Review Article Effects of Vaccinium Berries on Serum...

Review ArticleEffects of Vaccinium Berries on Serum Lipids: A Meta-Analysisof Randomized Controlled Trials

Yitong Zhu,1 Ya Miao,1 Zheying Meng,2 and Yuan Zhong1

1Department of Geriatrics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road,Shanghai 200233, China2Department of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,Shanghai Institute of Ultrasound in Medicine, No. 600 Yishan Road, Shanghai 200233, China

Correspondence should be addressed to Yuan Zhong; zhongyuan [email protected]

Received 16 March 2015; Revised 4 June 2015; Accepted 22 June 2015

Academic Editor: Sonia Piacente

Copyright © 2015 Yitong Zhu et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The beneficial effects of anthocyanins consumption on cardiovascular risk are supported by mechanistic and epidemiologicevidence. In order to explore the effects of Vaccinium berries rich in anthocyanins on serum lipids, we conducted a meta-analysisof relevant randomized controlled trials (RCTs). Sixteen studies with 1109 subjects were included in this meta-analysis. Significantheterogeneity confirmed differential effects between Vaccinium subclasses. The whortleberry group is significantly superior toplacebo in lipids improvement. Besides, bilberry groups show significant differences in reducing LDL-C and increasing HDL-Cin comparison with other treatments. For many of the other subgroups and comparison arms, there was insufficient evidence todraw conclusions about efficacy.

1. Introduction

Cardiovascular diseases, especially coronary heart disease(CHD) and stroke, are the leading causes of death worldwide[1]. One of the known risk factors for CHD is elevatedserum lipid [2, 3]. Previous studies suggest that increasinghigh density lipoprotein cholesterol (HDL-C) and reducingtriglycerides and small low density lipoprotein cholesterol(LDL-C) particles may have positive impact in prevention ofCHD [4]. Current guidelines support LDL-C as a primarytarget of therapy [5]. General recommendation for loweringelevated lipid is developing a healthy lifestyle, includingquitting smoking, exercising regularly, and low-oil, low-salt,low-fat diet. In reality, few people can strictly follow the aboverequirements, so drug therapy is of great necessity. As weknow, statins are the first choice prescribed to achieve the goalof lipid-lowering effect [6]. Considering residual cardiovas-cular risk that remains after statin therapy, such as declinesin hepatic function [7], muscle toxicity [8], and increasingrisks of diabetes [9, 10], there is a strong demand for novellipid-modifying agents that can be easily implemented bythe majority of the population. The substitute should be safe

without any toxic or side effect and rich in nutrients and havea prevention effect on hyperlipidemia. One of the promisingalternatives is Vaccinium berry.

Vaccinium is a genus of shrubs or dwarf shrubs in theplant family Ericaceae. The fruits of many species are eatenby humans and some are of medicinal value, includingcranberry, blueberry, bilberry, and whortleberry. The com-mon characteristic of the Vaccinium berries is the abundantpolyphenols content [11, 12], such as flavonols, phenolic acids,and anthocyanins. Anthocyanins have been reported to havea positive impact on inflammation, hypertension, hyper-glycemia, oxidative damage, obesity, and lipid metabolismdisorders [13–20]. In recent years, human and animal exper-iments have gradually found the lipids-lowering effects ofextracts from different plants rich in anthocyanins [15, 21–25]. However it is still controversial, because the results ofreported randomized controlled trials (RCTs) appear contra-dictory. Besides, different species of plants may have differenteffects on lipids metabolism. We cannot conclude whichsource of anthocyanins is having the most significant effect.In order to make clear the effect of Vaccinium berries, weconduct a meta-analysis of randomized controlled trials. We

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2015, Article ID 790329, 11 pageshttp://dx.doi.org/10.1155/2015/790329

2 Evidence-Based Complementary and Alternative Medicine

also selected Vaccinium berries based on the fact that theseberries are commercially available all over the world, andtherefore, our study findings may have guiding significanceto promote public health.

2. Methods

2.1. Search Strategy. The Cochrane Library, MEDLINE,EMBASE, Science Citation Index, The China JournalFull-Text Database, Chinese Scientific Journals Full-TextDatabase, and Chinese Biomedical Literature Databases weresearched from their earliest record toDecember 2014with theterms (cranberr∗ or whortleberr∗ or bilberr∗ or lingonberr∗or Blueberry Plant or Huckleberry Plant or Vacciniummacrocarpon or Vaccinium myrtillus or Vaccinium vitis-idaea), in combination with the medical subject headings.The related article function also was used to expand thesearch results. We did not restrict any languages duringthe searching. Hand searching was made by retrieving thereference lists of every obtained study for additional studies.Unpublished data were obtained through contacting authors.We identified ongoing trials by searching https://clinicaltrials.gov/, the UK National Research Register and Meta-Registerof controlled trials on the Internet.

2.2. Study Selection. Randomized controlled clinical trials(irrespective of language, date of trial, blinding, or publica-tion status) were included in meta-analysis as long as theywere conducted in adult subjects with a duration equal toor over two weeks and contained a true control group. Trialsonly with baseline and after treatment values for synthesizingrisk (mean) differenceswere included.Theoutcomemeasureswere differences of serum total cholesterol (TC), HDL-C,LDL-C, and triglycerides (TG) between postrandomizationbaselines and after treatments. Eligible interventions werecapsules of single isolated component ormixtures of differentkinds of anthocyanins from Vaccinium berries. Interventionsin forms of diets were also included as long as they comparedVaccinium berries containing treatments with Vacciniumberries depleting controls. Trials were excluded from meta-analysis if data required for pooling were missing (i.e.,baseline mean and standard deviation [SD], end mean andSD, or change by group) or if studies involved childrenor pregnant participants or patients with conditions thatrequired cholesterol-lowering medical treatment.

2.3. Data Extraction and Quality Assessment. All abstractsidentified by the above search strategies were assessed forsubject relevance. The full text of all relevant abstracts wasdownloaded from databases and meticulously assessed forinclusion. Data abstraction form was introduced to recorddetails of study design, participants, setting and timing,interventions, patient characteristics, and outcomes. Dataabstraction was strictly performed independently by tworeviewers, with disagreement solved by discussion with thethird researcher.

All studies that met the selection criteria were assessedfor methodological quality to determine the risk of biasfor each outcome. Two reviewers independently assessed

the risk of bias according to the criteria stated in theCochrane Collaboration Handbook [26], with disagreementsresolved by discussion with the third researcher. The fol-lowing methodological domains were considered: sequencegeneration, allocation concealment, blinding of participants,incomplete outcome data, selective outcome reporting, andother potential risk factors.

2.4. Statistical Analysis. We conducted the meta-analysis todetermine the effect of Vaccinium berries on TC, HDL-C, LDL-C, and TG after summarizing available data fromall trials reporting results. Blood lipid levels were unifiedin mmol/L. If cholesterol levels (TC, HDL, and LDL) ortriglyceride levels were published in mg/dL, amounts weremultiplied by a factor of 0.02586 for cholesterol and 0.0113for triglycerides to convert tommol/L. Results for continuousoutcomes were expressed as weighted mean difference. Allstatistical analyses were performed with Review Manager(RevMan version 5.1.6) [27] by inputting the number ofparticipants and themeans and SDs of lipid concentrations atendpoint in the two comparison groups. For groups with fourtreatment arms, we grouped together all the experimentalgroups and compared them with the control group, respec-tively [28].

Chi-squared statistic and 𝐼2 statistic were used to assessheterogeneity between trials and the extent of inconsistencyapart. If there was a significant heterogeneity, a random-effects statistical model was introduced to confirm the sum-mary results. A fixed-effect model was also applied to mergecase estimates and their 95% CIs, unless there was a sig-nificant heterogeneity. Subgroup analysis was introduced byVaccinium subclasses to explore obvious therapeutic differ-ences among trials. Sensitivity analyses were also performedby removing one study at a time to assess any impact of studyquality on the effect estimates.

3. Results

3.1. Trial Flow. FromFigure 1we can see the flowchart studiesfrom the initial results of publication searches to the finalinclusion. Sixteen trials of Vaccinium berries versus controlfor serum lipids with 19 comparison arms including 1109patients were recruited in this meta-analysis. Reasons forexclusion mostly were nonrandomization, lack of control,insufficient original data, or baseline values.

3.2. Study Characteristics. Characteristics of each trial weregiven in Table 1. The population being studied were adultswith or without some chronic diseases. Means of interven-tions varied from berry juice to capsules containing berryextracts. Cranberry is introduced in 7 trials, blueberry in3 trials, bilberry in 4 trials, and whortleberry in 2 trials.The average intake of anthocyanins was up to 742mg andlength of treatment was ranging from 2 to 24 weeks. Threetrials recruited healthy subjects while thirteen includedparticipants with cardiovascular risk factors. Two studiesjust recruited female, one recruited male, and ten recruitedsubjects with both genders.

Evidence-Based Complementary and Alternative Medicine 3

Table 1: Characteristics of the 16 included studies.

Trials Country Subject Design Sample size(I/C dropouts) Cranberry form Dosage of

anthocyanins Control Lengthof study

Duthie et al.2006 [29] UK Healthy subjects Parallel 11/9 (0) Cranberry juice 2.1mg/d Placebo 2w

Valentova etal. 2007 [28]

CzechRepublic Healthy women Parallel 21/20/16 (8) Dried cranberry juice 2.6mg/d and

7.8mg/d Placebo 4w and8w

Wang et al.2007 [30] Taiwan Healthy subjects Parallel 20/20 Cranberry vinegar Not stated Placebo 10w

Lee et al.2008 [31]

TaiwanChina Type 2 diabetes Parallel 15/15 (0) Cranberry capsule Not stated Placebo 12w

Basu et al.2011 [32] USA Women with

metabolic syndrome Parallel 15/16 (5) Cranberry juice 24.8mg/d Placebo 8w

Dohadwala etal. 2011 [33] USA Coronary artery

disease Crossover 44 (3) Cranberry 94mg/d Placebo 4w

Flammer etal. 2013 [34] USA Cardiovascular risk

factors Parallel 32/37 (15) Cranberry juicecocktail 69.5mg/d Placebo 8w

Riso et al.2013 [35] Italy

Men withcardiovascular risk

factorsCrossover 18 (2) Blueberry drink 375mg Placebo 6w

Stull et al.2010 [36] USA Obese,

insulin-resistant Parallel 15/17 Blueberry smoothie 668mg/d Placebo 6w

Basu et al.2010 [37] USA Obese, metabolic

syndrome Parallel 25/23 (18) Blueberry beverage 742mg/d Placebo 8w

Erlund et al.2008 [38] USA Cardiovascular risk

factors Parallel 35/36 (1) Bilberry, lingonberry 299mg/d Placebo 8w

Qin et al.2009 [25] China Dyslipidemic subjects Parallel 60/60 Bilberry, blackcurrant 320mg/d Placebo 12w

Zhu et al.2013 [39] China Hypercholesterolemia Parallel 73/73 (4) Bilberry, blackcurrant 320mg/d Placebo 24w

Lankinen etal. 2014 [40] Finland Metabolic syndrome Parallel 37/34 Bilberry whole grain,

fish Not stated Wholegrain 12 w

Kianbakht etal. 2014 [41] Iran Hyperlipidemia Parallel 40/40 (25) Whortleberry 7.35mg/d Placebo 8w

Soltani et al.2014 [42] Iran Hyperlipidemia Parallel 25/25 (4) Whortleberry 90mg/d Placebo 4w

I: intervention group; C: control group.

3.3. Risk of Bias in Included Studies. The assessment ofrisk of bias is presented in Figure 2. All sixteen trials wereclaimed as randomized, but only five trails clearly describedhow randomization was achieved. The attempts to maskparticipants and researchers were reported in 5 studies and 4studies, respectively, but none of the trials reported maskingthe outcome assessors. Allocation concealment was clearlyadequate in 8 trials. None of the trials carried out ITTanalysis. The dropout rates for the trials ranged from 0 to27.3%. We considered two trials [37, 41] to have unclear riskof bias for this domain, as we could not determine whetherthe high dropout of more than 20% could have affected thetreatment estimates.

For other potential sources of bias, we focused on twoaspects, namely, baseline comparability and the financialsupport on trials. The intervention and control groups in alltrials were reported or appeared to be comparable at baseline

for the lipid levels. Seven trials reported that the studiesreceived financial support from nonprofitable organizationsuch as university research grant.

3.4. Effects of Interventions

3.4.1. Outcome: Total Cholesterol. Figure 3 shows no signif-icant differences between intervention and control groupsin total cholesterol were found for comparisons betweencranberry, blueberry, bilberry, and controls. However, twotrials [41, 42] that compared whortleberry with placeboshow significant differences between the treatments favour-ing whortleberry (mean difference = −1.44 (95% CI: −2.32,−0.56)mmol/L; 𝑃 = 0.001).

Sensitivity analyses revealed that the heterogeneity ofincluded studies in cranberry group on total cholesterol washighly affected by the study performed by Lee et al. Whenthis study was removed from the analysis, the heterogeneity


Trials identified as potentiallyrelevant and screened for retrieval

(n = 400)

Potentially appropriate trials formore detailed assessment (n = 52)

Full-text articles assessed for

eligibility

Search results (n = 5998)

Papers clearly not relevant

Studies included in meta-analysis(n = 16)

RCTs excluded because ofnonhuman study, review,

duplicates, and no Vacciniumberries in the intervention or

no lipids as the outcome

Studies excluded withreasons (n = 36)

intervention (n = 5)

on outcomes (n = 25)

(n = 3)

Other sources (n = 669)Total: n = 6667

(n = 6267)

(n = 348)

(i) Not RCT (n = 2)(ii) Other nutritional

(iii) Acute effect (n = 1)(iv) Incomplete information

(v) Redundant publications

(i) Cochrane Library (n = 190)(ii) PubMed (n = 2346)

(iii) EMBASE (n = 3462)

Figure 1: Flow diagram of trial selection.

changed from 68% to 0%. However, it showed no significantdifference on the total effect in the cranberry group.

3.4.2. HDL-C. Significant differences were found in HDL-C among studies in bilberry groups (mean difference = 0.12(95% CI: 0.07, 0.17)mmol/L; 𝑃 < 0.001) and whortleberrygroups (mean difference = 0.32 (95% CI: 0.26, 0.38)mmol/L;𝑃 < 0.001) while no obvious differences were observed inHDL-C levels among cranberry and blueberry groups (shownin Figure 4).

3.4.3. LDL-C. Statistical differences were found in compar-isons of Vaccinium berries versus control in LDL-C levels(mean difference = −0.20 (95% CI: −0.28, −0.12); 𝑃 <0.001). Particularly, bilberry (mean difference = −0.30 (95%CI: −0.44, −0.17)mmol/L; 𝑃 < 0.001) and whortleberry(mean difference = −0.71 (95% CI: −1.00, −0.41)mmol/L;𝑃 < 0.001) groups show more benefit comparing with othertreatments. Changes are also observed in cranberry groups(mean difference = −0.13 (95% CI: −0.26, −0.01)mmol/L; 𝑃 =0.04). However, results pooled for three placebo-controlledtrails in blueberry groups show no significant differencesbetween intervention and control groups (shown in Figure 5).

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Kianbakht et al., 2014

Soltani et al., 2014

Duthie et al., 2006

Flammer et al., 2013

Lee et al., 2008

Dohadwala et al., 2011

Basu et al., 2010

Basu et al., 2011

Riso et al., 2013

Stull et al., 2010

Lankinen et al., 2014

Qin et al., 2009

Wang et al., 2007

Zhu et al., 2013

Erlund et al., 2008

Valentov a et al., 2007 a

Valentov a et al., 2007 b

Valentov a et al., 2007 c

Valentov a et al., 2007 d

Figure 2: Methodological quality of included studies.

Sensitivity analysis revealed that the heterogeneity ofincluded studies in cranberry group on LDL-C was highlyaffected by the study performed by Lee et al. When this studywas removed from the analysis, the heterogeneity changedfrom 55% to 0%. It showed significant difference on the totaleffect in the cranberry group (𝑃 value changed from 0.04 to0.99). Considering the study performed by Lee et al. is of


35.7%28.1%36.2%

0.00 [−0.59, 0.59]0.00 [−0.82, 0.82]−0.05 [−0.62, 0.52]−0.02 [−0.39, 0.35]

3635602073

224

19.5%19.6%21.0%18.3%21.7%

0.946

0.9880.7030.84

40

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−0.198

0.086

0.669

1.141

40

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53.8%−2.061 0.982

−0.881 0.791

−1.86 [−2.23, −1.49]−0.97 [−1.51, −0.42]

IV, random, 95% CI IV, random, 95% CIMean difference Mean difference

1.1.1 Cranberry versus placebo−0.145

−0.052

−0.01

−0.4

0.098

0.10

0.10.3

Subtotal (95% CI)

Subtotal (95% CI)

Test for overall effect: Z = 0.53 (P = 0.59)

0.8511.0220.6530.290.390.850.660.920.75

4415

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2015

1619

18190

−0.1

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371523232323

213

9.8%

9.4%11.2%

13.4%12.6%

11.5%10.9%

10.2%11.0%

−0.27 [−0.86, 0.31]−0.05 [−0.49, 0.39]0.02 [−0.60, 0.64]−0.04 [−0.19, 0.12]

−−0.70 [−0.98, 0.42]0.20 [−0.27, 0.67]0.10 [−0.31, 0.51]0.10 [−0.45, 0.65]0.30 [−0.16, 0.76]−0.06 [−0.29, 0.17]




0.1

1.253

0.877

25

18

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0.2

−0.2

−0.53

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0.9170.8540.8990.9240.94

3537602073

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−0.07

−0.049−0.059−0.23

−0.050.1

−0.147−0.283−0.27

0.02 [−0.41, 0.45]0.10 [−0.33, 0.53]−0.10 [−0.44, 0.24]−0.22 [−0.73, 0.28]−0.04 [−0.33, 0.25]−0.04 [−0.21, 0.12]

Heterogeneity: 𝜏2 = 0.07; 𝜒2 = 24.73, = 8 (P = 0.002); I2 = 68%df




Favours experimental Favours control−4 −2 0 2 4

65 65 100.0% −1.44 [−2.32, −0.56]

Study or subgroup Mean SD Mean SDTotal Total WeightControlExperimental

100.0%

100.0%

100.0%

58Subtotal (95% CI)

Subtotal (95% CI)

46.2%

1.1.2 Blueberry versus placebo

1.1.3 Bilberry versus placebo

1.1.4 Whortleberry versus placebo

Duthie et al., 2006Flammer et al., 2013

Dohadwala et al., 2011Basu et al., 2011

Lankinen et al., 2014Qin et al., 2009

Zhu et al., 2013

Erlund et al., 2008

Basu et al., 2010Riso et al., 2013Stull et al., 2010

Wang et al., 2007


Valentov a et al., 2007 aValentov a et al., 2007 bValentov a et al., 2007 cValentov a et al., 2007 d


Lee et al., 2008

Figure 3: Forest plot of comparisons of Vaccinium berries versus control (outcome: total cholesterol).

medium quality and does not match the exclusion standard,we can only suggest that cranberry may have some effect onreducing LDL-C.

3.4.4. Triglycerides. No significant differences were foundin TG between groups for all comparisons except forthe comparisons between whortleberry and control groups(mean difference = −0.36 (95% CI: −0.49, −0.24)) (shown inFigure 6).

3.4.5. Side Effects. Two trials [32, 33] reported side effectsof nausea or dyspepsia in a small number of participants inthe intervention groups (1 and 2 people, resp.). Basu et al.[37] reported a dropout of 27% in intervention group due

to nausea, vomiting, constipation, or diarrhea. However, thenumber was appreciably similar to that in placebo groups(28% dropouts due to personal reasons). Four trials stated nohealthy complaints of participants. Four trials [25, 28, 35, 42]investigated the biomarkers of hepatic and renal functionsor hematology. All reported no changes in liver function,biochemistry, or hematology. The rest of nine trials did nothave adequate information about side effects.

3.4.6. Publication Bias. Funnel plots use Begg’s test [43]of trials to investigate the effect of Vaccinium berries oncholesterol (TC, LDL, and HDL) and triglyceride levels,indicating no publication bias except for total cholesterol(shown in Figure 7).


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0.216

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0.31

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−0.03 [−0.19, 0.13]−0.05 [−0.15, 0.05]0.02 [−0.21, 0.25]−0.12 [−0.41, 0.17]

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0.00 [−0.06, 0.06]0.00 [−0.18, 0.18]0.02 [−0.50, 0.54]

Study or subgroup Mean SD Mean SDTotal Total WeightControlExperimental Mean difference Mean difference

1.4.1 Cranberry versus placebo

000

0

0 0

0

0


0.23 [0.06, 0.40]0.08 [−0.10, 0.26]0.23 [0.05, 0.41]0.08 [−0.11, 0.27]

23

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58

0.00 [−0.14, 0.14]0.07 [−0.15, 0.29]

0.12 [0.03, 0.20]0.16 [0.09, 0.23]

Heterogeneity: 𝜒2 = 15.01, = 7 (P = 0.04); I2 = 53%df



Test for overall effect: Z = 4.82


Favours control

Subtotal (95% CI)

Subtotal (95% CI)

Subtotal (95% CI)

Subtotal (95% CI)

0.04 [−0.01, 0.10]

0.00 [−0.05, 0.05]

0.12 [0.07, 0.17]

0.38 [0.32, 0.45]0.02 [−0.12, 0.16]0.32 [0.26, 0.38]

100.0%

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100.0%

100.0%

0.08

(P < 0.00001)Heterogeneity: 𝜒2 = 20.65, df = 1 (P < 0.00001); I2 = 95%

Test for subgroup differences: 𝜒2 = 65.98, df = 3 (P < 0.00001); I2 = 95.5%


IV, fixed, 95% CI IV, fixed, 95% CI




Favours experimental


Duthie et al., 2006Flammer et al., 2013


Basu et al., 2010

Basu et al., 2011

Riso et al., 2013Stull et al., 2010

Lankinen et al., 2014Qin et al., 2009Zhu et al., 2013

Erlund et al., 2008



Lee et al., 2008

Figure 4: Forest plot of comparisons of Vaccinium berries versus control (outcome: HDL-C).

4. Discussion

4.1. Main Summary of Findings. Sixteen RCTs with nineteencomparison arms involving 1109 patients were included inthis review. The findings from two trials [41, 42] clearlyshow that whortleberry is significantly superior to placeboin lipid reduction, decreasing the TC, TG, and LDL-C andincreasing HDL-C at the same time. However, given that the𝐼2 values were high (86% in TC, 80% in TG, 80% in LDL-C, and 95% in HDL-C), the results should be interpretedwith caution. Differences in the daily doses and sources ofanthocyanins, age of subjects, and lipids baseline values aswell as the different durations of the trials might contribute tosome extent to the observed statistical heterogeneity. Besides,bilberry groups show significant differences in reducing

LDL-C and increasing HDL-C in comparison with othertreatments. The lipids-lowering properties of anthocyaninshave been linked to the inhibition of cholesteryl ester transferprotein and the suppression of LDL oxidation, as well asimprovement in HDL-associated paraoxonase 1 activity [15,25, 39, 44]. For many other Vaccinium subclasses or othercomparison groups, there was insufficient evidence to drawconclusions about efficacy.

Valentova et al. [28] compared dried cranberry juice withplacebo in lipids reducing effects in two different antho-cyanins doses (400mg/d and 1200mg/d) and two differentdurations (4 weeks and 8 weeks). However, no significantchanges were found in four comparison arms, showing nodose-response and time-response effects. These may be dueto the poor absorption of anthocyanins. Various berry (but



−0.19

−0.19

16

44

9

15

23

23

23

23176158

−0.23 [−0.71, 0.24]

− −0.60 [−0.88, 0.32]0.08 [−0.29, 0.45]

0.03 [−0.34, 0.39]

−

−

0.01 [−0.32, 0.30]

−0.01 [−0.32, 0.30]

−0.18 [−0.77, 0.41]

−0.2−0.4

0.1

58

65

(P < 0.0001)

65



0

0 0

0


0.10 [−0.31, 0.51]

58






Subtotal (95% CI)

Subtotal (95% CI)

Subtotal (95% CI)

Subtotal (95% CI)

0.13 [− −0.26, 0.01]100.0%

14.9%6.3%

100.0%

100.0%

100.0%Heterogeneity: 𝜒2 = 5.06, df = =

=

1 (P 0.02 ); I2 = 80%

Test for subgroup differences: 𝜒2 = 19.97, df = 3 (P 0.0002); I2 = 85.0%

−2 −1 0

Favours experimental Favours control1 2

−0.129

−0.38

−0.4

−0.02

−0.11

−0.09

−0.2

0.673

0.853

0.652

0.387

0.7

0.51

0.71

0.49

15

15

15

44

11

20

19

16

18

0.103

−0.2

−0.026

0.2

−0.1

−0.1

0.678

0.895

0.687

0.387

0.52

0.52

0.52

0.52

7.2%12.2%4.6%21.2%11.7%16.6%9.8%16.8%

0.9540.279

2518 −0.2

−0.38

0.961.1140.27

231817

0.5

0.5

78.8%

0.10 [−0.34, 0.54]0.00 [−0.68, 0.68]0.02 [−− 0.21, 0.17]

−0.00 [−0.17, 0.17]

−0.499

−0.27

−0.35

0.7

0.904

0.695

0.52

37

25

20

73155

−0.031

0.004

0.01

0.8

0.962

0.663

35

25

20

73153

15.2%6.9%10.4%67.4%

0.00 [−0.35, 0.35]

0.27 [−− 0.69, 0.15]0.47 [−− 0.99, 0.05]

−0.30 [−0.44 −0.17, ]− −0.36 [−0.53, 0.19]

−1.429−0.296

1.1250.667

4025

−0.370.085

0.7850.807

4025

48.2%51.8%

[−1.48, ]1.06− 0.63−0.38 [−− 0.79, 0.03]

−0.71 [−1.00 −0.41, ]

(P < 0.00001)Test for overall effect: Z = 4.70




Duthie et al., 2006Dohadwala et al., 2011

Basu et al., 2010

Basu et al., 2011


Lankinen et al., 2014Qin et al., 2009Wang et al., 2007Zhu et al., 2013




Lee et al., 2008

Figure 5: Forest plot of comparisons of Vaccinium berries versus control (outcome: LDL-C).

nor cranberry) anthocyanin glycosides have been foundto be absorbed and excreted into urine unmetabolized byboth human beings and animals. Only 0.1% of the amountingested was excreted into the urine [45]. Ohnishi et al.[46] recently found that cranberry anthocyanins are excretedinto urine at a total amount of 5% of the dose consumedwithin 24 h with a maximum excretion period between 3and 6 h after consumption. Additional speculation is that themost abundant active material may not necessarily producethe highest concentrations of biologically active ingredients.Future studies should focus on the acute effect of antho-cyanins, trying to find its clinical relevant endpoint. Besides,as for bilberry and whortleberry, we need to explore thedose-dependent effect of anthocyanins and verify whethersynergistic effects are necessary with some other nutrients.

4.2. Strengths and Limitations. The importance of antho-cyanins as a part of heart healthy diet has been widely proved.Purified anthocyanins mixture reduced the inflammatoryresponse in hypercholesterolemic subjects [39] and con-sumption of thewild blueberry drink for 6weeks significantlyreduced the levels of oxidized DNA bases and increased theresistance to oxidatively induced DNA damage [35]. Epi-demiology studies support the protective effect of cranberryand blueberry on urinary tract infection [47–49]. As far aswe know, this report is the first systematic review assessingthe effectiveness of the range of Vaccinium subclasses richin anthocyanins on lipid improvement within RCTs. Thissystematic review, the most comprehensive to date, includesa quantitative pooling of results and assessment of risk of biasof included studies.


15

15

44

11

32

20

19

1618

190

16

44

379

15

23

23

2323

213

0.11 [0.01, 0.21]−0.03 [−0.31, 0.24]

−0.10 [−0.54, 0.34]

0.25 [−0.06, 0.56]0.17 [−0.12, 0.47]

0.50.5

0.13 0.679

2518

15

58

3735

6020

73225

35

36

25

40

602073

224

6525

40

65


00


−0.02 [0.36, 0.32]−0.06 [−0.35, 0.23]

−0.10 [−0.46, 0.26]−0.10 [−0.68, 0.48]

−0.10 [−0.54, 0.34]

−0.03 [−0.33, 0.27]

− −0.32 [−0.45, 0.19]− −0.87 [−1.32, 0.41]

−0.03

−0.11

[−0.39, 0.32]−0.08 [−0.40, 0.25]

−0.02 [ 0.31, 0.35]0.03 [−0.29, 0.35]

58

0.00 [−0.34, 0.34][−0.46, 0.24]





Heterogeneity: 𝜒2 = 0.25, = 4 (P = 0.99);(P = 0.52)

I2 = 0%df

Favours experimental Favours control

Subtotal (95% CI)

Subtotal (95% CI)

Subtotal (95% CI)

Subtotal (95% CI)

0.08 [0.01, 0.15]

−0.10 [−0.35, 0.15]

−0.05 [−0.20, 0.10]

− −0.36 [−0.49, 0.24]

100.0%

100.0%

100.0%

100.0%

(P < 0.00001)Heterogeneity: 𝜒2 = 5.07 , df = 1 (P 0.02 ); I2 == 80%

Test for subgroup differences: 𝜒2 = 35.31, df = 3 (P < 0.00001); I2 = 91.5%



−1 −0.5 0.5 10

0.068

−0.023

−0.14

−0.03

−0.02

−0.1

−0.1

−0.1

0.24

0.073

0.16

0.613

0.369

0.584

0.774

0.55

0.4

0.510.53

0.011

−

−

0.01

−0.044

0.102

−0.08

−0.08

−0.05−0.05

0

0.1130.6890.3460.6590.3870.570.570.520.52

56.6%7.3%5.5%6.3%2.8%4.8%6.3%5.1%5.2%





0.1

0.1

0.23

0.96

0.6

0.985

23

18

17

32.8%48.5%18.7%

−0.05

−0.643−0.786

−−

0.11

0.5760.7210.9750.0950.4940.91

0.060.10.1

−0.061−0.033

−0.323

−0.07

0.8940.7550.987

0.2420.949 0.081

0.560.93

0.350.68

18.1%18.9%17.8%20.5%24.7%

7.7%92.3%

Duthie et al., 2006Flammer et al., 2013Lee et al., 2008


Basu et al., 2010

Basu et al., 2011


Lankinen et al., 2014Qin et al., 2009Wang et al., 2007Zhu et al., 2013

Erlund et al., 2008




Figure 6: Forest plot of comparisons of Vaccinium berries versus control (outcome: triglycerides).

The shortcomings of the sixteen trials are represented inFigure 2. Several trials failed to contain adequate method-ological information, such as method of randomization,allocation concealment, blinding, funding, and dropouts,which are essential for assessing risk of bias. In conclusion,the included studies have moderate risk of bias. In addition,since purified anthocyanins extracted from berries used byQin et al. [25] and Zhu et al. [39] and berry diets inother researches both show the lipids reducing effect, it isnot clear whether the anthocyanins themselves (rather thanother bioactive substances) are solely or partially responsiblefor the observed effects, since the specific biological activeingredients mediating the lipids improvement of the berriesbelonging to the Vaccinium genus are not yet characterized.In addition, even though we have undertaken extensive

searches for published material, we still could not excludethe possibility that studies with negative findings remainunpublished.

5. Conclusion

5.1. Implications for Practice. Results from this reviewprovidesome evidence of the beneficial effects of bilberry andwhortleberry on lipids reduction. However, recommendingbilberry and whortleberry for lowering lipids levels is notjustifiable on current evidence because of the limited data. Asobjects in whortleberry group are diagnosed hyperlipidemiapatients whereas not all of the objects in other groups exhibitdyslipidemia, we cannot draw the conclusion that other typesof Vaccinium berries have no effect on lipids lowering. In


SE o

f cha

nge i

n m

ean

TC

Change in mean TC (mmol/L) Change in mean HDL-C (mmol/L)

Change in mean LDL-C (mmol/L) Change in mean TG (mmol/L)

SE o

f cha

nge i

n m

ean

HD

L-C

SE o

f cha

nge i

n m

ean

LDL-

C

SE o

f cha

nge i

n m

ean

TG

−4 −2

−2 −1 −1

0

0

2

1 0.5

−0.5

−0.5

−0.25 0

0

0.250.5

0.1

0.2

0.3

0.4

Cranberry versus placeboBlueberry versus placebo

Bilberry versus placeboWhortleberry versus placebo

SubgroupsCranberry versus placeboBlueberry versus placebo


Subgroups

Cranberry versus placeboBlueberry versus placebo


SubgroupsCranberry versus placeboBlueberry versus placebo


Subgroups

0

0.5

0.1

0.2

0.3

0.4

0

0.5

0.1

0.2

0.3

0.4

0

SE (MD)

SE (MD)

0.5

0.1

0.2

0.3

0.4

0 SE (MD)

SE (MD)

MD

MD

MD

MD

Figure 7: Funnel plots of trials included in the meta-analysis on the effect of Vaccinium berries on TC, HDL-C, LDL-C, and TG.

addition, although whortleberry can reduce serum lipids,it cannot always lower the lipids to the normal level asstatins do, so it can be just recommended as an adjunctinstead of replacement. More studies are needed beforethese berries can be widely recommended for cardiovascularhealth. Anyway, adding some berries in our daily diets is goodfor human health.

5.2. Suggestion to Future Trails. The included trials wereall small and had methodological problems. Further trialsshould be designed rigorously with large sample sizes toconfirm the effectiveness of Vaccinium berries for lipidsimprovement. Besides, further researches need to assessdose-response effects, be of adequate duration, and reportall primary outcomes. Additionally, anthocyanins are com-monly consumed as part of a normal diet, and a future focuson purified anthocyanins extracted from different subclassesof Vaccinium is needed to determine their specific lipids-lowering effects.

Disclosure

Yitong Zhu, Ya Miao, and Zheying Meng are co-first authors.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

Acknowledgments

This study was supported by grants from Natural ScienceFoundation of China (81300933) and Science and Technol-ogy Commission of Shanghai Municipality (13JC1401504).The authors thank Hongliang Tian (from Evidence-BasedMedicine Center, School of Basic Medical Sciences, LanzhouUniversity) for his generous advice.

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