Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript addresses an interesting and clinically relevant question and has the potential to make a useful contribution to the literature. The methodology is generally appropriate, but the manuscript would benefit from greater methodological clarity, more cautious interpretation of findings from small subgroups and heterogeneous studies, and improved presentation. Addressing the above comments would substantially strengthen the manuscript. I therefore recommend revision.

 

1. The authors should carefully review and clarify the numbers reported in the PRISMA flow diagram and the corresponding text, particularly the number of records excluded at each stage. The reported numbers should be internally consistent throughout the manuscript.

 

2. Several pooled outcomes show substantial statistical heterogeneity, particularly among healthy participants. The authors should provide a more detailed discussion of the potential sources of heterogeneity and avoid overinterpreting pooled estimates when heterogeneity is high.

 

3. The evidence for patients with coronary artery disease and metabolic syndrome is based on only two and one study, respectively. The conclusions regarding these populations should therefore be clearly described as preliminary or exploratory, and stronger clinical recommendations should be avoided.

 

4. Most included studies evaluated acute or short-term exercise interventions, whereas relatively few assessed longer-term interventions. The authors should emphasize this distinction when interpreting the findings and clarify whether the observed effects can reasonably be extrapolated to chronic exercise programs.

 

5. Important factors such as diet/meal timing, sleep, habitual physical activity, medication use, and environmental conditions were not consistently controlled across studies. This limitation deserves greater emphasis because these factors may independently influence circadian and cardiometabolic responses.

 

6. The finding of higher MPV following morning exercise in healthy individuals is interesting; however, the clinical significance of this acute change should be discussed cautiously. The authors should avoid implying that morning exercise necessarily increases thrombotic or ischemic risk without direct clinical outcome data.

 

7. The findings in patients with diabetes are inconsistent across individual studies, and the included studies also differ in exercise modality and diabetes type. The authors should provide a clearer explanation of this heterogeneity and be cautious when drawing conclusions applicable to all patients with diabetes.

 

8. The Abstract and Conclusions should be carefully aligned with the actual strength and certainty of the evidence. In particular, the manuscript should emphasize that there is currently no universally superior time of day for exercise, rather than suggesting a definitive advantage of evening exercise.

 

9. The manuscript would benefit from careful English-language editing. There are also several typographical, grammatical, figure-caption, and formatting issues that should be corrected throughout the manuscript.

 

 

Author Response

Dear reviewer, hello! Regarding your suggestions, we have attached them. Thank you very much for your efforts and support on this manuscript!

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

1. “Systematic reviews and original research articles should have a structured abstract of around 250 words and contain the following headings: Background/Objectives, Methods, Results, and Conclusions.” Why does the abstract you submitted contain this passage?

2. As this is a meta-analysis, I believe it should be registered with PRISMA. The current methodology states that the search scope begins in 2000, yet the results indicate that 8,889 ‘articles published before 2000’ were excluded; this represents a logical inconsistency. Furthermore, ‘lack of author information’ is cited as a reason for large-scale exclusion—can this really be used as a valid basis for excluding literature?

3. The article claims to have carried out a Grade assessment, but in fact no evidence of this has been provided. Furthermore, whilst the abstract states there are 41 references and 799 participants, how is it possible that the main text mentions only 21 studies included in the meta-analysis yet still arrives at a total of 799 participants? I believe there are serious and obvious errors in the statistical analysis methods.

There are far too many unbelievable errors here; for instance, parts of the declaration have even been included directly under ‘6. Patents’. Has the author actually read this article through carefully? Why are there so many elementary errors? Why would anyone fabricate data in a review article?

Comments on the Quality of English Language

Perhaps the author doesn’t understand English at all, but even so, could you please use a translation programme to translate it and then take a look at the specific content?

Author Response

Dear reviewer, hello! Regarding your suggestions, we have attached them. Thank you very much for your efforts and support on this manuscript!

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript addresses an important and timely question regarding whether the cardiovascular and metabolic effects of exercise timing differ between healthy and cardiometabolic populations. The restriction to randomized controlled and randomized crossover trials is a strength, and the population-specific presentation is potentially valuable. However, several methodological and reporting issues need to be addressed before the findings can be interpreted with confidence. In particular, clarification is required regarding the classification and number of included studies, the statistical handling of crossover trials, the definition of morning versus evening exercise, the consistency between the quantitative and qualitative syntheses, and the presentation of the meta-analytic results. Addressing these issues would substantially improve the methodological transparency and interpretability of the manuscript.

1. The manuscript reports 41 eligible studies and 799 participants, but subsequently states that 21 studies (references 16–36) were cited in the meta-analysis, while the qualitative synthesis refers to additional studies. Moreover, the exercise-type counts do not clearly reconcile with the total of 41 studies, and the risk-of-bias section reports 31 studies with some concerns and 8 at high risk while the graphical abstract presents a different classification that sums to 43 studies. In addition, reference 57 appears to duplicate reference 29, although both are used as separate studies in the text. Please provide a complete study-level table and carefully reconcile all study counts, participant numbers, study-design classifications, and reference numbers across the PRISMA diagram, main text, figures, and supplementary material.
2. Because crossover studies generate paired observations, the meta-analysis should account for the within-participant correlation between morning and evening conditions rather than treating the two conditions as independent parallel groups. The Methods section does not state how paired means and standard deviations were handled, whether within-participant correlations were extracted or imputed, or how carryover/period effects were incorporated into the effect-size calculations. Please provide the exact method and equations used to calculate effect sizes and standard errors for crossover trials, including the assumed or derived correlation coefficients where applicable, and explain how studies with multiple periods or outcomes were handled.
3. Please correct and standardize the effect-measure labels in Figures 3–6. The Methods and Results state that standardized mean differences (SMDs) were used, and the numerical estimates are reported as SMDs in the text; however, the forest plots are labeled “OR (95% CI).” This is inconsistent with the stated analysis and may substantially confuse readers regarding the interpretation of the pooled estimates. Please verify the underlying statistical calculations and revise the graphical labels, axis titles, and legends accordingly. It would also be preferable to clearly state whether the reported effect direction consistently represents morning minus evening or evening minus morning across every analysis.
4. Provide the GRADE assessment results rather than only describing the intention to apply GRADE. The Methods state that GRADE was applied to blood pressure, blood glucose, triglycerides, and MPV, but no Summary of Findings table, certainty ratings, or domain-specific downgrading decisions are presented in the manuscript. Please provide the GRADE evidence profiles and explain the reasons for downgrading or maintaining certainty for each primary outcome, particularly in view of the small number of studies, substantial heterogeneity for several outcomes, risk-of-bias concerns, and the predominance of acute exercise studies. In addition, references 14 and 15 are PRISMA-ScR and PRISMA-DTA papers rather than appropriate general methodological sources for the stated PRISMA 2020 framework or the specific publication-bias rationale. These references should be checked and replaced with appropriate methodological sources.
5. I think you should clarify the operational definition of “morning” and “evening” exercise and ensure that all included studies conform to these definitions. The Methods define the morning period as 06:00–11:00 and the evening period as 16:00–21:00, yet several included studies are explicitly described in the reference list as comparing morning with afternoon exercise rather than morning with evening exercise. This is particularly important for the diabetes and metabolic-syndrome analyses, where studies comparing morning versus afternoon exercise appear to be interpreted as evidence for morning versus evening exercise. Please provide the exact exercise time for each included study, explain the prespecified classification rule, and conduct appropriate sensitivity or subgroup analyses if afternoon studies were included. The distinction is important because “afternoon” and “evening” should not automatically be treated as equivalent exposure categories.
6. The eligibility criteria define diabetic individuals as including both diabetes and prediabetes, whereas the Results subsequently combine prediabetes, type 1 diabetes, and type 2 diabetes in a single subgroup. These populations have substantially different metabolic and physiological characteristics and may plausibly respond differently to exercise timing. In addition, one of the randomized trials classified under healthy individuals enrolled overweight/obese men, while another enrolled healthy exercise-trained adults. Please justify these classifications according to the prespecified eligibility criteria and, where possible, provide separate analyses or at least clearly acknowledge the resulting clinical heterogeneity. For example, the cited Moholdt trial specifically studied overweight/obese men rather than a conventionally healthy normal-weight population.
7. The diabetes meta-analysis includes three randomized crossover studies, whereas the qualitative synthesis refers to six diabetes-related studies and describes some afternoon-versus-morning findings as evening-versus-morning effects!!! Similarly, the qualitative hypertension section reports several studies favoring evening exercise despite the quantitative analysis showing no significant pooled difference. Please clearly distinguish studies contributing to quantitative synthesis from those considered only qualitatively, explain why particular studies could not be pooled, and ensure that the direction and timing of the interventions are described accurately.
8. The analysis indicates higher MPV immediately after morning exercise and during recovery, but the Discussion and Conclusion describe platelet-related outcomes as part of “more favorable regulation” associated with evening exercise. A higher MPV is not intrinsically a favorable outcome, and the included evidence appears to concern acute post-exercise responses rather than clinically meaningful long-term cardiovascular outcomes. Please distinguish statistical differences in an acute biomarker from evidence of clinical benefit or harm and avoid implying that morning exercise has a sustained prothrombotic or ischemic effect unless this is directly supported by the included studies. The discussion should also more clearly distinguish acute physiological responses from chronic adaptations.
9. Several citation issues should be corrected. For example, reference 57 appears to duplicate reference 29; reference 44 is apparently omitted from one of the statements claiming that all included studies were fully reported; and the manuscript uses references 14 and 15 as methodological support for publication-bias decisions even though they concern PRISMA extensions for scoping and diagnostic-accuracy reviews. The manuscript should also verify that every mechanistic statement in the Discussion is supported by the cited source and that observational evidence is clearly distinguished from randomized intervention evidence. For example, reference 11 reports observational associations between the timing of physical activity and incident cardiovascular disease rather than an exercise-timing randomized trial, so causal language should be avoided when discussing this evidence.
10. The search for this article was conducted more than a year ago and should therefore be updated. In addition, the full Embase search strategy should be provided in the supplementary file to ensure the reproducibility and repeatability of the search.
11. Figure 1 (PRISMA flow diagram) appears to be based on an outdated version of the PRISMA guidelines. Please use the most recent version of the PRISMA flow diagram. In addition, when submitting the revised manuscript, please provide the latest version of the PRISMA checklist. I would like to verify the revised manuscript against the PRISMA checklist because several aspects of the manuscript do not appear to be fully consistent with PRISMA reporting requirements. For example, according to the PRISMA checklist, the supplementary materials should include a list or table of studies that were excluded at the full-text screening stage, together with the specific reasons for their exclusion. However, I could not identify such a table in the current supplementary file. Please revise the manuscript and supplementary materials carefully and ensure that all relevant reporting items are addressed in accordance with the latest PRISMA checklist. This will allow me to properly assess the methodological and reporting quality of the manuscript during the next round of revision.

Author Response

Dear reviewer, hello! Regarding your suggestions, we have attached them. Thank you very much for your efforts and support on this manuscript!

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors,

Thank you for your careful consideration. All of my comments have been addressed. I have no further comments. 

Author Response

Dear reviewer：
We sincerely thank the reviewer for taking the time to reassess our revised manuscript and for confirming that all comments have been addressed. We are especially grateful for the reviewer’s thoughtful feedback and continued support throughout the review process. These contributions have been invaluable in strengthening our manuscript, and we greatly appreciate the care and expertise the reviewer has devoted to our work.

Reviewer 2 Report

Comments and Suggestions for Authors

Following the author’s revisions, the quality of the article has improved to some extent; its acceptance for publication may be considered.

Author Response

Dear reviewer：

We sincerely thank the reviewer for carefully reassessing our revised manuscript and for recognizing the improvements made in response to the comments. We are particularly grateful for the reviewer’s thoughtful guidance, continued support, and recommendation that the article be considered for publication. The reviewer’s feedback has made a valuable contribution to improving the quality and clarity of our work, and we truly appreciate the time and expertise devoted to our manuscript.