-->PONE-D-25-42229-->-->Association of hyperuricemia with coronary heart disease and other cardiovascular outcomes: A systematic review and dose-response meta-analysis-->-->PLOS ONE

Dear Dr. Lyu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Academic Editor

PLOS ONE

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Additional Editor Comments :

In this manuscript, Lyu et al. present a systematic review and meta-analysis of observational studies evaluating the association between hyperuricemia and coronary heart disease (CHD). By systematically searching Medline, the Cochrane Library, Embase, and two trial registration databases from inception to June 30, 2025, the authors identified 42 articles corresponding to 39 unique studies, encompassing a total of 1,082,880 participants. The pooled results demonstrated a statistically significant association between hyperuricemia and increased risk of CHD, as well as its individual components (CHD death, cardiovascular death, myocardial infarction). The dose–response analyses further suggested a linear relationship between serum uric acid (UA) and cardiovascular disease (CVD) risk, and a U-shaped association between serum UA and risk of CVD death among men. Despite the relevance of the research question and the adherence to a registered protocol, the overall certainty of the evidence was limited by the observational study designs. Several key aspects require clarification and further development before the manuscript can be considered suitable for publication.

Risk of Bias: Although the original protocol did not specify separate analyses for CHD-related outcomes, the authors expanded their work to include CHD death, CVD death, and myocardial infarction. While this approach is wisely comprehensive, it raises concerns regarding potential spin bias in relation to the primary outcome (CHD). Importantly, substantial heterogeneity was observed across included studies, arising from differences in association measures, uric acid assessment methods, and other study-level factors. The sources of this statistical heterogeneity should be explicitly examined and reported in relation to study characteristics and association measurements (HR,OR,RR). Furthermore, given the relevance of confounding factors in the relationship between hyperuricemia and CHD, meta-regression analyses should be performed at least for age, sex, and body mass index (BMI).

Discussion: The Discussion would benefit from additional depth. Specifically, the clinical relevance of the findings should be contextualized in light of potential therapeutic strategies. Moreover, possible mechanisms underlying the observed U-shaped association between serum uric acid and CVD mortality in men should be elaborated.

Language and Style: Minor typographical and grammatical errors should be carefully revised throughout the manuscript. For example, in the Abstract, the sentence “Among them, 2 article was assess as ‘Very high risk of bias’, 8 ‘High risk of bias’, 2 ‘Some concerns’” requires correction for grammar and style. A comprehensive language edit is recommended.Please also consider that Numbers with four or more digits should have a comma inserted at the thousands place for readability, such as 1,234 or 10,000.

Reporting Standards and Methodological Transparency: In addition to PRISMA reporting, adherence to the MOOSE guidelines (Stroup et al., JAMA 2000) should be explicitly documented, in line with the reporting standards referenced in the registered protocol. This will strengthen the methodological transparency and ensure consistency with accepted standards for meta-analyses of observational studies.

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Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. Does the manuscript adhere to the experimental procedures and analyses described in the Registered Report Protocol?

If the manuscript reports any deviations from the planned experimental procedures and analyses, those must be reasonable and adequately justified.-->

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

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-->2. If the manuscript reports exploratory analyses or experimental procedures not outlined in the original Registered Report Protocol, are these reasonable, justified and methodologically sound?

A Registered Report may include valid exploratory analyses not previously outlined in the Registered Report Protocol, as long as they are described as such.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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-->3. Are the conclusions supported by the data and do they address the research question presented in the Registered Report Protocol?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. The conclusions must be drawn appropriately based on the research question(s) outlined in the Registered Report Protocol and on the data presented.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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-->4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: The present is an intetesting paper aiming to evalaute impact of uricemia on CV outcomes. It is sound from a methodological point of view.

Some issues should be addressed

1) metaregression analysis for age, gender and BMI should be performed

2) more data about baseline features of each study should be added

3) recently bempedoic acid has emerged as a relevant therapy to reduce cholesterol levels, although increasing that of uric acid. Authors should comment on this (quote and comment on PMID: 38017541)

Reviewer #2: This manuscript addresses an important clinical and epidemiological question regarding the association between hyperuricemia and cardiovascular outcomes. The authors conducted a systematic review and dose-response meta-analysis with registration in PROSPERO and application of ROBINS-E and GRADE, which is commendable. The study is generally well-structured and the analyses are extensive, including sex-specific and dose-response models.

However, I suggest to adress the following points before this work can be considered for publication.

1. While the outcomes are indeed defined in both the main manuscript and the supplementary material, there is considerable heterogeneity in how individual studies defined them. Some cohorts relied on ICD codes, others on clinical/ECG confirmation, and some even included procedures such as CABG or PCI as part of the endpoint. Older cohorts often applied broader clinical definitions such as “typical angina” or “vascular disease.” This variability limits the comparability of studies and likely contributes to the high heterogeneity observed in pooled analyses. The authors should more explicitly acknowledge this as a major limitation. Furthermore, according to the registered protocol, the primary outcome was CHD, whereas the manuscript expands the scope to include additional outcomes (CVD, CVD death, MI). This expansion should be transparently reported as a deviation from the original protocol.

2. Some analyses, particularly the dose–response models, report very high heterogeneity (I² >90%). While subgroup analyses by sex were conducted, this is insufficient to explain such variability. Further exploration using meta-regression (e.g., by age distribution, mean follow-up duration, study region, publication decade, and level of confounder adjustment) would strengthen the analysis and provide more insight into sources of heterogeneity.

3. The GRADE assessments indicate that the overall certainty of evidence is low to very low. It would be advisable to include a stronger disclaimer regarding the potential for residual confounding and the inherent limitations of observational study designs.

4. The Supplementary Table S1 shows wide variability in cut-offs (5.2–7.7 mg/dL, sex-specific thresholds, SD-based definitions). This heterogeneity undermines comparability and external validity. The included studies also used diverse uric acid measurement methods (enzymatic, phosphotungstic, colorimetric, or unreported). This introduces potential misclassification bias. The impact of assay heterogeneity could be discussed.

5. The term hyperuricemia is introduced early in the Introduction, but its definition (“elevated serum uric acid levels, a condition known as hyperuricemia”) only appears in the third paragraph. For clarity and better framing, the definition should be provided the first time the term appears, ideally in the opening paragraph, to ensure readers understand the concept from the outset.

6. Several sentences are long and complex, which makes the manuscript difficult to read. Simplification and editing for concise scientific English are recommended. Topographical and grammatical errors should be corrected.

7. Abbreviations should be used consistently (e.g., CHD, CVD, MI).

8. The authors are encouraged to ensure that all figures (including supplementary figures) are cited in the text in numerical order at the point of first mention. This will improve clarity and consistency for the reader.

9. Supplementary Table S1 is dense and difficult to interpret. Organizing it by outcome type (CHD, CVD, MI) or by decade/region would improve readability.

10. Figures S1–S30 present multiple subgroup and sensitivity analyses, but the number of studies (k) and participants (n) contributing to each analysis is not always clear. This information should be explicitly included in each figure legend. In addition, not all supplementary figures are cited in the manuscript text. For clarity and transparency, each figure should be referenced at least once, in sequential order, at the relevant point in the Results or Discussion.

Reviewer #3: This study is understood to be a systematic review and meta-analysis that examines the relationship between hyperuricemia and cardiovascular disease risk.

The research procedures, methodologies, interpretation of results, and discussion were conducted with great fidelity, including prior protocol registration, making this an exceptionally well-executed and high-quality study. A notable strength of the text is its comprehensive inclusion of recent research findings, which serves to enhance its credibility and relevance.

While the paper meets the standards for publication in an international journal at present, the following suggestions are offered to enhance its value further.

Minor Point

A distinctive discovery from this study was the U-shaped association observed between serum uric acid levels and cardiovascular disease (CVD) mortality risk in men. In the conclusions, a discussion would be beneficial regarding physiologically plausible mechanisms that could explain why low uric acid levels are associated with an increased risk of cardiovascular disease (CVD) mortality.

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-->7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .-->

Reviewer #1: Yes:  fabrizio d'ascenzo

Reviewer #2: No

Reviewer #3: No

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Association of hyperuricemia with coronary heart disease and other cardiovascular outcomes: A systematic review and dose-response meta-analysis

PONE-D-25-42229R1

Dear Dr. Lyu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Andres Mauricio Acevedo-Melo, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. Does the manuscript adhere to the experimental procedures and analyses described in the Registered Report Protocol?

If the manuscript reports any deviations from the planned experimental procedures and analyses, those must be reasonable and adequately justified.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

-->2. If the manuscript reports exploratory analyses or experimental procedures not outlined in the original Registered Report Protocol, are these reasonable, justified and methodologically sound?

A Registered Report may include valid exploratory analyses not previously outlined in the Registered Report Protocol, as long as they are described as such.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

-->3. Are the conclusions supported by the data and do they address the research question presented in the Registered Report Protocol?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. The conclusions must be drawn appropriately based on the research question(s) outlined in the Registered Report Protocol and on the data presented.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

-->4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: authors should be congratulated for performing such a high level revisions>consequently the paper should be accpeted

Reviewer #2: I have reviewed the authors’ detailed response to the comments provided on the previous version of the manuscript, as well as the revised submission. The authors have appropriately and comprehensively addressed all the suggestions and concerns raised in the earlier review. I commend them for the quality of their revisions and the clarity of their responses. The manuscript now meets the standards for publication; however, I recommend a minor editorial review to correct a few residual grammatical or stylistic issues before final acceptance.

Reviewer #3: The description of the mapping procedures are now adequate and the innovative approach will be of interest to readers working with mapping procedures. The manuscript has been much improved and is in a nice condition now.

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-->7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .-->

Reviewer #1: Yes:  fabrizio d'ascenzo

Reviewer #2: No

Reviewer #3: No

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