Dapagliflozin for metabolic dysfunction-associated steatohepatitis with fibrosis: a promising therapeutic agent in biopsy-diagnosed patients

Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been proposed to replace non-alcoholic fatty liver disease (NAFLD) (1). The name change from NAFLD to MASLD reflects a shift in focus towards the underlying metabolic dysfunctions contributing to the condition. This change emphasizes that MASLD is primarily associated with metabolic disorders, such as type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome, rather than just being a liver-specific condition (2). MASLD is associated with increased morbidity and mortality compared to the general population without MASLD (2). In particular, T2DM patients with MASLD have substantially higher risks for morbidity and mortality compared to those with T2DM alone (3). Current global estimates indicate that MASLD affects approximately 38% of the adult population, and its prevalence is expected to exceed 55% by 2040 due to the ongoing rise in obesity and T2DM (4). Despite its high prevalence, therapeutic options for MASLD are still limited (5).

Metabolic dysfunction-associated steatohepatitis (MASH) has for years stood as a therapeutic desert. Despite decades of promising mechanistic rationale, no drug has definitively altered the natural course of this disease until the recent approval of resmetirom in the United States (6). However, it is still not possible to use this medication due to remaining barriers to clinical access, including regulatory, logistical, and high prices in many countries (7). Recent studies have explored the possibility of repurposing approved medications to alleviate steatosis, inflammation, and fibrosis in MASLD. Because existing safety, pharmacokinetic, and toxicity data are already available, enabling faster and more cost-effective development (8). Among these medications, a growing body of evidence supports the efficacy of anti-diabetic drugs, such as pioglitazone, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors in treating MASLD (9-11). Pioglitazone, an anti-diabetic medication as a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, has shown beneficial effects on liver histology in patients with steatohepatitis, both in those with and without T2DM (9). GLP-1RAs have been shown to have effects in resolving hepatic steatosis and inflammation (10). Furthermore, a dual agonist of the GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR) has shown efficacy in treating MASLD (11).

SGLT2 inhibitors have expanded their indications, demonstrating proven benefits for chronic kidney disease and heart failure, even in non-diabetic patients (12). Numerous recent studies and meta-analyses have demonstrated that SGLT2 inhibitors offer beneficial effects in patients with MASLD. Specifically, meta-analyses report significant improvements in liver enzyme levels and reductions in hepatic steatosis across SGLT2 agents (13). Empagliflozin has shown marked reductions in liver fat content in both diabetic and non-diabetic patients with MASLD in clinical trials (14), as well as reduced hepatic fibrosis in preclinical models (15). Additional clinical studies suggest empagliflozin provides a modest benefit against steatosis and fibrosis (16). Similarly, canagliflozin has demonstrated antifibrotic and antisteatotic effects in preclinical MASLD models, improving mitochondrial function and reducing oxidative stress (17).

Against this backdrop, Lin and colleagues examined the efficacy and safety of dapagliflozin in patients with MASH with fibrosis (18). This double-blind, randomized, and placebo-controlled trial enrolled 154 adults with biopsy-diagnosed MASH with or without T2DM. The results are encouraging: dapagliflozin outperformed placebo in achieving MASH improvement without worsening fibrosis (53% vs. 30%) and, importantly, nearly one-quarter of treated participants experienced complete resolution of MASH without fibrosis progression. For fibrosis regression, approximately 23% of participants in the dapagliflozin groups had an improvement in liver fibrosis of at least 1 stage without worsening of MASH compared to 8% in the placebo group. These biopsy findings support earlier non-invasive studies, providing consistent evidence that SGLT2 inhibitors reduce liver fat, stiffness, and enzymes, highlighting their hepatometabolic effects (19).

Earlier studies have showed that only GLP-1RAs or GLP-1/GIP agonists, such as semaglutide and tirzepatide, resulted in a statistically significant improvement in liver fibrosis without worsening of MASH in participants with or without T2DM (11). However, in the study by Lin et al. (18), dapagliflozin, when compared with the results from resmetirom trials, demonstrated a distinct pattern of histologic benefit in biopsy-confirmed MASH (6). While resmetirom achieved a higher placebo-adjusted rate of MASH resolution (approximately 20% vs. 15% with dapagliflozin), dapagliflozin produced a more pronounced improvement in liver fibrosis (placebo-adjusted 25% vs. 10–12% with resmetirom). This divergence likely reflects their fundamentally different mechanisms of action. Dapagliflozin exerts systemic metabolic effects, such as reducing insulin resistance, hepatic fat accumulation, and oxidative stress, whereas resmetirom directly activates hepatic thyroid hormone receptor-β to enhance lipid oxidation and resolve hepatocellular ballooning and inflammation. Therefore, the improvement in fibrosis demonstrated in this trial marks a significant advance in the translational trajectory of SGLT2 inhibitors, moving from metabolic surrogates of MASH resolution to histologically proven efficacy, as fibrosis regression was confirmed by paired liver biopsies at study completion.

Of note, the strengths of this study include its randomized controlled design in biopsy-confirmed MASH patients and the consistency of results across various analyses. However, a major issue with this study is the inability to definitively determine whether the benefits of dapagliflozin arise from direct effects on the liver or from broader metabolic improvements. In particular, dapagliflozin significantly reduced body weight, waist circumference, and abdominal visceral fat, contributing to a decrease in the MASLD activity score and improved MASH. So, this study suggests that, similar to other metabolic therapies, reducing excess adiposity is a key mechanistic pathway for resolving hepatic inflammation and ballooning in MASH. A preclinical study has demonstrated that dapagliflozin attenuates hepatic inflammation and fibrosis by reducing reactive oxygen species production and inhibiting nucleotide-binding and oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation (20). Therefore, it is likely that both the direct hepatic effects and the systemic metabolic improvements contributed to the observed outcomes. In fact, participants with T2DM experienced more improvement in fibrosis than non-diabetic patients in this study. Given the pathophysiology of MASH, this outcome is anticipated. MASH is fundamentally a multisystemic disorder. Its progression is driven not only by hepatocellular lipid accumulation but also by widespread insulin resistance, chronic inflammation, and adipose tissue dysfunction. These interacting systemic factors are especially prominent in patients with both MASH and T2DM, making them more responsive to the systemic metabolic benefits of SGLT2 inhibitors, which explains the added therapeutic benefit in those with the comorbidity vs. those with MASH alone. By lowering body weight, glucose, blood pressure, and lipids while promoting negative energy balance and ketone production, SGLT2 inhibitors appear to offer a synergistic profile highly congruent with the mechanistic underpinnings of MASH. Most studies using SGLT2 inhibitors were conducted on T2DM participants with MASLD. Only a few studies recruited MASLD participants without T2DM, including this study (21). About half of the participants in this study had diabetes.

In the future, large-scale studies are needed to elucidate the direct effects on the liver in participants without T2DM. Comparing the placebo effect between the dapagliflozin and resmetirom trials, the dapagliflozin trial reported a placebo MASH resolution rate of 8% over 48 weeks, while the resmetirom trial reported a placebo MASH resolution rate of approximately 9.7% over 52 weeks (9,18,22). The Lin et al. study did not actually report a stronger placebo-mediated MASH resolution rate compared with resmetirom. If anything, rates are comparable, and both are within the low-to-moderate single digits for biopsy-confirmed endpoints. Another issue is that the DEAN trial enrolled a relatively young, predominantly male, and exclusively Chinese cohort, raising questions about external generalizability to older, multi-ethnic populations where disease burden is equally high. Furthermore, the trial was relatively short (48 weeks) and not powered for long-term outcomes such as cirrhosis, hepatic decompensation, or hepatocellular carcinoma. Safety signals were benign in this study, but rare adverse effects—including ketoacidosis and genitourinary infections—require longer and broader evaluation in the MASH population.

Despite these issues, the most important implication of this trial is conceptual: dapagliflozin’s dual actions on systemic metabolism and hepatic histology strengthen the case for repositioning cardiometabolic drugs as disease-modifying agents in MASH. In doing so, they extend the paradigm shift already underway with GLP-1/GIP agonists. As SGLT2 inhibitors are already widely accessible, affordable, and integrated into diabetes, kidney, and cardiovascular care, the translational barrier to adoption is lower than with novel hepatocyte-targeted therapies.

Where do we go from here? Confirmation in larger, longer, and more diverse patient populations is essential, ideally with outcomes that extend beyond biopsy-defined surrogates to include clinical events. This combination therapy can potentially address multiple overlapping metabolic and fibrotic pathways, and several ongoing studies are specifically investigating these dual strategies. Synergistic combinations—SGLT2 inhibitors with GLP-1RAs, thyroid hormone receptor agonists, or antifibrotics—may offer the most powerful path forward, tackling the multifaceted biology of MASH. For example, dapagliflozin shows significant benefits for MASH resolution and fibrosis improvement, but trials to date have involved different, generally lower-risk populations compared to resmetirom studies. These data indicate that direct head-to-head data are lacking, so dapagliflozin cannot yet be recommended as a substitute for resmetirom in advanced fibrosis or MASH until more comparative evidence becomes available.

In summary, Lin and colleagues were the first to demonstrate that an SGLT2 inhibitor can significantly improve both steatohepatitis and fibrosis in biopsy-confirmed disease. This study provides the most substantial evidence to date that SGLT2 inhibitors can alter the progression of biopsy-confirmed MASH, compared to previous studies that relied primarily on imaging or serologic markers. If these results are reproduced in trials involving other SGLT2 inhibitors or confirmed by other studies, it would provide strong evidence for a potential class effect and reinforce the role of SGLT2 inhibitors in the treatment of MASH.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-728/prf

Funding: This commentary was supported by the Basic Science Research Program through the National Research Foundation (NRF) of Korea (No. RS-2023-00219399).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-728/coif). The authors have no conflicts of interest to declare.

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