Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a hot topic owing to its high global prevalence of 38% [
1], and the alarming rise in liver-related complications and hepatocellular carcinoma caused by MASLD [
2,
3]. Extensive effort have been made in the development of pharmacologic treatments in patients with MASLD. Resmetirom, a liver-directed thyroid hormone receptor-β agonist, and semaglutide, a glucagon-like peptide-1 receptor agonists (GLP1-RA) are two Food and Drug Administration-approved drugs in treating metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis based on its efficacy in achieving hepatic histological endpoints. Given the high prevalence of MASLD among patients with type 2 diabetes mellitus (T2D) [
4], and its association with rapid progression of MASLD [
5,
6], there is currently an unmet medical need in patients with low to intermediate fibrosis risk as there is no approved pharmacologic agents for the treatment of MASLD in the absence of steatohepatitis and clinically significant fibrosis.
Choi et al. [
7] conducted a large, target trial emulation through a retrospective cohort study involving 5,142 patients identified from large-scale electronic health record databases with T2D and MASLD (defined by hepatic steatosis index or diagnostic coding). Only patients with a low-to-intermediate fibrosis-4 index (FIB-4)≤2.67, i.e., non-high risk, were included. Fibrosis progression was defined as FIB-4>2.67, confirmed on ≥2 occasions within 1 year. A total of 2,571 propensity score-matched pairs were identified with balanced baseline characteristics. Remarkably, the authors demonstrated that sodium-glucose cotransporter-2 inhibitors (SGLT2-i) was associated with a 22% lower risk of liver fibrosis progression compared to dipeptidyl peptidase-4 inhibitors (DPP4-i). Notably, there was no significant difference in major adverse liver outcomes including cirrhosis, decompensation events, hepatocellular carcinoma or liver transplant incidence.
The meticulous study design allows robust comparisons between non-high risk patients with concomitant MASLD and T2D taking SGLT2-i or DPP4-i. The subgroup analyses consistently demonstrate the benefits of SGLT2-i among users of metformin, statins, and aspirin. Additionally, the modest changes in body-mass index, body weight and glycated hemoglobin (HbA1c) level (ranging from 0.3% to 6.2%) indicate that the primary benefits of SGLT2-i may stem from its direct effect instead of intermediate metabolic changes. While FIB-4 is positioned at the initial step of non-invasive assessment (NIT) in MASLD instead of confirmatory test for significant or advanced fibrosis [
8], this study examined the potential benefits of SGLT2-i in dynamic NIT changes in patients at the early phase of the care continuum. This study offers novel insights on preventing fibrosis progression in MASLD, highlighting the opportunity for timely intervention before the onset of advanced liver fibrosis and liver-related complications.
SGLT2-i have emerged as a ‘magic drug’ in the management of various cardiometabolic diseases. By inhibiting the sodium glucose cotransporter 2 in the proximal renal tubules, they effectively promotes glucosuria, leading to modest weight loss and improved glycaemic control [
9]. Beyond their glycaemic effects, they also promote vasoconstriction of the afferent arterioles and reduces the intraglomerular pressure due to a raised sodium concentration at the macula densa [
10]. Furthermore, numerous studies have proven their efficacy in reducing free radical generation and proinflammatory mediators [
11], thereby exerting an anti-inflammatory and anti-oxidising effects.
While SGLT2-i were initially introduced as a novel therapeutic agent for T2D, the magic of which continue to unfold in various cardiometabolic diseases. SGLT2-i have demonstrated remarkable benefits in the cardiorenal axis, showing promising results not only in patients with heart failure [
12], but also in patients with non-diabetic chronic kidney disease [
13]. Recently, there is growing discussion about the benefits of SGLT2-i regarding the cardio-renal-liver axis. Emerging evidence show that SGLT2-i can effectively reduce hepatic fat mass [
14], as well as potentially improve long-term survival, cardiovascular and liver-related outcomes in patients in MASLD [
15]. Recent study also confirmed the efficacy of SGLT2-i in reducing the risk of hepatic decompensation events in MASLD [
16]. Compelling findings from the recent DEAN trial indicated that 48 weeks of dapagliflozin treatment in patients with MASLD resulted in achievement of both hepatic histological endpoints [
17].
The study from Choi et al. [
7] certainly adds to the understanding of the benefits of SGLT2-i, extending its positive effects in patients with MASLD with a low to intermediate risk of fibrosis, who are more likely to present in the primary care or endocrinology setting compared to patients with high-risk of fibrosis. Given the retrospective nature of this study, future longitudinal research with extended follow-up across multiple centres is essential to evaluate the effects of SGLT2-i on fibrosis progression and liver-related outcomes in this patient population. This study, however, did not include serial elastography data or histological endpoint for comparison, as FIB-4 may not accurately reflect the stage of fibrosis [
18]. It would also be worthwhile to further explore the effect SGLT2-i in non-diabetic MASLD, as suggested by a randomized controlled trial that SGLT2-i can reduce hepatic steatosis in non-diabetic MASLD [
19]. Furthermore, the combination of GLP1-RA and SGLT2-i may produce synergistic effect on liver-related outcome in patients with concomitant MASLD and T2D, an area that has yet to be explored.
Evolving evidence underscore the efficacy of SGLT2-i as a ‘magic drug’ in the management of cardiometabolic diseases, with newer evidence accumulating in the management of MASLD. While current pharmacological treatment focus on achieving hepatic histological endpoints in MASLD, preventing fibrosis progression is equally important, emphasizing the need for timely intervention before advanced liver fibrosis and liver-related complications develop. Further evidence on the benefits of SGLT2-i in MASLD is eagerly anticipated.
FOOTNOTES
-
Authors’ contribution
KCY Ho was involved in drafting of the editorial. LY Mak was involved in the critical revision of manuscript and overall study supervision. The authors declare that they have participated in the preparation of the manuscript and have seen and approved the final version.
-
Conflicts of Interest
LY Mak received research grant support from Roche Diagnostics.
Abbreviations
dipeptidyl peptidase-4 inhibitors
glucagon-like peptide-1 receptor agonists
metabolic dysfunction-associated steatotic liver disease
sodium-glucose cotransporter-2 inhibitors
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Citations
Citations to this article as recorded by
- 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-
Jonggi Choi, Raymond T. Chung
Clinical and Molecular Hepatology.2026; 32(3): e369. CrossRef
