Dear Editor,
We sincerely appreciate the thoughtful and encouraging editorial titled “The magic of sodium-glucose cotransporter 2 inhibitors (SGLT2is) – Benefits in metabolic-dysfunction associated steatotic liver disease (MASLD) and type 2 diabetes mellitus” [
1]. We are particularly grateful for the editorial’s recognition of our study as a novel attempt to use target trial emulation with robust sensitivity analyses [
2].
As noted in the editorial, our study demonstrated a significant reduction in the progression of liver fibrosis associated with SGLT2i use compared with dipeptidyl peptidase-4 inhibitor use, as measured by serial fibrosis-4 (FIB-4) scores. However, the lack of a statistically significant difference in major adverse liver outcomes (MALO) between the two groups warrants further clarification. This is likely attributable to the composition of our cohort, where 79.0% of patients were classified as having low baseline FIB-4 scores and the remaining mostly had intermediate scores. In this early-stage population, the absolute incidence of MALO is expected to be low, and the statistical power may therefore be insufficient to detect meaningful differences within the limited follow-up period. Nevertheless, our findings are consistent with the natural history of MASLD, in which fibrosis progression typically precedes hepatic decompensation and other liver-related events by many years.
Indeed, a recent population-based study from Korea reported that SGLT2i use was associated with a significantly reduced risk of hepatic decompensation in patients with MASLD [
3], suggesting that the antifibrotic signals observed in our study may translate into long-term clinical benefits in broader or more advanced populations. Our study complements this growing body of evidence by focusing on early fibrosis progression as an intermediate outcome, thereby providing timely data that may help inform therapeutic decisions well before irreversible liver injury occurs [
4,
5].
As the editorial also noted, patients with advanced fibrosis are most likely to be referred to hepatology or liver specialty clinics. In contrast, individuals with low to intermediate FIB-4 scores–such as those included in our study–are often managed in primary care or endocrinology settings, where early therapeutic decisions are made. This observation further motivated our focus on this population, as the question of whether SGLT2is can alter disease trajectory in early-stage MASLD remains highly clinically relevant.
We acknowledge that reliance on the FIB-4 score as our primary outcome introduces inherent limitations, and we agree with the editorial that future studies leveraging transient elastography or liver biopsy could further validate our findings and improve confidence in the use of FIB-4 trends as an endpoint.
Finally, we share the editorial’s forward-looking view on the evolving therapeutic landscape of MASLD. In addition to SGLT2is, glucagon-like peptide-1 receptor agonists have also demonstrated significant benefit in patients with MASLD, including reduction in steatosis and fibrosis [
6,
7]. It is now crucial to explore whether combining these two classes could yield additive or synergistic effects on liver outcomes. We believe this represents a promising area for future research and are currently pursuing follow-up studies to evaluate such combination therapies in clinical practice.
In summary, we agree with the editorial’s perspective that early-stage MASLD represents a critical window for intervention, and we hope our findings will help inform future prospective studies.
FOOTNOTES
-
Authors’ contribution
J Choi and RT Chung are the guarantors of the article. J Choi and RT Chung drafted original manuscript and approved the final version of the manuscript.
-
Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
major adverse liver outcome
metabolic dysfunction-associated steatotic liver disease
sodium-glucose cotransporter-2 inhibitor
REFERENCES
- 1. Ho KC, Mak LY. The magic of sodium-glucose cotransporter-2 inhibitors: Benefits in metabolic dysfunction-associated steatotic liver disease and type 2 diabetes mellitus: 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;32:1413-1416.
- 2. 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.
- 3. Bea S, Ko HY, Bae JH, Cho YM, Chang Y, Ryu S, et al. Risk of hepatic events associated with use of sodium-glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists, and thiazolidinediones among patients with metabolic dysfunction-associated steatotic liver disease. Gut 2025;74:284-294.
- 4. Lin J, Huang Y, Xu B, Gu X, Huang J, Sun J, et al. Effect of dapagliflozin on metabolic dysfunction-associated steatohepatitis: multicentre, double blind, randomised, placebo controlled trial. BMJ 2025;389:e083735.
- 5. Cheung KS, Ng HY, Hui RWH, Lam LK, Mak LY, Ho YC, et al. Effects of empagliflozin on liver fat in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus: A randomized, double-blind, placebo-controlled trial. Hepatology 2024;80:916-927.
- 6. Sanyal AJ, Newsome PN, Kliers I, Østergaard LH, Long MT, Kjær MS, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med 2025;392:2089-2099.
- 7. Sanyal AJ, Bedossa P, Fraessdorf M, Neff GW, Lawitz E, Bugianesi E, et al. A phase 2 randomized trial of survodutide in MASH and fibrosis. N Engl J Med 2024;391:311-319.
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