PONE-D-24-25991First-line glaucoma monotherapy medication patterns in Finland during 1995–2019 based on a population-based studyPLOS ONE

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

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Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: No

Reviewer #5: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

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5. Review Comments to the Author

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Reviewer #1: As a reviewer for this article, I would like to express my overall positive evaluation of the study. The research, which analyzes the patterns of first-line glaucoma monotherapy in Finland from 1995 to 2019, undoubtedly involves a significant amount of work. It provides important insights into the treatment trends for glaucoma patients. The findings regarding the shift from beta-blockers to prostaglandin analogs, as well as the declining persistence rates among patients. At the same time, I was impressed by Table 2, Fig3, and Fig6. I was pleasantly surprised by the series of issues reflected through the indicator of delayed refills. Although the article focuses on the situation in Finland, I believe these results hold significant relevance for global clinical practice and future research. I appreciate the substantial contributions made by the author team in this study.

However, I believe some minor revisions are necessary before publication.

1. The subheadings of various sections in the article are of similar boldness and size. I recommend redistributing them to facilitate readers' immediate understanding of the overall structure of the article.

2. While the references provided by the authors are indeed well-targeted and authoritative, and they appear in their appropriate locations, it is worth noting that many of them are over 5 years old, with some reaching 10 years or even 20 years. In particular, references 5-8, which aim to showcase the research on medication adherence among glaucoma patients and highlight the importance of adherence in disease control, are review articles from 13-16 years ago. If possible, replacing these with more recent literature could enhance the persuasiveness of the article's arguments.

3. In the discussion section, a deeper exploration of the potential factors leading to changes in medication usage patterns could be beneficial, such as patients' subjective experiences, changes in healthcare policies, and the impact of patient education. The article frequently mentions that prostaglandins rapidly replaced beta-blockers; however, we know that prostaglandins are typically administered once daily. Could you further analyze whether the increased adherence is due to the reduced frequency of medication or fewer adverse effects associated with the drugs? I believe such analysis and outlook would provide meaningful guidance for clinical practice.

4. In line 340, you mention that the first-line medication situation in Finland differs from that in Israel. As this article is set to be published in a global open-access journal, it would be beneficial to provide an explanation for this difference to enhance its international relevance. A similar situation arises in line 308 regarding the potential reasons for better medication adherence among glaucoma patients in the United States. Addressing these points would significantly improve the article.

Reviewer #2: In the introduction, there is a need for the disease "glaucoma" to be well defined.

Minor grammatical edits is required and highlighted.

The manuscript describes a technically sound scientific research with data that supports the conclusion.

The statistical analysis is sound and rigorous with good illustrations.

Results were clearly presented. However, there are a lot of repetition of results in the discussion.

Reviewer #3: This is a very interesting study created with an amount of longitudinal linked data that is rarely available. Nonetheless, the small number of patients included in the analysis is something to be considered (n=141).

Lines 55 to 57 – laser is not only a first line therapy for those specific cases. It has a much broader indication as first-line therapy

Very good methodology.

Results – would mention the prevalence of glaucoma patients (as per this methodology) in the population sample - +- 2.2% which matches other studies from European countries. (eg https://pubmed.ncbi.nlm.nih.gov/28368997/)

Figure 3 – what is the unit of the y axis?

Figure 3 – what do you believe is the reason for the PGA trend shape? Increasing until 2014 and then decreasing?

Would maybe say something at the end of results regarding the frequency of switching to another monotherapy PGA versus switching to a fixed combination with timolol.

Discussion

Lines 307 to 315 – could the amount of PXF glaucoma in Finland (versus almost anywhere else) be a factor in the need to move from the initial therapy sooner?

Would it make sense to discuss the possibility for tachyphylaxis with betablockers?

I understand that the lower mean age with the beta blockers may indeed be biased, but could this also be because older patients may have more pathology that contra indicates betablockers and also the avoidance of PGA in young people since they can lead to PGA-related orbitopathy?

Reviewer #4: Very interesting research. Please expand on the possible reasons/implications of these findings in order to appeal to clinicians/a wider audience who may be interested in policy changes or intervention planning

Reviewer #5: This study investigates long-term patterns in first-line glaucoma monotherapy in Finland over a 25-year period, providing insights into treatment trends and persistence rates. It reveals an early decline in therapy continuation and a shift from beta-blockers to prostaglandin analogues, underscoring ongoing challenges in maintaining adherence to glaucoma treatment

• In the methods section: "The authors chose non-parametric tests (Mann–Whitney U and Kruskal–Wallis) due to data skewness. For added clarity, the authors might specify which variables were analyzed with each test, as this context would strengthen the rationale behind the analysis choices.

• In the discussion: the authors reference the same study from Israel (2003–2012) multiple times, which may create the impression of separate studies. Combining all comparisons with this study into a single paragraph would improve clarity and coherence.

• In the discussion: While the conclusion is strong, the authors could further highlight the broader implications of the findings and suggest practical pathways for enhancing glaucoma care. They might consider adding a brief note on future research directions, such as exploring factors influencing non-persistence, assessing the impact of newer treatment options on long-term outcomes, or evaluating patient education strategies to improve adherence

• In the discussion: The limitations are valid. To further strengthen this section, consider noting the potential impact of excluding patients who started on combination therapy, as this may affect the representativeness of the findings, making them most applicable to patients initiating monotherapy.

• In the discussion: The study reveals a significant early decline in the continuation of first-line monotherapy, as well as a shift from beta-blockers to prostaglandin analogues as the preferred first-line therapy. Notably, prostaglandin analogues showed greater persistence beyond five years compared to beta-blockers. Expanding the discussion to explore possible reasons for both the early decline and this therapeutic shift—such as factors affecting adherence, improved intraocular pressure (IOP) control, convenience, or fewer side effects—could provide deeper insights into the practical implications for glaucoma management.

• "The authors could consider revising the text to use active voice, as this adjustment may enhance the clarity and engagement of the writing."

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Reviewer #1: Yes: Bin Lin

Reviewer #2: Yes: Ojo Perpetua ODUGBO

Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

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First-line glaucoma monotherapy medication patterns in Finland during 1995–2019 based on a population-based study

PONE-D-24-25991R1

Dear Dr. Purola,

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Kind regards,

Andrzej Grzybowski

Academic Editor

PLOS ONE

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