Reaffirming the role of SGLT2 inhibitors in slowing fibrotic progression in MASLD: Correspondence to 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”

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.

Abbreviations

FIB-4

fibrosis-4

MALO

major adverse liver outcome

MASLD

metabolic dysfunction-associated steatotic liver disease

SGLT2i

sodium-glucose cotransporter-2 inhibitor