Analysis of Beneficial Effects of Flavonoids in Patients with Atherosclerosis Risk on Blood Pressure or Cholesterol during Random Controlled Trials: A Systematic Review and Meta-Analysis

Round 1

Reviewer 1 Report

The article presented for review concerns beneficial effect of flavonoids in patients at risk of atherosclerosis on blood pressure or cholesterol during randomized controlled trials. The manuscript presented for review is a review of data from randomized, controlled clinical trials involving patients, based on a meta-analysis.

Unfortunately, the manuscript is based only on 19 articles and a very short (half a month) data review period. The selected articles from the Scopus and PubMed databases covered only the period from April 1, 2023 to April 15, 2023. This is clearly an insufficient amount of data for a meta-analysis. Additionally, the topic of the role of flavonoids in the prevention of cardiovascular diseases, including atherosclerosis, and their beneficial effect on the lipid profile (including total cholesterol and its LDL fraction) and blood pressure is nothing new.

Taking into account the above, this is grounds for rejecting the article in this form.

Author Response

We thoroughly reviewed each of the comments and recommendations of all reviewers and addressed each of the mentioned points in the previous letter. Now, these revisions have significantly improved the quality and comprehensibility of our manuscript.

Regarding your specific comments on our work we would like to kindly give a response to every point.

1.-Unfortunately, the manuscript is based only on 19 articles and a very short (half a month) data review period.

A: In the literature, meta-analyses have ben accepted as level 1 evidence including even 8 analyzed articles (ref 41 of the manuscript) up to 133 articles (ref 15 of the manuscritp). The mean number of articles is between 10 and 20 on this topic, so we think that including 19 articles in our meta-analysis is a very valid and meaningful number to be analyzed.

2.-The selected articles from the Scopus and PubMed databases covered only the period from April 1, 2023 to April 15, 2023. This is clearly an insufficient amount of data for a meta-analysis.

A: the referred period is only the period in which the search was performed, the period for the performance of clinical trials was 1999 to 2018, which is a period of 19 years.

3 .- Additionally, the topic of the role of flavonoids in the prevention of cardiovascular diseases, including atherosclerosis, and their beneficial effect on the lipid profile (including total cholesterol and its LDL fraction) and blood pressure is nothing new.

A: It surely is not a "new" topic, since meta-analyses on this field have been performed since the early 2000s, however, our work contributes with evidence about which specific types of flavonoids lower LDLcr serum concentrations in individuals with hypercholesterolemia, and in which doses, and also that no improvement is found for blood pressure. It also represents an update on the data, reinforcing the fact that flavonoids should be considered as actual treatments for early targeting of LDLc to prevent atherosclerosis development and cardiovascular disease establishment. Many of the previous meta-analyses have even suggested that more clinical trials and meta-analysis, such as ours, should be performed improving the quality of results.

We attached a revised and improved version of our manuscript. Changes have been highlighted to be easily identified.

Author Response File: Author Response.docx

Reviewer 2 Report

Flavonoids are plant-secondary metabolites with cardiovascular protective properties. They can be classified into different groups: flavones, flavonols, flavanols, etc. The authors aim to conduct a meta-analysis of randomized controlled trials (RCTs) on the effects of different types of flavonoids on blood pressure and cholesterol levels, which are risk factors for atherosclerosis. The authors searched two databases (Scopus and PubMed) for RCTs using one class of flavonoids or pure flavonoids in relation to blood pressure or cholesterol in patients with atherosclerosis or its risk factors. They extracted data on the intervention characteristics, outcome measures, and risk of bias from 19 eligible studies. They performed a random effect model to obtain a weighted mean of the standardized mean difference (SMD) for each outcome. The meta-analysis showed no significant differences between placebo and treatment with different flavonoids on total cholesterol (TC) and blood pressure. However, there was a significant difference in LDL cholesterol (LDLc), indicating that flavonoid consumption can be associated with a lower risk of LDLc. The authors also found a moderate to high heterogeneity between studies, which could be due to the different types and doses of flavonoids used. Specific comments:

1.          The introduction does not provide a clear rationale for the research question. It should explain why it is important to study the effects of specific flavonoid classes or pure flavonoids on blood pressure and cholesterol in patients with atherosclerosis risk and how this review will fill the gaps in the existing literature.

2.          The methods section does not describe the search strategy in detail. It should report the exact search terms, the date of the last search, and the number of records retrieved from each database. It should also explain how the data extraction and quality assessment were performed, and how the potential sources of heterogeneity and publication bias were explored.

3.          The discussion section does not discuss the main findings in relation to the existing evidence. It should compare and contrast the results of this review with those of previous studies and meta-analyses on the same topic and explain the possible reasons for any discrepancies or inconsistencies. It should also discuss the strengths and limitations of this review and the implications for practice and research.

4.          The conclusion section does not provide a clear and concise summary of the main findings and implications. It should state the main conclusions of the review, the level of evidence and certainty of the results, the implications for clinical practice and policy, and the recommendations for future research.

5.          Please enlarge Figure 1, it is unclear (resolution) for publication.

6.          Please modify Table 2. It is not very clear using green and yellow to indicate low risk and concerns of the bias.

Author Response

We would like to sincerely thank the reviewers for their constructive input and significant suggestions made during the peer review process for our manuscript. We thoroughly reviewed each of the comments and recommendations and addressed each of the mentioned points in the previous letter. Now, these revisions have significantly improved the quality and comprehensibility of our manuscript.

Introduction: We are pleased to inform you that the introduction section has been meticulously refined to offer a more lucid and compelling rationale for our research question. We have taken great care to elaborate on the paramount importance and relevance of our study in the broader scientific context. The enhancements have been thoughtfully incorporated in lines ( 64 - 78, and 88-100).

Methods: With your valuable insights in mind, we have expanded the methods section to present you with a more comprehensive account of our search strategy. We now provide comprehensive information on the specific search keywords used, the timing of our latest search, and the specific number of documents retrieved from various databases. Moreover, we have included fundamental information on our meticulous approach to data extraction, rigorous quality assessment, and systematic exploration of potential sources of variation and publication bias, The enhancements have been thoughtfully incorporated in lines (118, 122 -127, 134-140, 146-153, and 161-165).

Discussion: The provided comments have prompted us to significantly enhance our discussion section. We have endeavored to facilitate a more exhaustive analysis of our primary findings in light of the existing evidence. You will get a thorough comparative analysis of our results alongside previous studies and meta-analyses on the same topic. We have taken care to elucidate the reasons behind any discrepancies or inconsistencies observed. Additionally, our revised discussion now includes a thorough exploration of both the strengths and limitations of our review, providing valuable insights into the implications for clinical practice and promising avenues for future research. The enhancements have been thoughtfully incorporated in lines (270-295 and 306-348).

Conclusion: In response to your guidance, the conclusion section has been restructured to provide a clear and straightforward summary of our primary findings and their far-reaching implications. We have explicitly stated the principal conclusions derived from our review, thoughtfully assessed the level of evidence and certainty of the results, and offered practical insights with policy implications. Furthermore, we have laid out robust recommendations for future research endeavors. The enhancements have been thoughtfully incorporated in lines (324 – 330 and 363 a 365).

In consideration of your valuable input, we have taken steps to optimize the clarity of Figure 1. These enhancements have been thoughtfully applied to ensure that the figure complies with the requisite publication standards, thereby enhancing its readability for your convenience.

We have attentively addressed your request by making specific adjustments to Table 2. In accordance with your guidance, we have replaced the green and yellow color scheme with a more user-friendly and visually intuitive representation. This revised approach effectively conveys the concepts of low risk and concerns of bias, aligning with your suggestions.

Once again, we extend our deepest appreciation for the valuable guidance and constructive feedback provided by the editorial team. We eagerly await your further advice and remain confident that our amended paper will be published in Scientia Pharmaceutica.

Author Response File: Author Response.docx

Reviewer 3 Report

The manuscript entitled "Analysis of Beneficial effects of flavonoids in patients with atherosclerosis risk on blood pressure or cholesterol during  Random Controlled Trials: A Systematic Review and Meta analysis" it is very sparse, poor in content and uninteresting due to the way in which the topic was presented, although it is interesting. The manuscript is based on few numbers of articles in literature and topic is not new and it is not described very well. The manuscript appears as a simple list.

I would have added several aspects regarding bioavailability or the mechanism of action that are totally missing. 

Author Response

We would like to sincerely thank the reviewers for their constructive input and significant suggestions made during the peer review process for our manuscript. We thoroughly reviewed each of the comments and recommendations and addressed each of the mentioned points in the previous letter. Now, these revisions have significantly improved the quality and comprehensibility of our manuscript.

Here we reply to each aspect of your valuable comments:

1) The manuscript entitled "Analysis of Beneficial effects of flavonoids in patients with atherosclerosis risk on blood pressure or cholesterol during  Random Controlled Trials: A Systematic Review and Meta analysis" it is very sparse, poor in content and uninteresting due to the way in which the topic was presented, although it is interesting. The manuscript is based on few numbers of articles in literature and topic is not new and it is not described very well. The manuscript appears as a simple list.

A1: In the literature, Meta-analyses are valuable evidence even with 8 analyzed papers. They can go up to hundreds of studies, however, this depends on the topic of choice, usually 10 to 20 included studies are a very well number of studies to perform meta-analysis, and we are in this range. We have expanded the discussion in order to highlight the importance of our work. You will see all changes highlighted in yellow.

2)There aren't scheme or figures in which the biological mechanism of these flavonoids are explained or their critical issues regarding their bioavailability.    

A2): We have designed two new figures, one with the chemical explanation of how flavonoids are acting as antioxidants and a final scheme that proposes how specific flavonoids benefit during atherosclerosis.

3) It doesn't show innovation and there are reviews and works in large quantities that describe these types of activities. Making the work more appealing to the reader would have been better precisely because it is not a new topic.

A3) We believe this topic, if not innovative, is a current topic under discussion that needs to be addressed and updated in order to come to a final conclusion regarding which flavonoids´ type and doses help to improve cholesterol parameters. Our findings are important to reinforce the fact that flavonoids help reduce risk of atherosclerosis not only in terms of mortality or cardiovascular disease development, as many other studies have demonstrated, but in terms of prevention in populations at risk such as postmenopausal women, obese individuals and dyslipidemic subjects. If specific flavonoids are taken regularly and the indicated doses, in early stages of the disease, we are able to prevent elevations of LDL cholesterol and prevent fatal outcomes of atherosclerosis.

4)I would have added several aspects regarding bioavailability or the mechanism of action that are totally missing. 

A4): you will find specific aspects in the new added section of the discussion highlighted in yellow

Author Response File: Author Response.docx

Round 2

Reviewer 3 Report

The authors have significantly improved the work with the different changes making it more fluid to read and fluid.  

The manuscript appears significantly improved especially in the "Discussion" section.