Numerous epidemiological studies have indicated a steep rise in cardiovascular disease (CVD) associated morbidity and mortality in Indians, majorly due to increased prevalence of hypertension, dyslipidemia, and insulin resistance in this population. Dyslipidemia is a modifiable risk factor of CVD and hence measurement of plasma lipids would help in identifying people at risk for CVD. According to the Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study, one of the largest studies conducted in India on individuals at risk for diabetes, the prevalence of various dyslipidemia in rural Indian population is 79% with predominantly high incidences of hypo high-density lipoprotein (HDL) cholesterol levels (72.3%) [
Plant polyphenols are abundantly found in the human diet and are known to possess various therapeutic potencies with a low number of side effects. Several natural compounds have shown encouraging results in modulating atherogenic lipid levels. Anthocyanins are class of polyphenols widely found in pigmented fruits and vegetables [
The Cochrane Handbook for Systematic Reviews of Interventions was used to plan and conduct this meta-analysis [
Literature search was performed using electronic databases: MEDLINE, EMBASE, PubMed, CINAHL, and the Cochrane Trial Register from inception to July 2017 using the search strategy presented in the online Supplementary Table
Flow diagram of the study selection process.
We included RCTs involving any population (healthy or diseased) that examined the effects of dietary crude or purified anthocyanin supplementations compared with placebo on lipid and inflammatory marker levels. Literature search was completed independently by both investigators, to identify studies meeting criteria for inclusion with contradictions being settled by repeat review and discussion. The studies included in the analysis were based on the following criteria: (1) RCTs that investigated the effects of supplementing dietary/purified anthocyanins on TC, TG, LDL, HDL, apolipoprotein A1, apolipoprotein B, hs-CRP, TNF-∞, and IL-6; (2) studies reporting the details of the anthocyanin dosage in terms of extract or purified form; and (3) studies mentioning at least 4 weeks of anthocyanin treatment were included in the analysis. Details retrieved from related publications were first author, years of data collection, year of publication, number of participants, age and sex of participants, administered daily dose of anthocyanin, study design, treatment duration, and mean and standard deviations of lipid profile and inflammatory markers in placebo and treatment group. Both the reviewers (Komal Shah and Pratik Shah) independently assessed the risk of bias as recommended by the Cochrane Handbook for Systematic Reviews of Interventions [
Changes in lipid levels and inflammatory markers associated with anthocyanin intake were extracted from each study in terms of mean difference (MD) with 95% CI levels. Based on Cochrane Handbook, the mean difference “the estimate of amount by which the experimental intervention changes the outcome on average compared with the control” was considered for the calculations. The difference between the change-from-baseline values for the anthocyanin and the placebo arms was derived from each trial for the end points of TC, TG, LDL, HDL, apolipoprotein A-1, apolipoprotein B, hs-CRP, TNF-∞, and IL-6. The formula for mean difference was typically derived by calculating change-from-baseline treatment and change-from-baseline control. Lipid levels which were expressed as mmol/L were converted to mg/dL (conversion factors for TC, HDL-C, and LDL-C = 38.67; TG = 88.545). Sources of heterogeneity were further explored using sensitivity and subgroup analysis. Subgroup analysis was performed by stratifying the studies based on participant’s health status (healthy versus diseased) and source of anthocyanin (dietary versus supplement). For sensitivity analysis trials were removed based on risk of bias rating as previously described by Higgins and Green [
The initial search revealed 412 articles of which 38 were reviewed in full with 17 meeting inclusion criteria and were meta-analyzed (Figure
Demographic and baseline parameter details of the studies included in the meta-analysis.
Study/year | Country | Intervention length | Population | Setting | Sources of anthocyanin | Sample size | Design | Anthocyanin dose | TC, mg/dL (mean ± SD) | TG, mg/dL (mean ± SD) | LDL, mg/dL (mean ± SD) | ||||
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Anthocyanin | Placebo | Anthocyanin | Placebo | Anthocyanin | Placebo | Anthocyanin | Placebo | ||||||||
Yang et al., 2017 [ |
China | 12 wk | Untreated diabetes | O | Capsule Medox (17 natural anthocyanins) | 80 | 80 | R, D, P | 80 mg |
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Zhang et al. 2016 [ |
China | Wk (12, 24) | Hypocholesterolemic | I | Capsule | 73 | 73 | R, D, P | 320 mg |
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Zhang et al., 2015 [ |
China | 12 wk | Nonalcoholic fatty liver disease | I | Bilberry, black current | 74 | 74 | R, D, P | 80 mg |
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Li et al., 2015 [ |
China | 24 wk | Diabetic | I | Capsule Medox (17 natural anthocyanins) | 29 | 29 | R, D, P | 80 mg |
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Davinelli et al., 2015 [ |
Italy | 4 wk | Smokers | O | Capsule (Maqui berry extract) | 16 | 26 | R, D, P | 273.5 mg |
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Lynn et al., 2014 [ |
UK | 6 wk | Healthy adult | O | Tart cherry juice | 25 | 21 | R, D, P | 162 mg |
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- | - | - | - |
Soltani et al., 2014 [ |
Iran | 4 wk | Hyperlipidemic patients | I | Fresh ripe berries of |
25 | 25 | R, D, P | 90 mg |
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Hassellund et al., 2013 [ |
New York | 12 wk | Prehypertensive men | I | Bilberry, black current | 26 | 26 | R, D, P | 500 mg | - | - | - | - | - | - |
Zhu et al., 2013 [ |
China | 24 wk | Hypocholesterolemic | O | Anthocyanin rich foods | 73 | 73 | R, D, P | 320 mg |
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Zhu et al., 2011 [ |
China | 12 wk | Hypocholesterolemic | O | Bilberry, black current | 73 | 73 | R, D, P | 320 mg |
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- | - |
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Dohadwala et al., 2011 [ |
Boston | 4 hr | Coronary artery disease | I | Cranberry juice | 22 | 22 | R, D, P | 94 mg |
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Basu et al., 2010 [ |
Oklahoma | 8 wk | Metabolic syndrome | I | Bilberry | 25 | 22 | R, D, P | 320 mg | - | - | - | - | - | - |
Mu et al., 2010 [ |
China | 12 wk | Hyperlipidemic patients | I | 30 | 28 | R, P | 200 mg |
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Curtis et al., 2009 [ |
UK | 12 wk | Healthy women | I | Elderberry | 26 | 26 | R, D, P | 500 mg |
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Qin et al., 2009 [ |
China | 12 wk | Dyslipidemic patients | I | Capsule Medox (17 natural anthocyanins) | 60 | 60 | R, D, P | 80 mg |
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Qin and Wenhua 2008 [ |
China | 45 days | Hyperlipidemic patients | I | Black rice | 51 | 51 | R, P | 200 mg |
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Karlsen et al., 2007 [ |
Norway | 3 wk | Healthy adults | O | Capsule Medox (17 natural anthocyanins) | 59 | 59 | R, D, P | 300 mg | - | - | - | - | - | - |
Study/year | Country | HDL, mg/dL (mean ± SD) | Apolipoprotein A-1, mg/dL (mean ± SD) | Apolipoprotein B, mg/dL (mean ± SD) | Serum TNF-a, pg/mL | Serum IL-6, pg/mL | Serum hs-CRP, mg/L | ||||||
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Anthocyanin | Placebo | Anthocyanin | Placebo | Anthocyanin | Placebo | Anthocyanin | Placebo | Anthocyanin | Placebo | Anthocyanin | Placebo | ||
Yang et al., 2017 [ |
China |
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Zhang et al. 2016 [ |
China |
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- | - | 1.74 (0.86–2.6) | 2.19 (0.93–3.82) |
Zhang et al., 2015 [ |
China |
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- | - | - | - | - | - | - | - | - | - |
Li et al., 2015 [ |
China |
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Davinelli et al., 2015 [ |
Italy |
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- | - | - | - | - | - | - | - |
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Lynn et al., 2014 [ |
UK | - | - | - | - | - | - | - | - | - | - | - | - |
Soltani et al., 2014 [ |
Iran |
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- | - | - | - | - | - | - | - |
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Hassellund et al., 2013 [ |
New York | - | - | - | - | - | - | - | - | - | - | - | - |
Zhu et al., 2013 [ |
China |
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- | - | - | - |
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- | - | - | - |
Zhu et al., 2011 [ |
China |
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- | - | - | - | - | - |
Dohadwala et al., 2011 [ |
Boston |
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- | - | - | - | - | - | - | - |
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Basu et al., 2010 [ |
Oklahoma | - | - | - | - | - | - | - | - | - | - | - | - |
Mu et al., 2010 [ |
China |
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- | - | - | - | - | - | - | - | - | - |
Curtis et al., 2009 [ |
UK |
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- | - | - | - |
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Qin et al., 2009 [ |
China |
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- | - | - | - | - | - |
Qin and Wenhua 2008 [ |
China |
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- | - | - | - | - | - | - | - | - | - |
Karlsen et al., 2007 [ |
Norway | - | - | - | - | - | - | - | - |
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- | - |
TC: total cholesterol, TG: triglyceride, LDL: low density lipoprotein, HDL: high density lipoprotein, O: outpatients, I: outpatients, R: randomized, D: double blind, and P: parallel trial.
Individual study estimates as well as the overall estimate of anthocyanin effect on various lipid parameters is presented in Figures
Forest plot for anthocyanin versus placebo group changes in (a) total cholesterol, (b) HDL cholesterol, (c) LDL cholesterol, and (d) triglyceride. Pooled effect estimates are shown as diamonds and data are expressed as mean differences with 95% CI. Interstudy heterogeneity was tested by using the Cochran
Forest plot for anthocyanin versus placebo group changes in (a) apolipoprotein A1 and (b) apolipoprotein B. Pooled effect estimates are shown as diamonds and data are expressed as mean differences with 95% CI. Interstudy heterogeneity was tested by using the Cochran
Figure
Forest plot for anthocyanin versus placebo group changes in (a) TNF-∞, (b) IL-6, and (c) hs-CRP. Pooled effect estimates are shown as diamonds and data are expressed as mean differences with 95% CI. Interstudy heterogeneity was tested by using the Cochran
Publication bias were assessed by Egger’s and Begg and Mazumdar rank correlation tests and funnel plot (Figures
Funnel plot for anthocyanin versus placebo group for assessment of publication bias in (a) total cholesterol, (b) HDL cholesterol, (c) LDL cholesterol, (d) triglyceride, (e) apolipoprotein A-1, and (f) apolipoprotein B.
Funnel plot for anthocyanin versus placebo group for assessment of publication bias in (a) TNF-
To the best of our knowledge, this is the first meta-analysis showing association of anthocyanin supplementation with inflammatory markers based on RCTs. Our findings suggested that except for TC levels all other lipid abnormalities are positively influenced by anthocyanin supplementation from either crude dietary or purified sources. Similarly, the levels of inflammatory markers (significant for TNF-∞ and nonsignificant for IL-6 and hs-CRP) were also found to reduce with anthocyanin treatment. Earlier Yang et al. [
Growing body of evidence has suggested a protective role of anthocyanins in humans and this effect is multifactorial. Chronic inflammation and lipid accumulation in the arteries are prime triggers for the development of atherosclerosis. Scattered reports have indicated a role of anthocyanins in improving the inflammatory and redox status of the system, reducing insulin insensitivity and lipid abnormalities. Few proposed mechanisms of action of anthocyanin are [
The current meta-analysis suffers from a limitation of significant heterogeneity in terms of the population being studied for effect of anthocyanin on lipid and inflammatory markers. We have included all the studies reporting the role of anthocyanin in improving lipid and inflammatory profile in healthy, dyslipidemic, hypertensive, and cardiovascular disease and metabolic syndrome patients. One major limitation of the study is the lack of available evidence (trials) reporting the effect of anthocyanin on few of the lipid and inflammatory parameters (apolipoproteins and hs-CRP, IL-6), which may have contributed in the nonsignificant association of these markers with anthocyanin supplementation. Hence, to substantiate these findings extensively large trials with greater sample sizes are needed to confirm the potential of anthocyanins in reducing TC, IL-6, and hs-CRP.
The present meta-analysis postulates a positive impact of anthocyanin supplementation on lipid profile and inflammatory markers. However, future trials are highly advocated in order to propose any recommendations, especially in case of inflammatory markers.
The authors declare that there are no conflicts of interest.
Supplementary Table 1: search strategy for studies assessing the effect of anthocyanin consumption on lipid and inflammatory marker levels in RCTs. Supplementary Table 2: Cochrane risk of bias. Supplementary Table 3: subgroup analysis. Supplementary Table 4: sensitivity analysis.