Dear Editor,
We appreciate the comments from Drs. Jean and Lai regarding their concerns for the true association of glucagonlike peptide-1 receptor agonists (GLP-1RAs) with hepatocellular carcinoma (HCC) and non-liver cancer among patients with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), given the long latency periods and heterogeneous progression patterns of different cancers [
1,
2]. However, we would like to point out that these associations are more likely to be underestimated if the risk factors of cancer at baseline have been well balanced. In this study, we have adjusted for a broad range of cancer-related covariates especially diabetes severity, common medical conditions (e.g., obesity and smoking), and medication use. Nonetheless, we agree that a sensitivity analysis that excluded outcomes diagnosed within the first 1 or 2 years of follow-up would be valuable for the robustness of these findings.
For the analysis of HCC outcome, significant inverse associations between GLP-1RA and incident HCC were observed after excluding HCC diagnosed within the first 1 (119 HCC cases excluded; hazard ratio [HR] 0.41, 95% confidence interval [CI] 0.27–0.63; P<0.001) or 2 years of followup (177 HCC cases excluded; HR 0.31, 95% CI 0.17–0.58; P<0.001) in the intention-to-treat design. Consistent results were observed in the per-protocol design (HR 0.30, 95% CI 0.20–0.47, P<0.001; and HR 0.22, 95% CI 0.12–0.40, P<0.001).
For the analysis of non-liver cancer, inverse but non-statistically significant associations were found after excluding non-liver cancer diagnosed within the first 1 (2,079 cancers excluded; HR 0.92, 95% CI 0.82–1.02;
P=0.120) or 2 years of follow-up (2,789 cancers excluded; HR 0.95, 95% CI 0.81–1.10;
P=0.469) in the intention-to-treat design. How-ever, the per-protocol design demonstrated significant associations (HR 0.69, 95% CI 0.62–0.78,
P<0.001; and HR 0.67, 95% CI 0.58–0.78,
P<0.001, respectively). The difference may be attributed to time-varying GLP-1RA use being addressed in the per-protocol effect [
3]. In addition, heterogeneity of cancers may partly account for the insignificant association, as the benefits of GLP-1RA were only observed on certain types of cancer (e.g., colorectal cancer) but it was not the aim of this study [
2].
In summary, we believe that GLP-1RA may have a protective effect against cancer development among patients with T2D and MASLD if they adhere to this treatment over time. Clinical randomized trials focusing on HCC and nonliver cancer might be unfeasible at this time point, motivating large-scale cohort studies to explore the anti-cancer effect of GLP-1RA that complements future clinical trials.
FOOTNOTES
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Authors’ contribution
Xianhua Mao and Mindie H. Nguyen: Conceptualization; Data acquisition and analysis; Writing--original draft; Writing—review and editing.
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Conflicts of Interest
Mindie H. Nguyen received research grants via Stanford University from Pfizer, Enanta, Astra Zeneca, GSK, Delfi, Innogen, Exact Science, CurveBio, Gilead, Vir Biotech, Helio Health, National Cancer Institute, Glycotest and personal fees from consulting/advisory board from Intercept, Exact Science, Gilead, GSK. Xianhua Mao has nothing to disclose.
Abbreviations
glucagon-like peptide-1 receptor
metabolic dysfunction-associated steatotic liver disease
REFERENCES
- 1. Jean SS, Lai CC. Early cancer risk reduction after GLP-1RA use: Signal or bias?: Letter to the editor on “Glucagon-like peptide 1 receptor agonist and reduced liver and non-liver complications in adults with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease: a target trial emulation study”. Clin Mol Hepatol 2026;32:e163-e164.
- 2. Mao X, Zhang X, Lai R, Cheung KS, Yuen MF, Cheung R, et al. Glucagon-like peptide 1 receptor agonist and reduced liver and non-liver complications in adults with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease: a target trial emulation study. Clin Mol Hepatol 2025;31:1084-1099.
- 3. Wester A, Shang Y, Toresson Grip E, Matthews AA, Hagström H. Glucagon-like peptide-1 receptor agonists and risk of major adverse liver outcomes in patients with chronic liver disease and type 2 diabetes. Gut 2024;73:835-843.
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