Title: Effects of Metformin on CIMT and FMD in PCOS Patients: a Systematic Review and
Meta-analysis
Version: 0 Date: 29 May 2024
Reviewer:  Hazem Mohamed Salamah
Reviewer's report:
I would like to express my pleasure to review this paper entitled "Effects of Metformin on CIMT
and FMD in PCOS Patients: a Systematic Review and Meta-analysis". The authors sought to
answer whether metformin reduces carotid intima media thickness  and increases flow-mediated
dilation (FMD) or not. However, the study is of low quality, with concerns about the reliability
of the conclusion.
Major revisions:
The results of  the study had very high heterogeneity and the authors results come from single-
arm studies comparing pretreatment values vs. posttreatment values. Moreover, they included
different study designs, including cross-sectional studies, which are not valid for answering
the research question as we are not sure if the outcomes or the intervention happened first.
Furthermore, the CIMT outcome seems to be driven by only one "Akram W, 2023" study, which
is a cross-sectional study, and it causes significant heterogeneity. All these causes raise concerns
regarding the reliability of their results and conclusions.
Authors need to be more rigorous in their study. Here is solutions for this:
1-We can see the high level of significant heterogeneity in the results, which is associated with
different study designs, including in one forest plot. In this case, very high heterogeneity, the
three different designs can't be pooled in one figure and conclusions should not be based on
figure 2 and 3 and 4, Instead, each design should be presented in the frost plot in a different
subgroup or separately in different forest plots and not in the table, as this will be the main
figures of the study.
2-The authors should state how confident they are in their conclusions based on the results of
the different study designs.
3. The author should perform sensitivity analysis through leave-one-out, whenever possible
with heterogeneity present and mention in the results if the sensitivity analysis produced any
significant change in the pooled estimate.
Other measures authors can take are to consider performing  more subgroups based on the
dose of metformin. Furthermore, the author should mention the method of measuring the
outcome employed by the included studies, as different methods may present different results
and sensitivity, and perform subgroup analysis based on the method or use a standardized mean
difference in case they found different methods instead of the mean difference.
Minor revisions:
Line 63 "Therefore, monitoring CIMT and FMD may help improve vascular health". I think
monitoring will not help, but reducing  CIMT and increasing FMD will.
Lines 68 to 70 "However, the actual cardiovascular protective effect of metformin on PCOS
remains to be further demonstrated. " what do you mean by  "actual cardiovascular protective
effect "?. This sentence is vague and it seems you mean that CIMT and FMD are the actual
parameters. Why is this? Support it with references. You need to talk more about how CIMT
and FMD directly affect clinical cardiovascular outcomes, with references with that
Line 89 and Line 100. From these, I concluded that CIMT and FMD are the primary outcomes
and NMD is the secondary outcome. It will help to mention clearly which are your primary
outcomes and which are your secondary outcomes.
Line 129 and Figure 1. What do you mean by "10 did not meet the appropriate criteria". I think
all the other causes fall under the term "did not meet the appropriate criteria" if the authors refer
to the inclusion criteria they used to include the studies. Please mention further what criteria
they didn't meet. Furthermore, in line 128, the authors excluded three studies due to "updated
data,"  while in their inclusion criteria, they stated that studies with the most updated data would
be included.
Line 101, line 143, and lines 133–134. The authors stated that they included 5 RCTs, 5 non-
RCTs, and two cross-sectional studies. However, they used Cochrane risk of bias tool 1, which
is designed for RCTs only. I recommend using. The ROBINS-I  tool developed by Cochrane
or to use other tools designed specifically for non-randomized clinical trials and cross-sectional
studies, as the Cochrane risk of bias is not valid for these designs.
The authors should mention in their limitations the fact that their evidence comes from single-
arm studies that lack a control group, even if the studies were RCTs, as they only used data from
one group and compared pre- versus  post-treatment.
The authors should mention the statistical plan of the subgroup analysis they performed and,
based on what criteria, they subgrouped studies  in the Statistical Analysis section.