Metformin as an Upstream Substrate-Modifying Strategy for Atrial Fibrillation in Metabolic Dysfunction: Mechanistic Rationale and Clinical Evidence

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript discusses the potential role of metformin as an upstream strategy in atrial fibrillation related to metabolic dysfunction. It brings together the pathophysiological rationale and the available clinical evidence in a generally useful way. The figures and summary tables are also helpful and improve readability.

That said, I think there are several aspects to revise before the paper can be considered for publication.

My first concern is the lack of clarity regarding how the literature review was performed. I understand that this is intended as a narrative review rather than a systematic review, but the reader still needs some basic methodological orientation. It would be helpful to explain how the literature was searched, which sources were used, how studies were selected, and how conflicting evidence was handled. As it stands, the basis on which the literature was assembled is not sufficiently transparent.

In several parts of the manuscript, the text seems to imply a protective effect of metformin on atrial fibrillation in terms that are stronger than the evidence really supports. Most of the clinical data discussed are observational, and although the overall hypothesis is plausible, the language should be more consistently cautious throughout the manuscript.

The section on clinical evidence is extremely useful, but it would benefit from a more critical discussion rather than mainly listing study findings. Differences between Asian and Western populations, incident AF versus established AF burden, post-ablation versus postoperative settings, and variations in endpoint definition and treatment exposure are all likely to matter and deserve more explicit interpretation.

The mechanistic discussion is broad and interesting, but it gives the impression that more established mechanisms and more speculative pathways are being presented on the same level. It would improve the paper if the authors more clearly distinguished between mechanisms supported by direct atrial or AF-related evidence and those inferred from broader cardiovascular or metabolic models.

The idea of metformin as a substrate-modifying therapy is certainly appealing and biologically plausible, but the current level of evidence still seems more supportive of a potential or emerging role than of a firmly established strategy. A more conservative wording would better match the data presented in the review.

Finally, the paper is readable overall, but there are repeated points, some awkward sentences, and a few passages that could be tightened for clarity and flow.

Author Response

Comment 1: This manuscript discusses the potential role of metformin as an upstream strategy in atrial fibrillation related to metabolic dysfunction. It brings together the pathophysiological rationale and the available clinical evidence in a generally useful way. The figures and summary tables are also helpful and improve readability.

That said, I think there are several aspects to revise before the paper can be considered for publication.

Response 1: We thank the reviewer for the thoughtful and constructive comments. We appreciate the positive assessment of the manuscript’s overall organization, mechanistic framework, and the inclusion of figures and summary tables. We have carefully considered the reviewer’s suggestions and revised the manuscript accordingly to improve clarity, balance, scientific rigor, and overall readability. Detailed point-by-point responses are provided below.

Comment 2: My first concern is the lack of clarity regarding how the literature review was performed. I understand that this is intended as a narrative review rather than a systematic review, but the reader still needs some basic methodological orientation. It would be helpful to explain how the literature was searched, which sources were used, how studies were selected, and how conflicting evidence was handled. As it stands, the basis on which the literature was assembled is not sufficiently transparent.

Response 2: We thank the reviewer for this valuable suggestion. We agree that additional methodological clarity would strengthen the manuscript. Accordingly, we added a concise description of the literature search strategy, sources reviewed, study selection approach, and handling of conflicting evidence to improve transparency regarding how the narrative review was conducted.

Comment 3: In several parts of the manuscript, the text seems to imply a protective effect of metformin on atrial fibrillation in terms that are stronger than the evidence really supports. Most of the clinical data discussed are observational, and although the overall hypothesis is plausible, the language should be more consistently cautious throughout the manuscript.

Response 3: We thank the reviewer for this important observation. We agree that the current body of clinical evidence is predominantly observational and does not establish a causal protective effect of metformin on atrial fibrillation. In response, we revised several statements throughout the manuscript to adopt more cautious and appropriately qualified language.

Comment 4: The section on clinical evidence is extremely useful, but it would benefit from a more critical discussion rather than mainly listing study findings. Differences between Asian and Western populations, incident AF versus established AF burden, post-ablation versus postoperative settings, and variations in endpoint definition and treatment exposure are all likely to matter and deserve more explicit interpretation.

Response 4: We thank the reviewer for this valuable suggestion. We agree that the clinical evidence section should not only summarize study findings but also interpret why the findings differ across populations, endpoints, and clinical settings. We have added a concise critical synthesis emphasizing differences between Asian and Western cohorts, incident AF versus established AF burden, ablation versus postoperative AF, and variability in endpoint definitions and exposure assessment.

Comment 5: The mechanistic discussion is broad and interesting, but it gives the impression that more established mechanisms and more speculative pathways are being presented on the same level. It would improve the paper if the authors more clearly distinguished between mechanisms supported by direct atrial or AF-related evidence and those inferred from broader cardiovascular or metabolic models.

Response 5: We thank the reviewer for this insightful comment. We agree that some mechanistic pathways discussed in the manuscript are supported by direct atrial or AF-specific experimental evidence, whereas others are extrapolated from broader cardiovascular, metabolic, or vascular models. To improve clarity and scientific balance, we revised the mechanistic sections to better distinguish established AF-related mechanisms from more hypothesis-generating pathways supported by indirect evidence.

Comment 6: The idea of metformin as a substrate-modifying therapy is certainly appealing and biologically plausible, but the current level of evidence still seems more supportive of a potential or emerging role than of a firmly established strategy. A more conservative wording would better match the data presented in the review.

Response 6: We thank the reviewer for this thoughtful comment. We agree that the current evidence base, while biologically compelling, remains largely observational and mechanistic, and therefore supports metformin primarily as a potential or emerging substrate-modifying strategy rather than an established therapy for atrial fibrillation prevention. In response, we revised several statements in the manuscript to adopt more cautious and appropriately qualified language.

Comment 7: Finally, the paper is readable overall, but there are repeated points, some awkward sentences, and a few passages that could be tightened for clarity and flow.

Response 7: We thank the reviewer for this constructive comment. We agree that several sections of the manuscript would benefit from improved conciseness and smoother transitions. In response, we carefully revised the manuscript to reduce repetition, improve sentence structure, and enhance overall readability and flow while preserving the scientific content and mechanistic detail.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have presented explicitly the role of metformin as an upstream therapy for cardiometabolic driven atrial fibrillation.

First they have correctly analyzed the pathophysiolic background of AF through electrical and structural remodeling.

Through the presentation of the pharmacology and mechanism of action of metformin they have proved the pleiotropic effects of the drug beyond glycemic control

They have lastly presented numerous clinical data.

The tables are solid, the figures are nice, citations are also correct.

Author Response

Comment 1: The authors have presented explicitly the role of metformin as an upstream therapy for cardiometabolic driven atrial fibrillation.
Response 1: We thank the reviewer for the positive assessment of our work and for recognizing the manuscript’s focus on metformin as a potential upstream substrate-modifying strategy in cardiometabolic-driven atrial fibrillation.

Comment 2: First they have correctly analyzed the pathophysiologic background of AF through electrical and structural remodeling.
Response 2: We appreciate the reviewer’s encouraging feedback regarding the mechanistic discussion of electrical and structural remodeling in atrial fibrillation.

Comment 3: Through the presentation of the pharmacology and mechanism of action of metformin they have proved the pleiotropic effects of the drug beyond glycemic control.
Response 3: We thank the reviewer for recognizing the comprehensive discussion of metformin’s pleiotropic cardiovascular and metabolic effects beyond glycemic regulation.

Comment 5: They have lastly presented numerous clinical data.
Response 5: We appreciate the reviewer’s positive comments regarding the breadth of clinical evidence summarized in the manuscript.

Comment 6: The tables are solid, the figures are nice, citations are also correct.
Response 6: We sincerely thank the reviewer for the positive feedback regarding the tables, figures, and overall referencing throughout the manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

This narrative review examines the potential role of metformin as an upstream, substrate-modifying therapy for atrial fibrillation (AF) in the context of cardiometabolic dysfunction. The authors integrate mechanistic data—highlighting mitochondrial modulation, AMPK activation, anti-inflammatory, and antifibrotic effects—with clinical observational evidence suggesting a modest reduction in incident AF among metformin users. While data are generally consistent for primary prevention, effects on established AF burden are limited, and postoperative AF results are neutral. The review appropriately emphasizes that current evidence is largely observational and calls for randomized trials to establish causality.

Major points:

#1
This manuscript is presented as a narrative review, but it lacks a clearly defined methodology for literature selection, including search strategy, inclusion/exclusion criteria, and assessment of study quality. Given the heavy reliance on observational data, the absence of a structured approach raises concerns regarding selection bias and overrepresentation of supportive studies. A more systematic framework or at least a transparent description of literature selection is necessary to strengthen credibility.

#2
The authors repeatedly suggest a “protective” effect of metformin on AF incidence, despite acknowledging confounding and heterogeneity. However, the discussion does not sufficiently emphasize key biases such as confounding by indication, immortal time bias, and differences in comparator therapies. The tone should be more cautious, clearly distinguishing association from causation, particularly given the inconsistent findings across Western cohorts.

#3
While multiple cohort studies are summarized, there is limited critical comparison between them. Differences in population (Asian vs Western), AF definition (hospitalization vs outpatient), and exposure duration are mentioned but not deeply analyzed. A structured synthesis (e.g., stratified interpretation or a summary table emphasizing heterogeneity drivers) would significantly improve the manuscript’s interpretability.

#4
The mechanistic sections (AMPK, oxidative stress, inflammation, fibrosis) are extensive but largely descriptive and sometimes repetitive. While biologically plausible, the manuscript does not clearly prioritize which mechanisms are most strongly supported by translational or human data. Condensation and stronger integration of mechanisms with clinical relevance (e.g., linking specific pathways to observed clinical endpoints) are needed.

#5
The manuscript concludes that metformin may be a “substrate-modifying therapy,” but does not clearly define how this should influence clinical practice. For example, it remains unclear whether metformin should be considered specifically for AF prevention beyond standard diabetes indications. A more explicit discussion positioning metformin relative to established risk-factor modification strategies (e.g., weight loss, BP control, SGLT2 inhibitors, GLP-1 agonists) would enhance clinical relevance.

Minor Points

#1
There are multiple minor grammatical inconsistencies and occasional awkward phrasing throughout the manuscript. Careful language editing is recommended to improve readability and professionalism.

#2
Figures (e.g., central illustration, mechanistic diagrams) and tables are informative but not sufficiently referenced or interpreted in the main text. More explicit linkage between figures and narrative discussion would improve clarity and educational value.

This is a well-written and comprehensive review with strong mechanistic grounding and clinically relevant focus. However, the manuscript currently lacks sufficient methodological rigor, critical appraisal, and clear clinical positioning. Addressing these issues would substantially improve its scientific impact and reliability.

Comments on the Quality of English Language

Please see my comment  in the above column.

Author Response

Comment 1: This manuscript is presented as a narrative review, but it lacks a clearly defined methodology for literature selection, including search strategy, inclusion/exclusion criteria, and assessment of study quality. Given the heavy reliance on observational data, the absence of a structured approach raises concerns regarding selection bias and overrepresentation of supportive studies. A more systematic framework or at least a transparent description of literature selection is necessary to strengthen credibility.

Response 1: We thank the reviewer for this important comment. In response, we added a concise methodological description at the end of the Introduction outlining the databases searched, keywords used, study selection approach, and inclusion of both supportive and neutral studies to provide a balanced narrative synthesis and improve transparency regarding literature selection.

Comment 2: The authors repeatedly suggest a “protective” effect of metformin on AF incidence, despite acknowledging confounding and heterogeneity. However, the discussion does not sufficiently emphasize key biases such as confounding by indication, immortal time bias, and differences in comparator therapies. The tone should be more cautious, clearly distinguishing association from causation, particularly given the inconsistent findings across Western cohorts.

Response 2: We thank the reviewer for this important comment. In response, we revised the manuscript to use more cautious language throughout and added discussion emphasizing that the current evidence is primarily observational and susceptible to residual confounding, confounding by indication, immortal time bias, heterogeneity in comparator therapies, and variation in AF endpoint definitions, particularly across Asian and Western cohorts.

Comment 3: While multiple cohort studies are summarized, there is limited critical comparison between them. Differences in population (Asian vs Western), AF definition (hospitalization vs outpatient), and exposure duration are mentioned but not deeply analyzed. A structured synthesis (e.g., stratified interpretation or a summary table emphasizing heterogeneity drivers) would significantly improve the manuscript’s interpretability.

Response 3: We thank the reviewer for this valuable suggestion. In response, we added a more structured interpretive synthesis to the clinical evidence section emphasizing major sources of heterogeneity across studies, including differences in population characteristics, AF endpoint definitions, comparator therapies, and treatment exposure duration. We also revised the discussion surrounding Table 3 to better contextualize variability in findings across cohorts. 

Comment 4: The mechanistic sections (AMPK, oxidative stress, inflammation, fibrosis) are extensive but largely descriptive and sometimes repetitive. While biologically plausible, the manuscript does not clearly prioritize which mechanisms are most strongly supported by translational or human data. Condensation and stronger integration of mechanisms with clinical relevance (e.g., linking specific pathways to observed clinical endpoints) are needed.

Response 4: We thank the reviewer for this insightful comment. In response, we revised the mechanistic sections to reduce repetition, improve conciseness, and better distinguish pathways supported by translational or atrial-specific evidence from those that remain more hypothesis-generating. We also strengthened integration between mechanistic pathways and clinically observed AF outcomes, particularly for oxidative stress, fibrosis, calcium handling, and inflammatory remodeling, which currently have the strongest translational relevance in AF pathophysiology.

Comment 5: The manuscript concludes that metformin may be a “substrate-modifying therapy,” but does not clearly define how this should influence clinical practice. For example, it remains unclear whether metformin should be considered specifically for AF prevention beyond standard diabetes indications. A more explicit discussion positioning metformin relative to established risk-factor modification strategies (e.g., weight loss, BP control, SGLT2 inhibitors, GLP-1 agonists) would enhance clinical relevance.

Response 5: We thank the reviewer for this important comment. In response, we revised the Conclusion to better position metformin within established AF risk-factor modification strategies and clarified that current evidence does not support its use specifically for AF prevention outside standard metabolic indications.

Comment 6: There are multiple minor grammatical inconsistencies and occasional awkward phrasing throughout the manuscript. Careful language editing is recommended to improve readability and professionalism.

Response 6: We thank the reviewer for this comment. In response, the manuscript underwent careful language revision to improve grammar, sentence structure, readability, and overall flow. Several awkward or repetitive passages were revised for clarity and consistency throughout the manuscript.

Comment 7: Figures (e.g., central illustration, mechanistic diagrams) and tables are informative but not sufficiently referenced or interpreted in the main text. More explicit linkage between figures and narrative discussion would improve clarity and educational value.

Response 7: We thank the reviewer for this helpful suggestion. In response, we revised the manuscript to incorporate more explicit references to the central illustration, mechanistic figures, and summary tables within the narrative discussion. Additional interpretive text was added to better integrate the visual elements with the corresponding mechanistic and clinical sections and improve overall clarity and educational value.

Comment 8: This is a well-written and comprehensive review with strong mechanistic grounding and clinically relevant focus. However, the manuscript currently lacks sufficient methodological rigor, critical appraisal, and clear clinical positioning. Addressing these issues would substantially improve its scientific impact and reliability.

Response 8: We thank the reviewer for the thoughtful assessment of our manuscript. In response, we improved methodological transparency, added a more critical synthesis of the clinical evidence, clarified distinctions between established and hypothesis-generating mechanisms, and refined the clinical positioning of metformin within broader AF risk-factor modification strategies. We believe these revisions have strengthened the rigor, balance, and clinical relevance of the manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript has improved substantially and is now much more balanced in its interpretation of the available evidence. The main concerns raised in the previous round have been addressed adequately. While some polishing would still be helpful, I do not see major remaining scientific concerns.