The effects of macro‐algae supplementation on serum lipid, glycaemic control and anthropometric indices: A systematic review and meta‐analysis of clinical trials

Abstract Introduction Macro‐algae products have been shown to ameliorate the metabolic disorders state. Thus, highlighting their function as supplementary therapeutic agents can be a novel strategy for clinical therapies. This systematic review and meta‐analysis of clinical trials aimed to summarize the effect of macro‐algae consumption on serum lipid profile, glycaemic control and anthropometric factors. Methods In this systematic review and meta‐analysis, a comprehensive search was performed for relevant studies published up to May 2023. The Cochran's Q test and I‐square (I 2) tests were used to evaluate heterogeneity across the included studies. The meta‐analysis was conducted using random‐effects model (DerSimonian and Laird), and weighted mean difference (WMD) was considered as the pooled effect size. Results Out of 8602 papers in the initial screening, eight clinical trials with a total of 438 participants were included into this meta‐analysis. The results indicated that macro‐algae supplementation significantly decreased serum levels of total cholesterol (TC) (WMD = −6.7 mg/dL; 95% CI: −12.59, −0.80; item = 0.026) and low‐density lipoprotein cholesterol (LDL‐c) (WMD = −8.25 mg/dL; 95% CI: −15.38, −1.12; p‐value = .023). There was an increase in level of high‐density lipoprotein cholesterol (HDL‐c) (WMD = 0.48 mg/dL; 95% CI: −2.05, 3.01; p‐value = .71) which was not statistically significant. Macro‐algae supplementation reduced body mass index (BMI) (WMD = −0.28 kg/m2; 95% CI: −0.96, 0.41; p‐value = .426), weight (WMD = −0.39 kg; 95% CI: −3.6, 2.83; p‐value = .81), waist circumference (WC) (WMD = −0.52 cm; 95% CI: −2.71, 1.66; p‐value = .64), fasting blood sugar (FBS) (WMD = −1.95 mg/dL; 95% CI: −5.19, 1.28; p‐value = .24) and HbA1c (WMD = −0.02%; 95% CI: −0.14, 0.09; p‐value = .66) in intervention group. Conclusions This meta‐analysis indicated that macro‐algae supplementation significantly decreased TC and LDL‐c level. It can also increase HDL‐c level and reduce anthropometric indices and glycaemic control factors.


| INTRODUC TI ON
Prevalent chronic diseases such as diabetes mellitus (DM), cardiovascular disorders and obesity are associated with higher mortality rate worldwide. 1,2 For instance, type 2 diabetes has become one of the most important metabolic diseases with a prevalence rate of 9%. 3,4 The common complications linked to the these diseases are hyperglycaemia, insulin resistance, inflammation, heart failure and stroke. 5 Many factors such as lifestyle and dietary components may influence on diabetes. 6,7 For example, regular consumption of fruits and vegetables as rich sources of natural antioxidants were reported to decline the risk of DM. In addition, antioxidant compounds like polyphenols have hypoglycaemic effects through the inhibition of carbohydrate digestive enzymes and improving the sensitivity of tissues to insulin hormone. [8][9][10] Finding alternative functional supplements such as antioxidant compounds to improve the quality of clinical therapies may have beneficial effects against the side effects of chemical drugs.
Recent studies indicated that seaweed polyphenols may have higher biological and pharmacological properties in comparison with other plant-derived phenolic compounds. [10][11][12][13] Algae polyphenolrich extracts (APREs) were reported to improve the blood glucose and serum lipids levels in a concentration-dependent manner. [14][15][16] Interestingly, algal products had no significant side effects 17 and may be considered as a safe supplementary ingredient for clinical recommendations. Similarly, non-toxic plant polyphenols are supposed to have a wide range of antidiabetic and anti-obesity biological properties. 9,18,19 Recently, marine milieu received more attention as a new sources of active components for enhancing the quality of diet against chronic diseases. 20 Some edible macroalgae such as Ascophyllum nodosum, Ecklonia cava, Ascophyllum nodosum and Fucus vesiculosus have been reported to contain large amounts of polyphenols in their structures. [21][22][23] Clinical studies also indicated that the consumption of edible seaweed may be effective against metabolic syndrome by modulating a variety of molecular signalling pathways. 14,17,24 However, the effectiveness of these marine products have not been comprehensively evaluated. So, this systematic review and meta-analysis aimed to assess the effect of macro-algae and marine polyphenols (MPs) on serum lipid levels, glycaemic profile and body mass index (BMI).

PRISMA guidelines (Preferred Reporting Items for Systematic
Reviews and Meta-Analyses) were applied as a framework for reporting this meta-analysis of Randomized Clinical Trials (RCTs). 25 The authors systematically searched the online databases including Scopus, Embase, PubMed, ProQuest and ISI for relevant clinical trials that investigated the effects of macro-algae supplementation on human lipid profiles, fasting blood glucose (FBG), HbA1c and anthropometric factors from the inception up to May 2023. The searches were conducted using the following Mesh keywords: ('Seaweed' OR 'macro-algae' OR 'marine algae') AND ('Clinical Trials as Topic' OR 'intervention' OR 'intervention*' OR 'trial' OR 'randomized' OR 'placebo' OR 'random' OR 'randomly' OR 'assignment' OR 'clinical trial' OR 'parallel' OR 'cross-over' OR 'RCT'). Additionally, a manual search of reference lists was performed to collect the studies that were not included by the online search.

| Inclusion and exclusion criteria
After removing all duplicates reports, two authors (SH. R and S. GH) carefully screened all collected papers according the titles and abstracts to find eligible studies. Next, all eligible studies were categorized based on their findings and contents. Authors (S. GH and M. Z) carefully checked all papers independently and only studies which met the following criteria were included in this meta-analysis: (i) articles in English language, (ii) papers which included population higher than 18 years old, (iii) RCTs, (iv) papers with enough data (i.e., mean SD [standard deviation], SE [standard error] and CI [confidence interval]) parameters in the beginning and the end of study for both intervention and control participants to measure the targeted factors including glucose and lipid profiles, and (v) intervention duration was equal or higher than 1 week. The outcomes were included in the final analysis if the number of documents related to the outcome was equal or more than three documents. Studies were also excluded if they investigated animal models, published as conference abstract, book chapter, editorials, and patents, or reported insufficient data about the outcome.

| Data extraction
The following data of selected articles were separately extracted by two authors (SH. R and S. GH), using a standard form included: the name of the first author, study place, the number of participants involved in both the intervention and control groups, the type and dose of supplementation with alga (g/day or mg/day), algal polyphenol concentration (mg/day), duration of intervention, the age and sex of the participants, type and design of the study, the outcomes of algal products supplementation and the related data for meta-analysis.

K E Y W O R D S
glycaemic control, integrative medicine, lipid profile, macro-algae, meta-analysis

| Quality assessment
Sh. R and Z. M assessed the quality of eligible included studies using Cochrane collaboration risk of bias tool. 17 Discrepancies between the researchers at each stage of quality assessment were resolved based on consensus or discussion with a third author (R. T).

| Statistical analysis
Stata version 13.0 (Stata Corp LP) was applied to perform statistical analysis. Random-effects model was employed with a 95% confidence interval (CI) for the calculation of the pooled weighted mean difference (WMD). The value of mean and SD was recorded for each result in the beginning and the end of the study using the calculation of the difference between the values before/after the intervention. The mean differences for the unreported SDs were calculated by applying the following formula: In addition, r was calculated and estimated between 0 and 1 values. 26 Besides, the formula = SE × √ n, where n = the number of individuals in each group, was used to measure SD parameter in those cases that reported SE instead of SD. The statistical heterogeneity

| RE SULTS
The process of the identification of the related studies is presented in Figure 1.   Table 2 shows the certainty of body evidence regarding outcomes using a modified GRADE approach. The certainty of the evidence was evaluated as moderate in two outcomes, low and very low for three considered outcomes. The presence of the risk of bias, indirectness and imprecision were the main factors downgrading the certainty of the evidence.

F I G U R E 3
Forest plot assessing the effect of seaweed supplementation on studied outcomes (the p-values are related to heterogeneity not outcomes).

| DISCUSS ION
The results of this meta-analysis of RCTs indicated that macro-algae supplementation significantly reduced TC and LDL-C concentra- ways. 35 Also, this extract decreased body weight gain and induced antioxidant defence systems in studied animals. In another paper, Kojima-Yuasa 11 described that the phenolic compounds of E. cava are effective agents for decreasing the blood glucose level and preventing hyperglycaemia-induced oxidative stress. Herein, the outcomes of this meta-analysis identified that the short-term consumption of whole product of brown macro-algae or its polyphenol-rich extracts could increase the level of HDL-C and decrease the level of TC, LDL-C and glycaemic control profiles. In addition, these macro-algae products also improved anthropometric factors but the result was not statistically significant.
In recent systematic review by Murray et al., 36 authors described that algal phenolic compounds could relatively reduce the level of FBG, TC and LDL in patients, which was in line with this study. 36 From these results, it seems that APREs are effective against blood glucose level and serum lipid profile, and therefore, these functional marine ingredients can be potential sources of supplementary agents for improving the health status of diabetic and obese patients or individuals suffered from cardiovascular disorders. As mentioned previously, inconsistent effects were observed on the effects of APREs on BMI, and this type of supplementation has apparently few or no effects on these parameters.
In addition, short-term macro-algae supplementation had no significant effect on triglyceride, HDL-c and anthropometric factors.
No clear mechanism has been reported in the literature, and further long-term clinical studies will be required to accurately determine

| CON CLUS ION
The outcomes of the current meta-analysis suggest that the short-

ACK N O WLE D G E M ENTS
The authors would like to thank Shiraz University of Medical Science and MBRC to financially support the current study as well as Mr. H.

Rasouli and Professor Dianna Magliano for their recommendations
during preparing the final draft of the current paper.

FU N D I N G I N FO R M ATI O N
Funding for this study was provided by Shiraz University of Medical Sciences.

CO N FLI C T O F I NTE R E S T S TATE M E NT
All authors read the manuscript before the submission process, and they declared that there was no conflict of interest to list their name in this paper.

DATA AVA I L A B I L I T Y S TAT E M E N T
All data will be made available upon request.

E TH I C S S TATEM ENT
The study was approved by the ethics committee of Shiraz University of Medical Sciences, Shiraz, Iran.