Metabolic dysfunction-associated steatotic liver disease (MASLD) has rapidly emerged as the leading cause of chronic liver disease globally and is now a major contributor to cirrhosis, hepatocellular carcinoma, and liver-related mortality [
1,
2]. Its tight biological and epidemiological link with type 2 diabetes mellitus (T2DM) underscores a shared metabolic and inflammatory milieu that accelerates fibrogenesis and places diabetic individuals at disproportionately high risk for liver-related events-even in the absence of cirrhosis [
3]. Such adverse hepatic consequences are mainly mediated by insulin resistance, hyperglycemia and elevated circulating fatty acids [
4,
5]. However, there are currently no specific biomarkers for evaluating early-stage liver disease, nor are there targeted treatments that can efficiently improve patient outcomes [
6]. Accordingly, these findings suggest that disrupting these pathogenic processes could offer a promising strategy to reduce the risk of progression to more advanced stages of liver disease.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors primarily exert their therapeutic effect by blocking SGLT2 transporters in the proximal renal tubules, thereby promoting urinary glucose excretion and reducing plasma glucose levels. Beyond glycemic control, these agents increase renal sodium delivery, decrease intraglomerular pressure, and confer well-established cardiovascular and kidney protection, with growing evidence also supporting benefit in metabolic liver disease [
7]. Emerging mechanistic and clinical evidence suggests that SGLT2 inhibitors exert antifibrotic effects within the liver. Experimental models demonstrate attenuation of stellate cell activation, oxidative and endoplasmic reticulum stress, and inflammatory signaling, alongside enhanced autophagy and β-oxidation [
8]. These biological actions are mirrored in clinical studies, which report improvements in liver stiffness, steatosis, and histologic activity, with fibrosis stabilization or regression in some patients [
9]. Meta-analyses further corroborate reductions in noninvasive fibrosis markers such as liver stiffness measurement, Fibrosis-4 index (FIB-4), and the non-alcoholic fatty liver disease fibrosis score [
10,
11]. Collectively, these data support a potential disease-modifying role for SGLT2 inhibitors in MASLD, whereas the hepatic benefits of dipeptidyl peptidase-4 (DPP-4) remain uncertain.
The study by Choi et al. [
12], used two large, complementary real-world cohorts drawn from the Mass General Brigham Health System in the United States and the Asan Medical Center in South Korea to assess the comparative hepatic effects of SGLT2 inhibitors versus DPP-4 inhibitors in patients with MASLD and T2DM who were at low-to-intermediate risk for liver fibrosis. By applying a rigorous target-trial emulation framework and a new-user, active-comparator design, the investigators attempted to minimize key observational biases and closely approximate the conditions of a randomized clinical trial in routine clinical practice. Within this framework, they evaluated both progression of liver fibrosis-measured longitudinally using repeated FIB-4 assessment-and the development of major adverse liver outcomes (MALO), while incorporating extensive prespecified subgroup, sensitivity, and mediation analyses to test the robustness and biological plausibility of their results. Across these complementary analytic strategies, SGLT2 inhibitor therapy was consistently associated with a significantly lower risk of fibrosis progression compared with DPP-4 inhibitor use alone. These findings extend existing mechanistic and clinical evidence by demonstrating that the potential antifibrotic benefits of SGLT2 inhibitors are observable in a large, diverse, real-world population, even among individuals without advanced fibrosis at baseline.
Most previous studies have focused on late stages of liver disease, such as cirrhosis and hepatocellular carcinoma, which are generally regarded as irreversible [
13]. Recent our multinational data indicate that the use of SGLT2 inhibitors is linked to a substantially reduced risk of hepatocellular carcinoma, with an adjusted hazard ratio of 0.43 (95% confidence interval, 0.29–0.63), as demonstrated in a large Tri-NetX cohort of adults with MASLD and T2DM [
14]. The importance of the present study lies not only in its large, well-characterized cohorts derived from two independent national data sources, but also in its focus on MASLD as an earlier stage in the liver-disease spectrum. Importantly, mediation analysis demonstrated that changes in body weight, body mass index, and glycated hemoglobin (HbA1c) accounted for only a small proportion of the observed antifibrotic effect associated with SGLT2 inhibitor use. This finding suggests that liver protection is not mediated exclusively through metabolic improvement. Rather, it aligns with mechanistic hypotheses-supported by preclinical and histologic data-that suppression of hepatic lipogenesis, attenuation of oxidative stress, modulation of the insulin-glucagon axis, and direct regulation of inflammatory and fibrotic signaling pathways together contribute to therapeutic benefit. Taken together, these observations support the notion that SGLT2 inhibitors may exert direct hepatic actions in MASLD.
Nonetheless, the study also highlights the necessity for careful consideration in interpreting its clinical significance. First, although SGLT2 inhibitor therapy was associated with a lower risk of fibrosis progression, there was no statistically significant difference in the incidence of MALO during the follow-up period. This observation suggests that the hepatic benefits of SGLT2 inhibitors may be most pronounced at earlier stages of liver disease, before advanced complications emerge, and that longer-term observation may be required to detect differences in hard clinical endpoints. Secondly, as FIB-4 is used as non-invasive surrogate marker, it cannot perfectly replace pathological diagnosis of liver fibrosis. Moreover, this analysis did not distinguish potential heterogeneity in hepatic benefit across individual SGLT2 inhibitor agents. Given emerging evidence that cardiometabolic outcomes may differ between drugs within this class, future studies will be essential to determine whether antifibrotic effects are uniform or agent-specific.
To date, several agents, including glucagon-like peptide-1 (GLP-1) receptor agonists and thyroid hormone receptor-β agonists, resmetirom, have been identified as effective treatments for MASLD [
15,
16]. Each therapeutic approach targets distinct pathogenic mechanisms and may be applied at different stages of disease progression, influenced by factors such as genetic background, lifestyle, and regional variation. In this context, the study by Choi et al. [
12] provides compelling real-world evidence supporting the hepatoprotective effects of SGLT2 inhibitors in patients with MASLD and T2DM, reinforcing their potential role in preventing liver disease progression. Looking ahead, the availability of genomic data, including whole-genome sequencing from patients treated with SGLT2 inhibitors would allow the identification of genetic determinants of treatment response and may facilitate the development of individualized precision-medicine strategies (
Fig. 1). Beyond genomics, integrated multi-omics approaches incorporating transcriptomic, proteomic, and metabolomic profiling within the same cohorts may further enable the discovery of novel biomarkers and therapeutic response signatures. Another important area for investigation is whether SGLT2 inhibitors exert additive or synergistic effects when combined with emerging MASLD therapies such as GLP-1 receptor agonists or resmetirom, and whether their benefits extend to individuals with more advanced fibrosis-particularly with respect to long-term hepatic and oncologic outcomes (
Fig. 1). Collectively, these research directions will be critical to redefining early-stage intervention strategies and advancing precision-guided care in MASLD.
FOOTNOTES
-
Authors’ contribution
Conception and design: Yang-Hsiang Lin, Ching-Chih Hu, and Chih-Lang Lin. Drafting of the manuscript: Yang- Hsiang Lin. Revising critically the manuscript: Yang-Hsiang Lin, Ching-Chih Hu, and Chih-Lang Lin. Approval of final manuscript: Yang-Hsiang Lin, Ching-Chih Hu, and Chih-Lang Lin.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Figure 1.A conceptual framework for personalized medicine in patients with MASLD and T2DM. This image was created with Biorender. GLP-1, glucagon-like peptide-1; T2DM, type 2 diabetes mellitus; MASLD, metabolic dysfunction-associated steatotic liver disease; SGLT2i, sodium-glucose cotransport-2 inhibitors.
Abbreviations
major adverse liver outcomes
metabolic dysfunction-associated steatotic liver disease
sodium-glucose cotransporter-2
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Citations
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- Reply to correspondence 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-intermediat
Yang-Hsiang Lin, Ching-Chih Hu, Chih-Lang Lin
Clinical and Molecular Hepatology.2026; 32(3): e434. CrossRef - 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-interme
Jonggi Choi, Raymond T. Chung
Clinical and Molecular Hepatology.2026; 32(3): e372. CrossRef
