Dear Editor,
We sincerely thank the authors for their thoughtful correspondence and for their interest in our editorial discussing the role of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in metabolic dysfunction-associated steatotic liver disease (MASLD) complicated by type 2 diabetes mellitus (T2DM) [
1,
2] for recognizing and aligning with these perspectives. We appreciate the opportunity to further clarify and contextualize the clinical and mechanistic implications of these findings.
We especially appreciate that the authors emphasized the clinical importance of real-world data, the fact that liver-related outcomes cannot be merely inferred from concomitant glycemic control, and the need to make disease-modifying therapies available for this population of people. MASLD has emerged as one of the top causes of chronic liver disease worldwide [
3]. T2DM in particular is a major accelerator for fibrosis progression and all sorts of adverse liver outcomes [
4,
5]. Hence it is essential that therapeutic strategies which can simultaneously tackle metabolic dysfunction and liver disease be developed. As pointed out in the editorial, SGLT2is have focused increasing attention due to their pleiotropic metabolic effects, including improved insulin resistance and body weight loss as well as decreased cardiometabolic risk, all of which are tightly interconnected with MASLD pathology.
As highlighted in both the original article and the correspondence, most prior real-world studies evaluating SGLT2is in MASLD have focused on late-stage or “hard” liver outcomes, such as hepatic decompensation and hepatocellular carcinoma (HCC) [
6,
7]. Although these outcomes are clinically important, their relatively low incidence in early-stage disease limits statistical power and may obscure meaningful therapeutic effects occurring earlier in the disease course. In this context, longitudinal assessment of fibrosis progression using validated, time-updated noninvasive markers-such as the fibrosis-4 (FIB-4) index-provides a pragmatic and clinically relevant approach to capturing disease dynamics over time. Liver fibrosis is a progressive, time-dependent process that may advance despite preserved liver function and the absence of overt clinical events. Serial evaluation with FIB-4 enables dynamic risk stratification and is particularly informative in populations with predominantly low-to-intermediate fibrosis risk at baseline. Evidence demonstrating that SGLT2is are associated with a lower risk of fibrosis progression compared with other glucose-lowering agents supports the concept that these therapies may modify the natural history of MASLD, rather than merely delaying late-stage complications. 1 Moreover, another important issue is the endocrine disorders, especially thyroid function parameters like thyroid-stimulating hormone, free triiodothyronine, and free thyroxine. Given the involvement of thyroid dysfunction in MASLD,8 future investigations should consider stratifying patients receiving SGLT2is according to thyroid status (hypothyroidism vs. hyperthyroidism).
We also acknowledge the importance of comparative effectiveness studies across glucose-lowering therapies. Large-scale analyses have demonstrated that SGLT2is and glucagon-like peptide-1 receptor agonists (GLP-1RAs), compared with sulfonylureas and dipeptidyl peptidase-4 inhibitors (DPP-4is), are associated with lower risks of hepatic decompensation and HCC [
1,
9-
11]. Collectively, these findings suggest that SGLT2is may confer benefits across the spectrum of liver disease, from early fibrosis progression to more advanced clinical outcomes.
Additionally, the substantial comparisons of antidiabetic agents with combined therapies, treatment sequences and patient stratification based on fibrosis stage combined with metabolic risk and other parameters such as thyroid status are essential for further investigation. Notably, prospective studies that employ well-validated non-invasive fibrosis markers as indicator with long-term follow-up are crucial for determining through what mechanism metabolic improvement associates with reduced liver-related events and regression of fibrosis.
In conclusion, accumulating real-world and emulated trial evidence supports an expanding role for SGLT2is in the management of MASLD complicated by T2DM. Beyond glycemic control, SGLT2is appear to confer clinically meaningful benefits in slowing fibrosis progression and, when initiated earlier in the disease course, may ultimately reduce the risk of hepatic decompensation and HCC. Further prospective studies with long-term follow-up and validated noninvasive markers will be essential to refine patient selection and optimize treatment strategies.
FOOTNOTES
-
Authors’ contributions
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.
Abbreviations
dipeptidyl peptidase-4 inhibitor
glucagon-like peptide-1 receptor agonist
metabolic dysfunction-associated steatotic liver disease
sodium-glucose cotransporter-2
REFERENCES
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