Title: Efficacy and Safety of PPAR agonists in Primary Biliary Cholangitis: A Systematic
Review and Meta-Analysis of Randomized Controlled Trials
Version: 1 Date: 27 Jan 2025
Reviewer's report:
In this study, Saeedian et al. reviewed the use of PPARs as second-line therapies for PBC. The
study is relevant and well-conducted.
Introduction
Please update the list of medications approved for second-line therapy to include seladelpar and
elafibranor.
Mention that fibrates are used as off-label options in several countries.
Correct the description of bezafibrate: it is a pan-PPAR.
Include information about ciprofibrate and pemafibrate, which have demonstrated efficacy in
small studies.
In Section 3.3, please define "PBS."
Methods
The review reports a large number of outcomes. It is essential to clearly define the primary and
secondary outcomes in the Methods section. What was the definition of pruritus for example?
The combination of different types of PPARs may not be appropriate, as differences exist in
mechanisms of action and outcomes (e.g., safety, ALP reduction rates, and pruritus control).
Are the baseline characteristics comparable between the studies included? Baseline ALP values
strongly impact the effects of lowering and/or normalizing liver tests.
What is the percentage of patients with advanced fibrosis or cirrhosis in the different studies?
This strongly influences the efficacy of second-line therapies and could impact subgroup
analyses.
Is it possible to stratify the analysis by the presence or absence of cirrhosis or advanced fibrosis?
One of the major challenges in PBC meta-analyses is the lack of uniformity in data presentation
across trials, with some reporting lab test results as multiples of the ULN and others as absolute
values. How did the authors address this issue?
Results
Please include baseline liver biochemistry (especially ALP and bilirubin) and the percentage of
patients intolerant to UDCA in Table 1.
Discussion
Since 2015, several meta-analyses on fibrate therapy in PBC have been published. The authors
should compare their findings in depth with these prior studies.
Comment on the potential impact of baseline imbalances (e.g., ALP levels, fibrosis degree,
inclusion criteria) on post-treatment subgroup comparisons.
Minor
There are several typographical errors. Please review and correct them.
Title: Efficacy and Safety of PPAR agonists in Primary Biliary Cholangitis: A Systematic
Review and Meta-Analysis of Randomized Controlled Trials
Version: 1 Date: 27 Jan 2025
Reviewer's report:
In this study, Saeedian et al. reviewed the use of PPARs as second-line therapies for PBC. The
study is relevant and well-conducted.
Introduction
Please update the list of medications approved for second-line therapy to include seladelpar and
elafibranor.
Mention that fibrates are used as off-label options in several countries.
Correct the description of bezafibrate: it is a pan-PPAR.
Include information about ciprofibrate and pemafibrate, which have demonstrated efficacy in
small studies.
In Section 3.3, please define "PBS."
Methods
The review reports a large number of outcomes. It is essential to clearly define the primary and
secondary outcomes in the Methods section. What was the definition of pruritus for example?
The combination of different types of PPARs may not be appropriate, as differences exist in
mechanisms of action and outcomes (e.g., safety, ALP reduction rates, and pruritus control).
Are the baseline characteristics comparable between the studies included? Baseline ALP values
strongly impact the effects of lowering and/or normalizing liver tests.
What is the percentage of patients with advanced fibrosis or cirrhosis in the different studies?
This strongly influences the efficacy of second-line therapies and could impact subgroup
analyses.
Is it possible to stratify the analysis by the presence or absence of cirrhosis or advanced fibrosis?
One of the major challenges in PBC meta-analyses is the lack of uniformity in data presentation
across trials, with some reporting lab test results as multiples of the ULN and others as absolute
values. How did the authors address this issue?
Results
Please include baseline liver biochemistry (especially ALP and bilirubin) and the percentage of
patients intolerant to UDCA in Table 1.
Discussion
Since 2015, several meta-analyses on fibrate therapy in PBC have been published. The authors
should compare their findings in depth with these prior studies.
Comment on the potential impact of baseline imbalances (e.g., ALP levels, fibrosis degree,
inclusion criteria) on post-treatment subgroup comparisons.
Minor
There are several typographical errors. Please review and correct them.
Please review this paper.
user
Title: Efficacy and Safety of PPAR agonists in Primary Biliary Cholangitis: A Systematic
Review and Meta-Analysis of Randomized Controlled Trials
Version: 1 Date: 27 Jan 2025
Reviewer's report:
In this study, Saeedian et al. reviewed the use of PPARs as second-line therapies for PBC. The
study is relevant and well-conducted.
Introduction
Please update the list of medications approved for second-line therapy to include seladelpar and
elafibranor.
Mention that fibrates are used as off-label options in several countries.
Correct the description of bezafibrate: it is a pan-PPAR.
Include information about ciprofibrate and pemafibrate, which have demonstrated efficacy in
small studies.
In Section 3.3, please define "PBS."
Methods
The review reports a large number of outcomes. It is essential to clearly define the primary and
secondary outcomes in the Methods section. What was the definition of pruritus for example?
The combination of different types of PPARs may not be appropriate, as differences exist in
mechanisms of action and outcomes (e.g., safety, ALP reduction rates, and pruritus control).
Are the baseline characteristics comparable between the studies included? Baseline ALP values
strongly impact the effects of lowering and/or normalizing liver tests.
What is the percentage of patients with advanced fibrosis or cirrhosis in the different studies?
This strongly influences the efficacy of second-line therapies and could impact subgroup
analyses.
Is it possible to stratify the analysis by the presence or absence of cirrhosis or advanced fibrosis?
One of the major challenges in PBC meta-analyses is the lack of uniformity in data presentation
across trials, with some reporting lab test results as multiples of the ULN and others as absolute
values. How did the authors address this issue?
Results
Please include baseline liver biochemistry (especially ALP and bilirubin) and the percentage of
patients intolerant to UDCA in Table 1.
Discussion
Since 2015, several meta-analyses on fibrate therapy in PBC have been published. The authors
should compare their findings in depth with these prior studies.
Comment on the potential impact of baseline imbalances (e.g., ALP levels, fibrosis degree,
inclusion criteria) on post-treatment subgroup comparisons.
Minor
There are several typographical errors. Please review and correct them.
assistant