Review for 10.1186/s12876-025-04211-4 (2025)

Title: Association Between GLP-1 Receptor Agonists as a Class and Colorectal Cancer Risk:
A Meta-Analysis of Retrospective Cohort Studies
Version: 0 Date: 24 May 2025
Reviewer:  Karunia Valeriani Japar
Reviewer's report:
This manuscript addresses an important and timely clinical question regarding the association
between GLP-1 receptor agonists (GLP-1 RAs) and colorectal cancer (CRC) risk in patients
with type 2 diabetes mellitus (T2DM). The authors have conducted a systematic review and
meta-analysis following PRISMA guidelines, synthesizing data from seven retrospective cohort
studies with a substantial combined sample size. The topic is highly relevant given the increasing
use of GLP-1 RAs in diabetes and obesity management and ongoing concerns about their long-
term safety profile, particularly regarding malignancy risk.
Strengths
The study is well-structured, adhering to established systematic review and meta-analysis
methodology (PRISMA), and uses the Newcastle-Ottawa Scale for quality assessment.
The literature search appears comprehensive, covering multiple databases and including a large
patient population (over 5 million individuals).
The statistical approach is appropriate, with random-effects models and heterogeneity
assessment using the I² statistic.
The manuscript provides a balanced discussion, acknowledging both the findings and the
limitations of the current evidence base.
Major Concerns
Interpretation of Results: The manuscript reports a significantly increased risk of CRC among
GLP-1 RA users (RR 2.31; 95% CI: 1.82–2.93), but notes that the incidence of CRC was
not significantly higher compared to other drugs (OR 1.73; 95% CI: 0.21–14.18, p=0.61;
I²=100%). This apparent discrepancy between risk and incidence requires clearer explanation.
The difference may stem from how "risk" and "incidence" are defined or measured across
studies, or from the statistical power and heterogeneity of the included data. The authors should
elaborate on this point to aid reader understanding.
Heterogeneity: The high heterogeneity observed in the analysis of CRC incidence (I²=100%)
raises concerns about the comparability of included studies. While the authors mention
this, further exploration of sources of heterogeneity (e.g., differences in patient populations,
comparator drugs, follow-up duration, or study design) would strengthen the manuscript.
Confounding and Bias: The reliance on retrospective cohort studies introduces the risk of
residual confounding, especially given the complex interplay of diabetes, obesity, and cancer
risk. The manuscript acknowledges this but could benefit from a more detailed discussion
of potential confounders (e.g., duration/severity of diabetes, concurrent medications, lifestyle
factors) and how these were addressed or not addressed in the included studies.
Clinical Implications: The conclusion emphasizes the need for further research but should
also provide more concrete guidance for clinicians based on current evidence, including the
limitations of observational data and the importance of individualized risk assessment when
prescribing GLP-1 RAs.
Minor Points
Language and Clarity: The manuscript would benefit from careful editing for grammar and
clarity. Some sentences are awkwardly phrased or repetitive.
Figures and Tables: Ensure that all referenced figures (e.g., PRISMA flowchart, forest plots,
funnel plots) and tables are included and clearly labeled in the final submission.
References: The reference list is comprehensive. Please ensure all citations are correctly
formatted and correspond to the text.
Summary
This meta-analysis provides valuable insight into a clinically significant question but is limited
by the observational nature of included studies and substantial heterogeneity. The results suggest
a possible association between GLP-1 RA use and increased CRC risk, but not a significant
difference in CRC incidence compared to other drugs. The manuscript would be improved by
clearer explanation of these findings, deeper exploration of heterogeneity and confounding, and
more practical clinical recommendations. With these revisions, the study will make a meaningful
contribution to the literature on GLP-1 RA safety