Title: The Safety and Efficacy of Liraglutide Combined with Metformin in Clinical Treatment
of Polycystic Ovary Syndrome Patients: A Meta-Analysis
Version: 1 Date: 02 Feb 2025
Reviewer's report:
The manuscript presents a meta-analysis that compares efficacy and safety of a dual
therapeutic intervention with liraglutide and metformin for Polycystic Ovary Syndrome (PCOS)
management. Authors conducted an exhaustive search in several databases and included 12
randomized controlled trials (RCTs) in their analysis. Report findings reveal that dual therapy
is beneficial over monotherapy with metformin with regard to several important outcomes, but
with increased gastrointestinal-related adverse events. Although with a well-designed study,
several concerns regarding the statistical, scientific, grammar, and structure aspects prevail.
Major Remarks
Heterogeneity: Heterogeneity between many included studies in the review, according to meta-
analysis, is high. Despite using a random-effect model for dealing with high heterogeneity, it
is important to explore sources of variation, including variation in patient populations, disease
severity, dosing with drugs, and administration protocols. There must be a deeper analysis in
the manuscript regarding sources of variation in such studies.
Small Study Population and Short Study Duration: Authors acknowledge the drawback of small
study populations and short duration in trials included in analysis. There is an impairment in
generalizability and a high chance of significant bias in such studies. In future studies, GWAS
studies, larger study populations and prolonged follow-up duration must be included to confirm
observations.
Lack of Consistency in Reporting: There is a lack of uniformity in reporting baseline values in
studies included in review. For example, several studies don't report body mass index (BMI).
Notwithstanding, such an omission not having an impact in any manner on meta-analysis, but
such biases can develop in case of such studies. There can be an improvement in overall validity
with a stricter and uniform reporting criterion in such included studies.
Clinical Significance: Despite having established statistical significance for many outcomes, its
clinical importance deserves a deeper analysis. For example, a significant difference in BMI
doesn't necessarily mean a meaningful improvement in patients' status. A deeper discussion must
explore in detail how such a finding can actually impact the patient population in a significant
manner.
Dose of Liraglutide and Metformin: The studies under consideration have a lot of variation in
dosages of liraglutide and metformin taken. Some studies report dosages of liraglutide at 0.6
mg TID, and yet others at 1.2 mg QD, with varying dosages of metformin, such as 500 mg TID
in one, 1000 mg BID in another, and 250 mg TID in a third one. All such variation in dosages
can have a significant impact in terms of effectiveness in treatment. The studies don't explore
why such a variation in dosages and its impact in terms of effectiveness in treatment must go
into a discussion in the analysis.
Minor Remarks
The discussion section needs to acknowledge previous findings in the genetic nature of
translational and post-translational regulation and vitamin D receptor polymorphisms in PCOS
aetiology with the following references:
1) Heidarzadehpilehrood R., Pirhoushiaran M., Osman M.B., et al. (2024) High-Throughput
RNA Sequencing of Peripheral Blood Mononuclear Cells Reveals Inflammatory State in
Women with PCOS. Archives of Medical Research 56, 103129. 2) Heidarzadehpilehrood R.,
Hamid H.A. & Pirhoushiaran M. (2024) Vitamin D receptor (VDR) gene polymorphisms and
risk for polycystic ovary syndrome and infertility: An updated systematic review and meta-
analysis. Metabolism Open, 100343. 3) Heidarzadehpilehrood R. & Pirhoushiaran M. (2024)
Biomarker potential of competing endogenous RNA networks in Polycystic Ovary Syndrome
(PCOS). Non-coding RNA Research 9, 624–640.
The manuscript contains a variety of minor grammar mistakes and stylistic discrepancies. In
specific, in the "Results" section, excessive use of "However" and "Although" for starting
sentences reflects a need for increased cohesion at a transition level. Implementation of such
edits will make the overall manuscript easier to read.
For headings for Figures and Tables, Figures 2 and 3 have headings "Bias risk distribution map
for the literature" and "The literature bias risk summary map," respectively. Nevertheless, such
headings don't specify the exact contents of the maps, including specific biases being evaluated,
and don't specify definitions for respective items in the map. Likewise, in Table 1, there is no
general statement for the acronyms and abbreviations utilized; for example, 'T/C' isn't mentioned
in the accompanying legend for the table.
For uniformity in abbreviations, in the manuscript, 'FBG' is utilized for representing fasting
blood glucose, but sometimes full form is utilized in its stead. In addition, 'two-hour postprandial
glucose' isn't consistently abbreviated '2hPG' but sometimes full form is utilized for it. There
should be a uniform format adopted in the whole manuscript.