Dear Editor,
We thank the authors of the editorial for their thoughtful commentary on our study [
1,
2]. We particularly appreciate their recognition of our study’s strengths, including its relevance to the real-world clinical scenario, ascertainment of granular fibrosis outcomes, and focus on a patient population often encountered in primary care or endocrinology rather than hepatology settings.
Our study demonstrated that among patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM) with low-to-intermediate fibrosis burden, initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2is) is associated with a significantly lower risk of progression to liver fibrosis than initiation of dipeptidyl peptidase-4 inhibitors (DPP4is), as assessed by serial fibrosis-4 (FIB-4) scores. As the editorial noted, most real-world studies on SGLT2i in MASLD have focused on “hard” clinical outcomes such as hepatocellular carcinoma (HCC) or hepatic decompensation [
3,
4]. However, longitudinal evaluation of fibrosis progression using validated non-invasive markers remains underexplored, especially in early-stage patients. Our study fills this important evidence gap by employing fibrosis progression as an intermediate outcome using time-updated FIB-4 scores, which are widely available and clinically meaningful. We also agree with the editorial’s comment that serial histologic assessment in large populations is impractical, and therefore, longitudinal studies based on surrogate outcomes similar to ours provide a feasible and informative alternative.
Notably, the editorial also highlighted the absence of a statistically significant difference in major adverse liver outcomes between SGLT2i and DPP4i users in our study. As we have highlighted in our article, this finding is likely due to the predominance of low fibrosis risk at baseline, leading to lower event rates and limited statistical power for latestage outcomes. Supporting this interpretation, a recent population-based study from Korea showed that SGLT2i use is associated with a significantly reduced risk of hepatic decompensation among patients with MASLD, consistent with long-term benefits suggested by our fibrosis-based findings [
3,
4].
Moreover, in a large-scale target trial emulation covering over 38,000 eligible patients with T2DM, we compared the effectiveness of SGLT2is, glucagon-like peptide-1 receptor agonists (GLP-1RAs), DPP4is, and sulfonylureas for reducing hepatic decompensation risk. Over a median follow-up of 3.1 years, patients who initiated SGLT2is (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.43–0.98) and GLP-1RAs (HR 0.58, 95% CI 0.38–0.88) had significantly lower hepatic decompensation risk than those who initiated with sulfonylureas, with similar trends seen in pairwise comparison with DPP4is [
5]. In a separate international cohort study using harmonized data from Mass General Brigham (USA) and Asan Medical Center (Korea), we also observed a significantly lower risk of HCC with SGLT2i use than with the use of sulfonylurea and DPP4i (subdistribution HR: 0.44 and 0.53, respectively), supporting the potential chemopreventive benefits of SGLT2is in patients with MASLD and T2DM [
6].
We also agree with the editorial’s suggestion for future research evaluating GLP-1RAs in combination with SGLT2is. Indeed, our group has pursued several follow-up investigations in this area. In a recently completed study mirroring the design of our SGLT2i analysis, we evaluated the comparative effectiveness of GLP-1RAs versus DPP4is in 2,238 propensity score-matched pairs of patients with MASLD and T2DM with low-to-intermediate fibrosis risk. In that study, we found that GLP-1RA use is associated with a significantly lower risk of fibrosis progression (HR 0.75, 95% CI 0.65–0.87) [
7]. These results suggest that both GLP- 1RAs and SGLT2is may offer meaningful antifibrotic benefit in this population.
Taken together, our growing body of work supports the role of SGLT2is and GLP-1RAs as promising agents for not only intermediate outcomes such as fibrosis progression but also for harder outcomes, including HCC and hepatic decompensation. We believe these therapies deserve further evaluation, especially when used in combination. Additionally, the editorial authors’ contributions to this field, including their recent work using TriNetX to examine SGLT2is and HCC risk [
8], help to advance our shared goal of improving outcomes in patients with T2DM and MASLD.
FOOTNOTES
-
Authors’ contribution
J Choi and RT Chung are the guarantors of the article. J Choi and RT Chung drafted the original manuscript and approved the final version of the manuscript.
-
Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
dipeptidyl peptidase-4 inhibitors
glucagon-like peptide-1 receptor agonists
metabolic dysfunction-associated steatotic liver disease
sodium-glucose cotransporter-2 inhibitor
REFERENCES
- 1. Choi J, Fulop D, Nguyen VH, Przybyszewski E, Song J, Carroll A, et al. Comparative risk of fibrosis progression with sodium-glucose cotransporter-2 vs. dipeptidyl peptidase-4 inhibitors in metabolic dysfunction-associated steatotic liver disease and type 2 diabetes mellitus with low-to-intermediate fibrosis. Clin Mol Hepatol 2026;32:305-317.
- 2. Lin YH, Hu CC, Lin CL. Challenges and innovations in MASLD and T2DM: Strengthening personalized medicine with SGLT2 inhibitors: Editorial on “Comparative risk of fibrosis progression with sodium-glucose cotransporter-2 vs. dipeptidyl peptidase-4 inhibitors in metabolic dysfunction-associated steatotic liver disease and type 2 diabetes mellitus with low-to-intermediate fibrosis”. Clin Mol Hepatol 2026;32:1417-1420.
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- 5. Choi J, Verma A, Nguyen VH, Przybyszewski E, Song J, Carroll A, et al. Comparative effectiveness of antidiabetic therapies on hepatic decompensation in patients with type 2 diabetes: A target trial emulation. JHEP Rep 2025;7:101624.
- 6. Choi J, Nguyen VH, Przybyszewski E, Song J, Carroll A, Michta M, et al. Association of sodium-glucose cotransporter-2 inhibitors with reduced hepatocellular carcinoma risk in patients with type 2 diabetes. Am J Gastroenterol 2025 Dec 16. doi: 10.14309/ajg.0000000000003889.
- 7. Choi J, Kamath T, Nguyen VH, Przybyszewski E, Song J, Carroll A, et al. GLP-1RA and liver fibrosis progression in MASLD and type 2 diabetes: target trial emulation using propensity score matching. Liver Int 2025;45:e70447.
- 8. Soong RS, Chen WM, Jao AT, Lee MC, Wu SY, Lin CL. SGLT2 inhibitors and the risk of hepatocellular carcinoma in patients with MASLD and Type 2 diabetes. Diabetes Metab 2025;51:101698.
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