Symptomatic Adverse Events and Quality of Life Related to Incretin-Based Medicines for Obesity: A Systematic Review Involving >400,000 Subjects

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript obesities-3555789 summarizes symptomatic adverse events of incretin-based therapies by conducting a systematic review. This manuscript is well-written and comprehensive; however, minor revision would be helpful.

1. Please mention the specific type of adverse events at the X axis title of Figures 2-6 (e.g. % of patients reporting AE -> % of patients reporting nausea).
2. Adding a figure or a table summarizing the data of body composition changes (#3.3) will increase readability.

Author Response

Comment 1: Please mention the specific type of adverse events at the X axis title of Figures 2-6 (e.g. % of patients reporting AE -> % of patients reporting nausea). 

Response: Thank you for your comment. We have implemented this in full by changing the axis titles, e.g. from “% of patients reporting an AE” to “% of patients reporting nausea”. This has been implemented as appropriate for each figure.

Comment 2: Adding a figure or a table summarizing the data of body composition changes (#3.3) will increase readability.

Response: Thank you for your comment. We have replaced the text with Table 1 in Section #3.3 to increase readability.

Reviewer 2 Report

Comments and Suggestions for Authors

Current report described the effects of incretin-based therapies (IBTs) on the symptomatic adverse events (AEs) and patient-reported outcomes reported in 48 clinical and 33 real-world evidence (RWE) studies. Please conduct the concerns below.

1. Bias in the database search was not mentioned. Why?
2. Cochrane review methodology to identify citations seems better to follow a scientific report but not a book as described in Reference 25^th.
3. In the used data, “more female than male patients” that needs to discuss in detail.
4. In each figure, results were hard to follow. Please describe the details in legends. Additionally, variations were not indicated in clear.
5. The dermatologic and immunologic events were not identified in the current studies. It needs a suitable reason to explain this weakness.
6. Novelty of current report was not mentioned in conclusion.

Author Response

Comment 1: Bias in the database search was not mentioned. Why?

Response: A bias assessment of the included studies was performed as part of the systematic review. We have included the following statements in the manuscript:

• In the methods section: “Quality appraisal of randomized trials, non-RCTs, and RWE was conducted using the Cochrane risk-of-bias (RoB) tool [26], the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies [27], and the methodology checklist provided in Appendix D of the NICE guidelines manual [28], respectively.”
• In the results section: “Based on the Cochrane RoB tool, the quality of the RCT studies was rated as high, although there was one open-label study, and reporting of attrition and detection bias was unclear in 23/41 and 18/41 publications, respectively. Based on the EPHPP Quality Assessment Tool for Quantitative Studies, the quality of the two non-RCT studies included was moderate. For the RWE publications, the assessment was generally positive, or the questions were not applicable.”

Comment 2: Cochrane review methodology to identify citations seems better to follow a scientific report but not a book as described in Reference 25^th.

Response: We referenced the print edition. However, latest methodology was used, and we have updated the reference to the latest online version

Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.5 (updated August 2024). Cochrane, 2024. Available from www.training.cochrane.org/handbook.

Comment 3: In the used data, “more female than male patients” that needs to discuss in detail.

Response: Thank you for your comment. In the discussion we have added the following statement to address this known issue in obesity studies.

“In high-income countries like the US, Canada, Australia, and most of Europe, obesity rates are comparable between men and women. However, a higher proportion of women participate in weight-loss clinical trials [89]. This could be due to several reasons, including higher health-seeking behavior and stronger societal pressures related to body image.”

Comment 4: In each figure, results were hard to follow. Please describe the details in legends. Additionally, variations were not indicated in clear.

Response: We appreciate the reviewer’s constructive comments. In the revised version of the manuscript we have now amended the figures to include specific labels i.e. ‘clinical publications’ and ‘RWE publications’ instead of ‘A’ and ‘B’. The number of publications for each IBT has been stated more clearly i.e. ‘Liraglutide (16 publications)’, and we have rewritten the figure legend to indicate the bubble sizes for the graphs.

The intent of this systematic review was to present data in a descriptive way. Variations were not indicated nor was an attempt to estimate variability made based on pooled or meta-analytical approach. 

Comment 5: The dermatologic and immunologic events were not identified in the current studies. It needs a suitable reason to explain this weakness.

Response: Thank you for raising this point, indeed we have identified these AEs. We have added a short section (#3.6) in the manuscript to address these AEs. We have added that these AEs were not systematically listed in all the publications, most likely due to heterogeneity in study observations and methods of data capture, and therefore only a limited number of studies report on this. We have now added the percentages available from the included papers. As can be seen, the majority of dermatologic AEs were injection site reactions. Other AEs included rashes, pruritus, urticaria, cellulitis, and oedema peripheral. Immune system disorders were investigated in one publication, but no events were reported.

Comment 6: Novelty of current report was not mentioned in conclusion.

Response: We previously included a statement in the discussion section: “To the best of our knowledge, this is the first review to systematically gather data relating to AEs associated with IBTs for the treatment of obesity.” We have reiterated this point in the conclusion.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript is well written and followed a robust methodology of systematic reviews.

Author Response

Comment: The manuscript is well written and followed a robust methodology of systematic reviews.

Response: Thank you for your review.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

It has been revised in a good way.