Aflibercept and Brolucizumab in Diabetic Macular Edema: A Focused Review of Efficacy, Safety, and Clinical Considerations

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors I am pleased to review the manuscript by Ana Maria Dascalu and colleagues, entitled “Aflibercept and Brolucizumab in Diabetic Macular Edema: A Focused Review of Efficacy, Safety, and Clinical Considerations”, which provides a narrative overview of two important anti-VEGF agents used in the management of diabetic macular edema (DME). The topic is clinically relevant, timely, and of interest to ophthalmologists involved in retinal disease management. Overall, the manuscript is well written, logically structured, and comprehensively addresses pharmacology, efficacy, safety, and real-world considerations.   I believe the authors may consider the following revisions to further strengthen the manuscript: 1. Please consider adding a list of abbreviations before the reference section to facilitate quick reference for readers.   2. In the section introducing “Among currently available anti-VEGF agents,” it would be helpful to include all anti-VEGF agents currently used in clinical practice (Clin Case Rep. 2025;13(10):e71250). In addition, the authors should clearly explain why the present manuscript focuses exclusively on a comparison between aflibercept and brolucizumab. For example, is this choice based on treatment recommendations within the authors’ clinical practice in Romania? Are aflibercept and brolucizumab the only agents approved for DME in Romania, or is there another rationale supporting the initial scope of this review? Clarifying this point would strengthen the justification for the manuscript’s focus.   3. In the manuscript file I downloaded, Table 2 appears without visible table borders. In addition, I suggest formatting Tables 1 and 2 using a three-line table style. It would also be helpful to adjust the font size or row spacing of Table 1 to ensure that it fits within two pages.   4.Although treatment burden is discussed, the authors may consider adding a brief discussion, either in the Discussion section or another appropriate section, addressing issues related to drug cost and patient accessibility for these two agents, as these factors are highly relevant to real-world clinical decision-making. (Pharmaceuticals (Basel). 2025;18(11):1620. ; JMIR Public Health Surveill. 2023;9:e49852. ; BMC Health Serv Res. 2022;22(1):573. )

Author Response

Dear reviewer,

Thank you for your time and meaningful comments that helped us increase the value of our manuscript. We have carefully revised our paper, addressing to all issue, as follows:

Reviewer 1:

I am pleased to review the manuscript by Ana Maria Dascalu and colleagues, entitled “Aflibercept and Brolucizumab in Diabetic Macular Edema: A Focused Review of Efficacy, Safety, and Clinical Considerations”, which provides a narrative overview of two important anti-VEGF agents used in the management of diabetic macular edema (DME). The topic is clinically relevant, timely, and of interest to ophthalmologists involved in retinal disease management. Overall, the manuscript is well written, logically structured, and comprehensively addresses pharmacology, efficacy, safety, and real-world considerations.   I believe the authors may consider the following revisions to further strengthen the manuscript:

1. Please consider adding a list of abbreviations before the reference section to facilitate quick reference for readers.  

Response: we added a list of abbreviations before References, as required.

2. In the section introducing “Among currently available anti-VEGF agents,” it would be helpful to include all anti-VEGF agents currently used in clinical practice (Clin Case Rep. 2025;13(10):e71250). In addition, the authors should clearly explain why the present manuscript focuses exclusively on a comparison between aflibercept and brolucizumab. For example, is this choice based on treatment recommendations within the authors’ clinical practice in Romania? Are aflibercept and brolucizumab the only agents approved for DME in Romania, or is there another rationale supporting the initial scope of this review? Clarifying this point would strengthen the justification for the manuscript’s focus.  

Response: We revised this section, as required and updated the references. We added:

Multiple anti-VEGF agents are currently available for the treatment of diabetic macular edema, including Aflibercept, Bevacizumab, Brolucizumab, Conbercept, Ranibizumab, and Pegaptanib,  and more recently Faricimab 9(Clin Case Rep. 2025;13(10):e71250). While broad comparisons across all agents may provide a general overview of treatment efficacy, they often limit clinically practical interpretation. A more focused comparison between therapies with clearly distinct pharmacologic and clinical characteristics may therefore be more informative for decision-making in daily practice.

In this context, aflibercept and brolucizumab represent two agents with contrasting therapeutic profiles. Aflibercept is widely used as a reference anti-VEGF therapy supported by extensive long-term evidence, whereas brolucizumab was introduced with the aim of improving treatment durability but has raised safety considerations requiring careful patient selection. In routine clinical practice in our region, these agents are frequently selected as first-line or switch options, making their comparison particularly relevant when balancing treatment burden against safety profile.

 

3. In the manuscript file I downloaded, Table 2 appears without visible table borders. In addition, I suggest formatting Tables 1 and 2 using a three-line table style. It would also be helpful to adjust the font size or row spacing of Table 1 to ensure that it fits within two pages.  

Response: We have corrected the table 1 and 2 as required.

 4.Although treatment burden is discussed, the authors may consider adding a brief discussion, either in the Discussion section or another appropriate section, addressing issues related to drug cost and patient accessibility for these two agents, as these factors are highly relevant to real-world clinical decision-making. (Pharmaceuticals (Basel). 2025;18(11):1620. ; JMIR Public Health Surveill. 2023;9:e49852. ; BMC Health Serv Res. 2022;22(1):573. )

Response: Thank you for the suggestion. We totally agree that given that both aflibercept and brolucizumab are high-cost biologic agents requiring repeated intravitreal administration, a concise discussion of pricing considerations, reimbursement variability, and potential implications for patient adherence and healthcare resource utilization would strengthen the manuscript’s real-world applicability and policy relevance. We have added in the Discussions a section about costs and patients accessibility, as suggested.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors reviewed the current knowledge about the efficacy and safety of aflibercept and brolucizumab in eyes with DME. While the paper is generally well written, there are some questions about the literature search and review design. Specific comments are listed below.

 

1. While the authors searched the literatures between 2015 and 2025, the first report on brolucizumab appeard in 2022. Thus, the search should have included many papers on aflibercept. However, the data is barely reflected in the review. The meaningful comparison is in Table 1 and 2, and the data is based on 9 studies. Given that the authors investigated many papers on real-world aflibercept data, more detailed analysis incorporating the data with real-world brolucizumab data would enhance the value of the review.
2. Related to the above comment, the authors sometimes state a generalized comment such as “These studies suggest that patients achieving early disease control may be more likely to maintain stable visual and anatomical outcomes on extended dosing regimens [20-26]” in line 269. However, to address the question, the data comparing early and late disease control. Wasn’t there a specific study that addressed the issue? The value of the narrative review lines partly in summarizing many studies that address specific comments. If the authors focus primarily on RCTs, a systematic review would be more suitable.
3. Line 216, VIVID and VISTA is associated with Table 1, but they do not appear in the table.
4. While the authors concluded that brolucizumab is better in durability, it is not totally proven by the presented data. A head-to-head comparison was done in only one study (Rubsam et al.). The trials compared brolucizumab 12w vs aflibercept 8w. The design does not tell if alibercept 12w is inferior to brolucizumab 12w or not.
5. Diabetic retinopahy is referred in the abstract, but it is not the focus of the review. Considering that anti-VEGF agents are also used for diabetic retinopathy, removing the term may help to avoid misunderstandings.

Author Response

Dear reviewer,

Thank you for your time and meaningful comments that helped us increase the value of our manuscript. We have carefully revised our paper, addressing to all issue, as follows:

The authors reviewed the current knowledge about the efficacy and safety of aflibercept and brolucizumab in eyes with DME. While the paper is generally well written, there are some questions about the literature search and review design. Specific comments are listed below.

1. While the authors searched the literatures between 2015 and 2025, the first report on brolucizumab appeard in 2022. Thus, the search should have included many papers on aflibercept. However, the data is barely reflected in the review.

Response: Thank you for the observation. We totally agree that aflibercept has a longer and broader evidence base in DME compared with brolucizumab, which first reported pivotal DME data in 2022. We added in Table 1 the studies using Aflibercept only in DME, based on the fact that this agent appeared prior to brolucizumab and there is more clinical evidence in using aflibercept. We discuss the significant findings in studies documenting aflibercept 2 mg in RCT and real-life studies, as well as the most recent use of 8 mg aflibercept.

2. The meaningful comparison is in Table 1 and 2, and the data is based on 9 studies. Given that the authors investigated many papers on real-world aflibercept data, more detailed analysis incorporating the data with real-world brolucizumab data would enhance the value of the review.

Response: Thank for the comment. We have revised the tables and added other real-world studies documenting the clinical outcomes and safety of Brolucizumab, as recommended. We enlarged the discussion including the main findings in these studies.

 

3. Related to the above comment, the authors sometimes state a generalized comment such as “These studies suggest that patients achieving early disease control may be more likely to maintain stable visual and anatomical outcomes on extended dosing regimens [20-26]” in line 269. However, to address the question, the data comparing early and late disease control. Wasn’t there a specific study that addressed the issue? The value of the narrative review lines partly in summarizing many studies that address specific comments. If the authors focus primarily on RCTs, a systematic review would be more suitable.

Response: We thank the reviewer for this comment. We agree that generalized statements should be supported by clearly identified evidence, particularly when addressing specific clinical questions such as the relationship between early disease control and long-term outcomes.

In the revised manuscript, we have clarified the relevant section by explicitly identifying the key studyies that directly compared early versus delayed disease control and their association with subsequent visual and anatomical outcomes.

Regarding the reviewer’s suggestion that a systematic review may be more appropriate if the focus is primarily on randomized controlled trials (RCTs), we would like to clarify that our intent was to provide a narrative synthesis integrating evidence from RCTs, extension studies, and real-world data to offer a clinically contextualized perspective. To make this clearer, we have revised the Methods/Introduction section to explicitly describe the scope and rationale of the narrative approach and to explain why a formal systematic review methodology was not applied.

We believe these revisions enhance the clarity, transparency, and value of the manuscript while maintaining its intended narrative framework.

 

4. Line 216, VIVID and VISTA is associated with Table 1, but they do not appear in the table.

Response: Thank you for the observation. We have corrected. In table 1, we discussed studies with aflibercept only in treatment of DME.

 

5. While the authors concluded that brolucizumab is better in durability, it is not totally proven by the presented data. A head-to-head comparison was done in only one study (Rubsam et al.). The trials compared brolucizumab 12w vs aflibercept 8w. The design does not tell if alibercept 12w is inferior to brolucizumab 12w or not.

Response: thank you for your observation. This is indeed true. We rephrase the paragraph, stating that though the results may suggest that brolucizumab is better in durability,more evidence are needed to sustain this idea. The trials compared brolucizumab 12w vs aflibercept 8w, but there are no data comparing with aflibercept 12w.

6. Diabetic retinopahy is referred in the abstract, but it is not the focus of the review. Considering that anti-VEGF agents are also used for diabetic retinopathy, removing the term may help to avoid misunderstandings.

Response: Thank you for the observation, we have corrected.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The reviewer has no additional comment.