Statin Therapy and Cardiovascular Prevention: Contemporary Evidence, Challenges, and Future Directions—A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript addresses an important and highly relevant public health topic, namely the role of statin therapy in cardiovascular prevention, and it succeeds in presenting a broad overview that integrates clinical efficacy, medication adherence, statin-associated muscle symptoms (SAMS), and emerging concepts in precision medicine. The paper is generally well written and logically structured, and its emphasis on behavioural and physiological determinants of treatment success provides a useful perspective that extends beyond traditional discussions focused solely on lipid lowering and cardiovascular outcomes.

However, some improvements are needed and specifically:

1) A major limitation, however, is the absence of a clearly described review methodology. The authors do not specify whether the article is intended as a narrative, scoping, or systematic review, nor do they provide information regarding literature search strategies, databases consulted, inclusion criteria, or methods used to select and evaluate the evidence. As a result, it is difficult for readers to assess the comprehensiveness of the review and the potential for selection bias. Greater methodological transparency is essential for strengthening the scientific credibility of the manuscript.

2) The discussion devoted to muscle function, including handgrip strength, skeletal muscle mass, and phase angle, is interesting and potentially innovative, but it occupies a disproportionately large portion of the review relative to the currently available evidence linking these measures specifically to statin therapy. In several sections, the manuscript tends to move from established evidence to more speculative interpretations without sufficiently distinguishing between what is well supported and what remains an emerging research hypothesis. The authors should provide a more balanced appraisal of the literature, acknowledge existing uncertainties, and avoid overstating the clinical relevance of these biomarkers at the present stage of evidence.

3) Importantly, the authors may wish to consider citing and discussing the article by Costa et al,  Social Determinants of Health and Vascular Diseases: A Systematic Review and Call for Action. Soc. Sci. 2023, 12, 214. https://doi.org/10.3390/socsci12040214. While the current review provides an extensive discussion of behavioural determinants of statin adherence, including medication beliefs, risk perception, nocebo effects, and patient-provider communication, it pays relatively little attention to how broader social determinants influence statin use and cardiovascular prevention. Of particular relevance is the discussion of gender disparities in peripheral arterial disease (PAD). The review highlights evidence that women are less likely to receive guideline-recommended statin therapy and may demonstrate lower adherence to statin treatment compared with men. The authors further discuss how gender-related beliefs and concerns regarding medication can influence treatment compliance and symptom perception, including a greater tendency to report adverse effects among women who hold negative expectations regarding pharmacological treatment. These findings resonate strongly with the present manuscript's discussion of statin-associated muscle symptoms (SAMS), medication beliefs, and the nocebo effect. Incorporating this literature would strengthen the manuscript by extending the discussion of adherence beyond individual psychological factors to include social and gender-related determinants of treatment behaviour. Such an addition would also be consistent with the manuscript's emphasis on patient-centred care and precision prevention, highlighting that successful statin therapy depends not only on biological and behavioural mechanisms but also on social inequalities and gender-specific barriers to treatment initiation, persistence, and outcomes.

4) Also, there are concerns regarding the validity and verifiability of several cited references, many of which are listed as recent 2024–2025 publications and guidelines. These references should be carefully checked to ensure that they correspond to genuine, published sources. In addition, the manuscript would benefit from reducing repetitive content across sections dealing with adherence, SAMS, muscle function, and precision medicine, while providing a more critical discussion of the strengths, limitations, and remaining controversies in the field. For these reasons, I would recommend substantial revision before the manuscript can be considered for publication.

 

Author Response

RESPONSE TO REVIEWERS

Manuscript Title: Statin Therapy and Cardiovascular Prevention: Contemporary Evidence, Challenges, and Future Directions—A Narrative Review

Dear Editor and Reviewers,

We would like to express our sincere appreciation to the Editor and Reviewers for their careful evaluation of our manuscript and for the insightful comments and suggestions provided. We are grateful for the constructive feedback, which has substantially improved the clarity, structure, scientific rigor, and overall quality of the manuscript.

In response to the comments, we have undertaken a major revision of the manuscript. The principal changes include:

• Addition of a dedicated Review Methodology section and explicit designation of the article as a narrative review.
• Reorganization of the manuscript into a more evidence-based and logically structured format.
• Reduction of repetitive material across sections.
• Expansion of the discussion on social determinants of health and gender disparities.
• More critical appraisal of statin-associated muscle symptoms (SAMS) and muscle function outcomes.
• Inclusion of contemporary non-statin lipid-lowering therapies.
• A more balanced discussion of precision medicine, including limitations relating to implementation, accessibility, cost-effectiveness, and external validity.
• Greater emphasis on areas of uncertainty and future research priorities.

Detailed responses to each comment are provided below.

 

Reviewer 1

We thank the reviewer for the thoughtful and constructive comments.

Comment 1

A major limitation is the absence of a clearly described review methodology. Greater methodological transparency is essential for strengthening the scientific credibility of the manuscript.

Response

We appreciate this important observation. In response, we have added a new section entitled "Review Methodology"immediately after the Introduction.

The revised section now:

• explicitly identifies the article as a narrative review;
• describes the databases searched (PubMed/MEDLINE, Scopus, Web of Science, Embase, and Cochrane Library);
• specifies the search period (January 2015–March 2026);
• outlines the search terms used;
• describes inclusion and exclusion criteria; and
• explains the narrative approach used for evidence synthesis.

These additions enhance transparency and allow readers to better assess the scope and selection of the evidence.

Comment 2

The discussion devoted to muscle function occupies a disproportionately large portion of the review and tends to move from established evidence to more speculative interpretations.

Response

We agree with the reviewer and have substantially revised Section 7.

Specifically:

• the section has been reduced by approximately 40–50%;
• repetitive material was removed;
• stronger distinctions were made between established findings and emerging hypotheses;
• the discussion of handgrip strength, skeletal muscle mass, and phase angle was condensed;
• additional emphasis was placed on the limitations of existing evidence and the lack of causal data.

The revised section now presents these physiological measures primarily as markers of overall health and frailty rather than established biomarkers of statin-related effects.

Comment 3

The authors should consider discussing the role of social determinants of health and gender disparities.

Response

We thank the reviewer for this valuable suggestion.

A new subsection entitled:

"Social Determinants of Health and Gender Inequalities"

has been incorporated into Section 5.

The discussion now includes:

• socioeconomic inequalities;
• health literacy;
• healthcare accessibility;
• gender disparities in statin utilization and adherence;
• sex-related differences in symptom reporting;
• cultural and social influences on treatment persistence.

We have incorporated and discussed the article by:

Costa M et al. (2023). Social Determinants of Health and Vascular Diseases: A Systematic Review and Call for Action. Soc Sci. 12:214.

These additions strengthen the patient-centred perspective of the review and broaden the discussion beyond individual behavioural factors.

Comment 4

Concerns exist regarding the validity and verifiability of several references. The manuscript would also benefit from reduced repetition and more critical discussion.

Response

We appreciate this important observation.

In response:

• the manuscript was extensively edited to reduce overlap among sections;
• discussions concerning adherence, SAMS, muscle function, and precision medicine were streamlined;
• several references were carefully checked and updated;
• greater emphasis was placed on limitations, controversies, and areas of uncertainty.

Overall, the revised manuscript adopts a more critical and balanced perspective.

Reviewer 2 Report

Comments and Suggestions for Authors

1. The review lacks a dedicated methodology section describing the sources of information and literature search strategy. The authors should clearly state which databases were searched (e.g., PubMed, Scopus, Web of Science, Embase), the search period, keywords used, inclusion/exclusion criteria, and the process by which evidence was selected and synthesized. Without this information, the comprehensiveness and reproducibility of the review cannot be adequately assessed.
2. Although the review cites several contemporary guidelines and influential publications, the process by which these sources were identified is not described. The authors should clarify whether the review represents a systematic search, a scoping review, or a narrative synthesis based on expert selection of key references.
3. The current structure is topic-based rather than evidence-based. The review repeatedly shifts between biological mechanisms, clinical efficacy, behavioral factors, muscle physiology, and precision medicine without explaining why these domains were selected or how they connect. The structure should have the section of review methodology, including databases, search strategy, eligibility criteria, and study selection process, after the introduction section. Next, authors disclose evidence of effectiveness through data extraction from selected guidelines, articles, etc. 
4. The section on muscle function outcomes is informative but appears disproportionately extensive relative to the overall scope of statin therapy and cardiovascular prevention. The authors should either provide stronger justification for this emphasis or condense the section and focus on outcomes with more direct clinical relevance to cardiovascular prevention.
5. The manuscript should explicitly state the review type (narrative review, scoping review, or systematic review). If this is intended as a narrative review, the authors should acknowledge this and describe how the literature was selected. If a systematic approach was used, reporting should follow PRISMA guidelines.

Author Response

RESPONSE TO REVIEWERS

Manuscript Title: Statin Therapy and Cardiovascular Prevention: Contemporary Evidence, Challenges, and Future Directions—A Narrative Review

Dear Editor and Reviewers,

We would like to express our sincere appreciation to the Editor and Reviewers for their careful evaluation of our manuscript and for the insightful comments and suggestions provided. We are grateful for the constructive feedback, which has substantially improved the clarity, structure, scientific rigor, and overall quality of the manuscript.

In response to the comments, we have undertaken a major revision of the manuscript. The principal changes include:

• Addition of a dedicated Review Methodology section and explicit designation of the article as a narrative review.
• Reorganization of the manuscript into a more evidence-based and logically structured format.
• Reduction of repetitive material across sections.
• Expansion of the discussion on social determinants of health and gender disparities.
• More critical appraisal of statin-associated muscle symptoms (SAMS) and muscle function outcomes.
• Inclusion of contemporary non-statin lipid-lowering therapies.
• A more balanced discussion of precision medicine, including limitations relating to implementation, accessibility, cost-effectiveness, and external validity.
• Greater emphasis on areas of uncertainty and future research priorities.

Detailed responses to each comment are provided below.

 

 

Reviewer 2

We thank the reviewer for the insightful comments.

Comment 1

The review lacks a dedicated methodology section describing the sources of information and literature search strategy.

Response

We fully agree and have added a comprehensive Review Methodology section following the Introduction.

The section now specifies:

• review design;
• databases searched;
• search strategy;
• time frame;
• inclusion and exclusion criteria;
• approach used for evidence synthesis.

Comment 2

The review should clarify whether it represents a systematic review, scoping review, or narrative synthesis.

Response

We thank the reviewer for this suggestion.

The manuscript now clearly states that it is a Narrative Review.

The title, abstract, introduction, and methodology section have all been revised accordingly.

Comment 3

The current structure is topic-based rather than evidence-based.

Response

We appreciate this recommendation and have reorganized the manuscript into a more coherent structure.

The revised organization is:

1. Introduction
2. Review Methodology
3. Mechanisms of Action of Statins
4. Statins in Primary and Secondary Prevention
5. Medication Adherence and Persistence
6. Statin-Associated Muscle Symptoms
7. Muscle Function and Physiological Outcomes
8. Contemporary Guidelines and Precision Cardiovascular Prevention
9. Future Directions
10. Conclusions

This revised structure improves the logical flow and integration of the different domains addressed in the review.

Comment 4

The section on muscle function outcomes appears disproportionately extensive.

Response

We agree and have substantially condensed this section.

The revised version:

• reduces the overall length considerably;
• removes repetitive discussions;
• emphasizes limitations of the available evidence;
• distinguishes established evidence from emerging hypotheses;
• avoids overstating the clinical significance of these biomarkers.

Comment 5

If a systematic approach was used, reporting should follow PRISMA guidelines.

Response

We appreciate the reviewer's comment.

Because the objective of the present article was to provide a broad synthesis of clinical, behavioural, physiological, and precision medicine aspects of statin therapy, we considered a narrative review design to be the most appropriate approach.

This has now been explicitly stated throughout the manuscript, and the methodology section has been expanded to improve transparency regarding evidence selection and synthesis.

Reviewer 3 Report

Comments and Suggestions for Authors

First of all, I would like to thank the authors for their valuable work. However, I believe there are a few points that need clarification.

1- Firstly, regarding the methodology of the study. The article is presented as a review article. However, the type of review is not specified by the authors (narrative, systematic, or scope-determining review). This issue needs clarification. In addition, a brief explanation of the literature search strategy, the databases searched, the search terms used, the inclusion criteria for the study, and the time period examined would increase transparency and reproducibility.

2- The article is a comprehensive review of statins; however, it is descriptive rather than critical in some places. In particular, several sections summarize only the existing evidence without adequately addressing the debates or limitations. For example, when looking at the section on statin-related muscle symptoms, it would be better to make a better distinction between true statin-induced myopathy, statin intolerance, and the nocebo effect; it should also emphasize the difficulty of establishing causal relationships between them.

3. The relationship between statins and muscle function should be established based on evidence. It should clarify whether statins directly affect muscle function (using biomarkers such as creatine kinase) or whether the effects occur primarily through symptoms, aging, and decreased physical activity.
4. The article emphasizes genetic risk profiling, pharmacogenomics, artificial intelligence, and digital health in relation to the use and side effects of statins; however, limitations regarding clinical application in daily practice, cost-effectiveness, accessibility, and validation in real-world populations should also be addressed.
5. A more detailed discussion of non-statin lipid-lowering therapies should also be included. Although the article focuses on statins, current cardiovascular prevention practice increasingly includes combination therapies. The discussion of ezetimib, PCSK9 inhibitors, bempedoic acid, and other emerging therapies, particularly in patients with statin intolerance, could be expanded.
6. The terminology used in the article should also be standardized. For example, the terms "statin-related muscle symptoms," "statin intolerance," and "muscle toxicity" should not be used interchangeably.

Author Response

RESPONSE TO REVIEWERS

Manuscript Title: Statin Therapy and Cardiovascular Prevention: Contemporary Evidence, Challenges, and Future Directions—A Narrative Review

Dear Editor and Reviewers,

We would like to express our sincere appreciation to the Editor and Reviewers for their careful evaluation of our manuscript and for the insightful comments and suggestions provided. We are grateful for the constructive feedback, which has substantially improved the clarity, structure, scientific rigor, and overall quality of the manuscript.

In response to the comments, we have undertaken a major revision of the manuscript. The principal changes include:

• Addition of a dedicated Review Methodology section and explicit designation of the article as a narrative review.
• Reorganization of the manuscript into a more evidence-based and logically structured format.
• Reduction of repetitive material across sections.
• Expansion of the discussion on social determinants of health and gender disparities.
• More critical appraisal of statin-associated muscle symptoms (SAMS) and muscle function outcomes.
• Inclusion of contemporary non-statin lipid-lowering therapies.
• A more balanced discussion of precision medicine, including limitations relating to implementation, accessibility, cost-effectiveness, and external validity.
• Greater emphasis on areas of uncertainty and future research priorities.

Detailed responses to each comment are provided below.

 

 

Reviewer 3

We thank the reviewer for the encouraging remarks and valuable suggestions.

Comment 1

The review type and literature search strategy should be clarified.

Response

We fully agree.

The manuscript now explicitly identifies itself as a Narrative Review, and a detailed methodology section describing databases, search terms, eligibility criteria, and evidence synthesis has been added.

Comment 2

Several sections are descriptive rather than critical. Distinctions between true statin-induced myopathy, statin intolerance, and the nocebo effect should be strengthened.

Response

We appreciate this important recommendation.

Section 6 was extensively revised.

The new section clearly differentiates:

• true statin-induced myopathy;
• statin intolerance;
• nocebo effects;
• clinical diagnosis and differential diagnosis;
• management approaches.

Greater emphasis has also been placed on the challenges of establishing causality and on the multifactorial nature of symptom perception.

Comment 3

The relationship between statins and muscle function should be established on the basis of evidence.

Response

We agree.

The section on muscle function outcomes has been substantially condensed and rewritten.

The revised section:

• highlights the limited evidence linking statins directly to muscle function;
• emphasizes the influence of ageing, sarcopenia, and physical inactivity;
• presents handgrip strength, skeletal muscle mass, and phase angle as exploratory rather than established biomarkers.

Comment 4

Discussion of non-statin therapies should be expanded.

Response

We thank the reviewer for this suggestion.

Section 6 now includes expanded discussion of:

• ezetimibe;
• PCSK9 inhibitors;
• bempedoic acid;
• inclisiran.

Their role in contemporary lipid management and in patients with statin intolerance is now discussed in greater detail.

Comment 5

Limitations regarding pharmacogenomics, artificial intelligence, and digital health should be discussed.

Response

We appreciate this observation.

Section 8 was comprehensively revised to provide a more balanced discussion of precision cardiovascular prevention.

The revised section now addresses:

• limitations of clinical implementation;
• cost-effectiveness;
• accessibility;
• digital divides;
• algorithmic bias;
• external validation;
• underrepresentation of African populations;
• challenges in translating precision medicine into routine practice.

These revisions provide a more critical perspective and avoid overstating the current readiness of these approaches for widespread clinical implementation.

Comment 6

Terminology should be standardized.

Response

We agree and have revised the manuscript accordingly.

Terminology has been standardized throughout the manuscript to ensure consistent use of:

• Statin-associated muscle symptoms (SAMS) as the umbrella term;
• Statin intolerance as a clinical syndrome;
• Statin-induced myopathy for objectively confirmed muscle injury.

Ambiguous and interchangeable terminology has been minimized.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript now sounds good

Author Response

Thank you for accepting the new version 

Reviewer 2 Report

Comments and Suggestions for Authors

1. The addition of a dedicated Review Methodology section partially addresses the original concern. However, the current search strategy includes only representative keywords. At least one full electronic search string (e.g., the PubMed search) should be included, preferably in the Supplementary Materials.
2. The authors should clarify the study selection process that is not stated, such as who screened the articles, whether screening was performed independently by more than one reviewer, and how disagreements were resolved. Even for a narrative review, a brief description of the selection process would improve reproducibility.
3. Regarding priority to guidelines, systematic reviews, and randomized trials, it does not explain how studies were judged as "high quality." A brief explanation would strengthen the methodological rigor.
4. The revised structure improves the manuscript's logical flow and readability. However, it remains primarily topic-based rather than evidence-based. The revised manuscript is still organized primarily by subject areas: Mechanisms of Action, Primary and Secondary Prevention, Medication Adherence, etc. These are all topics, rather than sections synthesizing and critically appraising the available evidence. Within each thematic section, the authors should strengthen the critical synthesis by explicitly distinguishing high-quality evidence from emerging or conflicting evidence, highlighting areas of consensus and controversy, and identifying remaining knowledge gaps. This would better fulfill the objective of providing an evidence-based narrative review.

Author Response

Thank you for the constructive comments and hence we have tried to adjust the paper accordingly. Please see new version. 

1.The addition of a dedicated Review Methodology section partially addresses the original concern. However, the current search strategy includes only representative keywords. At least one full electronic search string (e.g., the PubMed search) should be included, preferably in the Supplementary Materials.

A supplementary section has been added. Thank you for highlighting this deficiency.

 

2. The authors should clarify the study selection process that is not stated, such as who screened the articles, whether screening was performed independently by more than one reviewer, and how disagreements were resolved. Even for a narrative review, a brief description of the selection process would improve reproducibility.

 New section added; After eliminating duplicates, screening of titles and abstracts was done independently by two reviewers based on the objectives of this narrative review. Subsequently, full-text screening was done independently by two reviewers. In case of any disagreement in determining eligibility or interpretation, resolution was achieved by consensus after discussion. Since this is a narrative review, inter-rater agreement measures were not computed.

 

 

3. Regarding priority to guidelines, systematic reviews, and randomized trials, it does not explain how studies were judged as "high quality." A brief explanation would strengthen the methodological rigor.

 

Added; The quality of evidence is judged by the study design and the robustness of the methodology. Highest preference was given to international evidence-based clinical guidelines, Cochrane systematic reviews, high-quality systematic reviews and meta-analysis, randomized controlled trials, and good quality prospective cohort studies. In cases of conflicting evidence, higher importance was given to studies with low risk of bias, large sample size, long follow-up period, and multiple studies with consistent results.

 

4. The revised structure improves the manuscript's logical flow and readability. However, it remains primarily topic-based rather than evidence-based. The revised manuscript is still organized primarily by subject areas: Mechanisms of Action, Primary and Secondary Prevention, Medication Adherence, etc. These are all topics, rather than sections synthesizing and critically appraising the available evidence. Within each thematic section, the authors should strengthen the critical synthesis by explicitly distinguishing high-quality evidence from emerging or conflicting evidence, highlighting areas of consensus and controversy, and identifying remaining knowledge gaps. This would better fulfill the objective of providing an evidence-based narrative review.

 

Section 4 onwards has been changed to Evidence based synthesis as well as areas of controversy. Also medicine adherence section has been modified to similar structures and overall, there is now less focus on section synthesis but holistically appraises the literature on a more evidence based manner.

 

Hope the  new edits will be satisfactory. 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

First of all, I would like to thank the authors for their valuable work. In line with the peer review suggestions, the authors have significantly improved the text in terms of structure, methodology and scientific content. In addition, the text has been significantly strengthened as a result of a more detailed discussion of statin intolerance, social determinants in health, precision medicine and updated evidence.
In conclusion, it is suitable for publication in its current form.

Author Response

Thank you for accepting the new version