three on E-selectin, ICAM-1, and VCAM-1 (see Fig. 2).

2.3. Data extraction For each selected study, information was extracted on the authors last name, publication year, country, baseline characteristics of the study population (sample size, sex, age, and health status), study design (crossover or parallel), intervention duration, the use of run-in or washout periods, hesperidin dose (mg/day), the kind of the diet or any other intervention carried out in the control group, the number of participants who completed the follow-up period. The data extraction was done by two independent authors (YK and EL) and the possible discrepancies were resolved by discussion with ASA and MM.

3.2. Study and participant characteristics Table 1 shows the characteristics of the studies that were included 9

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Fig. 1. Flowchart of the study selection process.

unclear [21,52]. We did not find any selective reporting in the included studies; therefore, they were rated as low risk of bias. Since each study was considered as unclear risk of bias for at least one of the six key domains, we found the overall quality of studies to be “unclear”.

in the present systematic review. Three studies were conducted in Iran [21,22,50], and the others were conducted in Netherland [51], France [23], and Italy [52]. Of the total six RCTs that assessed the effect of hesperidin supplementation on the inflammatory markers, two studies were crossover in design and consisted of 48 participants [23,52]. Two of the studies supplemented hesperidin for 6 weeks [50,51] and one for 8 weeks [22]. The duration of crossover studies were lower and were conducted for 3 [52] and 4 [23] weeks. In the majority of trials, the supplemented dose was 450–600 mg/day, whereas one study [23] used a dosage of 292 mg/day of hesperidin for the intervention group. Three studies administered the same amounts of cellulose [22,51,52] to the control groups, and the other studies supplemented the starch as placebo [21,23,50]. Both placebos were similar in dose and appearance to hesperidin. Two studies targeted patients with type 2 diabetes [22,50], two studies were conducted on healthy overweight individuals [23,51], one study included individuals with myocardial infarction [21], and one study assessed the effect of hesperidin supplementation on inflammatory markers among patients with metabolic syndrome [52]. All included trials enrolled subjects aged 30–60 years. The majority of included studies consisted of both genders and only one study was performed on male adults [23].

3.4. Meta-analysis C-reactive protein (CRP). Five trials with 228 subjects provided information on changes of CRP levels following hesperidin supplementation [21–23,50,52]. As shown in Table 3, the results showed no significant decrease in CRP levels after hesperidin supplementation, compared with placebo groups (WMD = −0.69 mg/L, 95% CI: −1.46, 0.08, P = 0.079), and the between-study heterogeneity was high (Q statistic = 12.20, P = 0.016; I2 = 67.2). Subgroup analysis was performed based on the studies’ design and duration. The hesperidin supplementation significantly reduced CRP levels in studies with parallel design (WMD = −0.72 mg/L, 95% CI: −1.35, −0.09, P = 0.024), with no heterogeneity among these studies (Q statistic = 0.55, P = 0.758, I2 = 0%). However, the changes in CRP levels were not significant in cross-over studies. The intervention period also modified the effects of hesperidin supplementation; as a significant decrease was seen in studies with duration of more than 4 weeks (WMD = −0.76, 95% CI: −1.39, −0.12, P = 0.02), and no between-study heterogeneity was observed (Q statistic = 0.17, P = 0.678, I2 = 0%) (Table 3). Interleukin 6 (IL-6). The meta-analysis of four relevant studies [21–23,50] revealed that hesperidin supplementation does not significantly affect circulating IL-6 levels (WMD = −0.22 pg/mL, 95% CI: −0.92, 0.47, P = 0.534). It is also worth mentioning that no evidence of the between-study heterogeneity was found (Q statistic = 3.2, P = 0.362, I2 = 6.3%). E-selectin. The analysis of three RCTs with 167 participants [21,51,52], revealed that hesperidin supplementation also had no significant effect on E-selectin levels (WMD = −1.89 ng/mL, 95% CI: −6.07, 2.29, P = 0.376). The between-study heterogeneity was shown to be considerable (Q statistic = 5.12, P = 0.077, I2 = 60.9%).

3.3. Risk of bias assessment As shown in Table 2, four studies reported the details of random sequence generation and had a low risk of bias for this domain [21,23,50,51], however, the remaining two studies did not state any method for randomizing, therefore were regarded as unclear risk of bias [22,52]. Only one study explained the method used for allocation concealment [50]. Furthermore, all studies were double-blind RCTs and were categorized as low risk of bias for blinding of participants and personnel, however, only two studies asserted blinding of outcomes assessment [23,51]. The majority of the studies adequately addressed the lack of incomplete outcome data [22,23,50,51], and others were 10

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Fig. 2. Forest plots for the meta-analysis of controlled trials which assessed the effects of hesperidin supplementation on circulating CRP levels based on study design (A), and study duration (B).

Intercellular adhesion molecule-1 (ICAM-1). The pooled mean difference of ICAM-1 levels between hesperidin and placebo groups in the three included studies [23,51,52] also revealed a non-significant effect (WMD = −7.62 ng/mL, 95% CI: −16.26, 1.00, P = 0.083), with no evidence of between-study heterogeneity (Q statistic = 0.32, P = 0.851, I2 = 0%).

Vascular cell adhesion molecule-1 (VCAM-1). Meta-analysis of three clinical trials [23,51,52] which assessed the effect of hesperidin intake on VCAM-1 levels showed a significant reducing effect of hesperidin supplementation compared with placebo (WMD = −22.81, 95% CI = −44.7, −0.92, P = 0.041), and no between-study heterogeneity was observed (Q statistics = 1.89, P = 0.389, I2 = 0%). 11

a

24 (9F/15M)

45 23F/22M

Italy

Iran

21-65 int:53 con:50 int:53.2 con:53.4

50–65

Parallel

Cross-over

Cross-over

Parallel

8 wk

3 wk

4 wk

4 wk

6 wk

6 wk

Duration (wk)

600 mg/d Hesperidin 500 mL of the control drink + 292 mg hesperidin 500 mg/d Hesperidin 500 mg/d Hesperidin

450 mg/d hesperidin

500 mg/d hesperidin

Intervention group

500 mg/d cellulose

500 mL of the control drink + 292 mg starch 500 mg/d cellulose

600 mg/d starch

500 mg/d cellulose

500 mg/d starch

Control group

a

CRP, IL-6, ICAM-1, VCAM-1 CRP, ICAM-1, VCAM1, E-selectin CRP, IL-6

E-selectin, ICAM-1 , VCAM-1a CRPa, E-selectin, IL-6

CRPa, IL-6a

Reported data

Healthy overweight individuals Patients with myocardial infarction Healthy overweight individuals Patients with metabolic syndrome Patients with diabetes

Patients with diabetes

Notes about participants

12

Random sequence generation

Low Low Low Low Unclear Unclear

Study, Year (reference)

Homayouni et al., 2018 [51] Salden et al., 2016 [52] Haidari et al., 2015 [21] Morand et al., 2011 [23] Rizza et al., 2011 [53] Eghtesadi et al., 2016 [22]

Low Unclear Unclear Unclear Unclear Unclear

Allocation concealment Low Low Low Low Low Low

Blinding of participants and personnel Unclear Low Unclear Low Unclear Unclear

Blinding of outcome assessment

Low Low Unclear Low Unclear Low

Incomplete outcome data

Low Low Low Low Low Low

Selective reporting

Unclear Unclear Unclear Unclear Unclear Unclear

Overall assessment of risk of bias

F: female, M: male, RCT: randomized controlled trial, int: intervention, con: control, CRP: C-reactive protein, IL-6: interleukin 6, ICAM-1: intracellular adhesion molecule-1, VCAM-1: vascular cell adhesion molecule-

24 (24M)

France

Parallel

30–65 Inta:51.3 cona:54 18-65 int:54 con:53 40–65 Parallel

RCTa design

Age (year)

Table 2 Risk of bias assessment according to the Cochrane collaboration's risk of bias assessment tool.

1.

Eghtesadi et al., 2016 [22]

75 (22F/53M)

Iran

68 (39F/29M)

Netherland

Haidari et al., 2015 [21] Morand et al., 2011 [23] Rizza et al., 2011 [53]

60 (32F/28M)

Iran

Homayouni et al., 2018 [51] Salden et al., 2016 [52]

Number, Sex (F/ M)a

Country

Study, Year (reference)

Table 1 Characteristics of the randomized clinical trials that were included in the systematic review.

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Table 3 Meta-analysis showing the effects of hesperidin supplementation on inflammatory markers based on different subgroups as well as the overall analysis (all analyses were conducted using random effects model). Markers

CRPa (mg/L) Study design Parallel Crossover Study duration ≤4 wk > 4 wk IL-6a (pg/mL) ICAM-1a (ng/mL) VCAM-1a (ng/mL) E-selectina (ng/mL)

No. of studies

Meta-analysis

Heterogeneity

WMDa (95% CI)

P effect

Q statistic

P within group

I2 (%)

P between-group

5

−0.69 (−1.46, 0.08)

0.079

12.20

0.016

67.2

–

3 2

−0.72 (−1.35, −0.09) −0.90 (−2.66, 0.85)

0.024 0.315

0.55 10.14

0.758 0.001

0 90.1

0.221

3 2 4 3 3 3

−0.72 (−2.21, 0.77) −0.76 (−1.39, −0.12) −0.22 (−.092, 0.47) −7.62 (−16.26, 1.00) −22.81 (−44.70, −0.92) −1.89 (−6.07, 2.29)

0.346 0.02 0.534 0.083 0.041 0.376

10.26 0.17 3.20 0.32 1.89 5.12

0.006 0.678 0.362 0.851 0.389 0.077

80.5 0 6.3 0 0 60.9

0.184 – – – –

a WMD: weighted mean difference, CRP: C-reactive protein, IL-6: interleukin 6, ICAM-1: intracellular adhesion molecule-1, VCAM-1: vascular cell adhesion molecule-1.

3.5. Sensitivity analysis and publication bias

reducing inflammatory markers; however previous reviews have supported the potential inverse association between hesperidin and chronic inflammation [53,54]. A recent systematic review of human studies which investigated the association between dietary polyphenols and metabolic syndrome, reported anti-inflammation effects of hesperidin supplementation [53]. Moreover, several in vitro and animal studies have suggested anti-inflammatory properties for the citrus flavonoid hesperidin [55–57]. A number of mechanisms might explain the anti-inflammatory effects of hesperidin, especially reduction in VCAM-1 levels that is shown by either human or in vitro studies. High production of vasodilatory mediators such as nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) by polyphenols can stimulate the phosphorylation of protein kinase B (PKB), AMP kinase and eNOS, and so cause a decrease in VCAM-1 levels [58]. The significant inhibition of TNF-α-induced VCAM-1 protein expression might be through the regulation of the Akt and protein kinase C (PKC) pathway; this might contribute to the inhibition of the adhesion of monocytes to the endothelium [59]. Thus, it has been suggested that hesperidin may have potential therapeutic benefits for pathological diseases such as malignancy or atherosclerosis in which VCAM-1 is involved [54]. There are several hypotheses which might explain the non-significant effect of hesperidin on the majority of inflammatory markers. Hesperidin was administered in much higher doses (100 mg/kg to 400 mg/kg), and for longer durations (more than 8 weeks) in animal studies [60–62] when compared to the clinical trials included in the present study. The bioavailability of hesperidin is also limited, possibly because of its conversion into insoluble metabolites by colonic micro-

By omitting a study done by Morand et al. [23], the overall effect of hesperidin supplementation on CRP levels changed to a significant decreasing effect (WMD = −1.05 mg/L, 95% CI: −1.78, −0.31). Furthermore, removing a study by Salden et al. [51] could cause a significant reduction in circulating E-selectin levels after hesperidin supplementation (WMD = −4.05 ng/mL, 95% CI: −7.28, −0.81). Similarly, the meta-analysis of hesperidin supplementation effect on VCAM-1 levels was sensitive to all the three included studies; which their removal changed the results to non-significant results [23,51,52]. Other pooled effects were not sensitive to any of the included studies. There was no evidence of publication bias for studies evaluating the effect of hesperidin intake on circulating CRP and IL-6 levels by observing the funnel plots (Fig. 3). 4. Discussion The current evidence shows that hesperidin does not significantly affect circulating CRP, IL-6, E-selectin, and ICAM-1. However, there was a considerable reduction of CRP levels in studies with more than 4 weeks and studies with parallel design. Showing that longer hesperidin supplementation might be more effective in reducing inflammatory markers. Meanwhile, a significant decrease in VCAM-1 levels was also observed after hesperidin supplementation. To our knowledge, the current study is the first meta-analysis of RCTs in this regard. In the light of these findings, it can be mentioned that there is no strong evidence associated with the effectiveness of hesperidin intake in

Fig. 3. Begg's funnel plots (with pseudo 95% CIs) depicting the effect sizes (difference in means) versus their standard errors (SEs) for controlled trials which assessed the effects of hesperidin supplementation on circulating CRP (A), and IL-6 (B) levels. 13

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flora which leads to poor absorption in the small intestine, like many other flavonoids [63]. Therefore, it should be mentioned that hesperidin metabolites might not reach their sufficient plasma concentrations to induce anti-inflammatory effects, in the included trials. It is reported that 130–220 mg hesperidin can cause the plasma concentration of hesperetin metabolites to reach 1.3–2.2 μmol/L [64,65]. Consumption of 450 mg hesperidin also leads to circulating plasma concentration of approximately 1 μM of hesperetin [64]. Indeed, it is possible that such concentration may not be sufficient to have any effect on inflammatory factors. On the other hand, it has been mentioned in a study done by Yamada et al. that glucosyl hesperidin is absorbed more efficiently than hesperidin; therefore, it has a higher bioavailability compared to the same doses of hesperidin [66]. Unlike hesperidin, glucosyl hesperidin is a water-soluble derivative [67]. As a result, administrating the watersoluble form of hesperidin in animal studies can be the potential reason why hesperidin has shown beneficial effects on inflammatory markers in some animal models [67,68]. Our findings have several potential limitations that are worth to be taken into consideration: (i) the included studies were conducted on participants with different characteristics, (ii) the follow-up period was 6 weeks or lower for the majority of the included RCTs, (iii) the limited number of studies were conducted in this field specifically on some of the inflammatory markers such as ICAM-1, VCAM-1, E-selectin, and IL6 which provided inconclusive results; therefore, more high quality clinical trials need to be conducted to reach a more solid result regarding the effect of hesperidin on their circulating levels, and (iv) although the included studies were all RCTs in their design which are considered as high quality in terms of methodological principles, but based on the risk of bias assessment, all of them were judged to be as “unclear”; which means that further research is likely to have an important impact on our confidence in the estimate of effects. In summary, the findings of the present systematic review and metaanalysis showed that the hesperidin supplementation, have a significant reducing effect on VCAM-1 levels, however, no considerable effect was observed for circulating CRP, IL-6, E-selectin, and ICAM-1 levels. Moreover, it should be mentioned that supplementation with hesperidin might significantly reduce CRP levels in RCTs with longer duration. Regarding the limited studies that have been done in this field, more high quality randomized controlled clinical trials are needed to support the current results.

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Conflict of interest All authors described that they have no conflict of interest to report. Authors’ contributions The authors’ responsibilities were as follows: ASA, MM and NRJ conceived the study and designed the search strategy; MM and NRJ conducted the study selection; YK and EL conducted data extraction; NRJ and EL evaluated the risk of bias of included studies; ASA, MM and NRJ conducted the data analysis and interpretation of results; EL and NRJ wrote the first draft of the manuscript; ASA revised the manuscript; and all authors read and approved the final version of the manuscript. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.cbi.2019.04.016. Transparency document Transparency document related to this article can be found online at https://doi.org/10.1016/j.cbi.2019.04.016. 14

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