Review for 10.1186/s12876-025-03732-2 (2025)

Title: Analyzing NAFLD Interventional Clinical Trial Registration Based on the
ClinicalTrials.gov Database
Version: 2 Date: 26 Jan 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-While the multiple-strike theory is introduced, a bit more explanation of how these factors
interrelate (e.g., liver-gut axis, intestinal microbiota) could enhance clarity. For instance, a
brief mention of how gut microbiota alterations may influence liver inflammation and fat
accumulation could be helpful for a more comprehensive understanding.
-The statistics from China are crucial, but it would be valuable to include more global context
to highlight how the prevalence and burden of NAFLD in other regions compare. For instance,
the prevalence of NAFLD in the U.S. or Europe could give a broader perspective on the global
burden.
-The study mentions using ClinicalTrials.gov but does not specify if there were any additional
databases or sources considered for a more robust search. While ClinicalTrials.gov is a primary
source, acknowledging if other databases were consulted (e.g., PubMed, WHO International
Clinical Trials Registry Platform) could improve the comprehensiveness of the data.
-The statistical analysis section mentions the use of SAS software for frequency and percentage
calculations, but it would be helpful to elaborate on why this method was chosen. Was any
advanced analysis, such as regression modeling or time series analysis, used to explore trends
over the years?
-While the list of drug targets is useful, it could be even more valuable to discuss the efficacy
or challenges associated with these drug classes. For example, how effective are PPAR agonists
or GLP-1 analogs in treating NAFLD, and what are the hurdles they face in clinical trials?
-The mention of herbal medicines (silymarin and Korean red ginseng) stands out. It would be
helpful to briefly explore why these specific herbs were chosen and what results (if any) have
been observed. Is there any data on their effectiveness, or are these trials still in the early stages?
-While the inclusion of percentages (e.g., 8.77% of trials focused on behavioral interventions,
13.73% on dietary supplements) adds useful context, some readers may benefit from additional
explanation regarding how these figures relate to the broader dataset. For instance, a brief
comparison of the prevalence of lifestyle-focused trials versus pharmacological ones might help
highlight trends more clearly.
-The discussion delves into some detailed mechanistic pathways, such as the roles of FXR,
PPARs, and FGF21. While these points are insightful, the explanations could be more concise
and more clearly tied to the clinical implications. The mechanisms of action for certain drugs
(e.g., FXR agonists) could be summarized in simpler terms to improve accessibility for a wider
audience. Providing more tangible examples of how these mechanisms translate into clinical
outcomes might also strengthen the argument.
-The section mentions that there is a higher prevalence of NAFLD in men, and suggests a
potential hormonal influence in postmenopausal women, yet the discussion on gender is brief.
Expanding on gender-based differences in NAFLD progression and response to treatment would
add depth, especially given that gender-specific therapies might become an important area for
future trials.
-While the discussion briefly mentions the increasing prevalence of NAFLD in children, this
could be expanded. Specific trends, challenges, or findings related to pediatric clinical trials
would be valuable. Since NAFLD in children is an emerging concern, a deeper focus on how
clinical trials are addressing pediatric populations would strengthen this section.
-The study touches on the growing trend toward using non-invasive methods for assessing liver
fibrosis and NASH improvement. Expanding on which specific technologies or biomarkers are
being explored in clinical trials would be helpful. This section feels somewhat underdeveloped,
given the increasing relevance of non-invasive diagnostics in clinical practice.