Redefining Liver Disease in the Metabolic Era: From NASH to MASH and the Rise of Obesity‐targeted Therapies

The paradigm shift from Non‐alcoholic Steatohepatitis (NASH) to Metabolic Dysfunction–associated Steatohepatitis (MASH) reflects a deeper understanding of the pathophysiology underpinning liver injury in the context of obesity, diabetes, and metabolic syndrome. This evolving nomenclature from NASH to MASH is more than a semantic update—it mirrors a fundamental change in how we conceptualize liver disease, moving away from a definition based solely on the exclusion of alcohol consumption toward one that highlights the central role of metabolic dysregulation.   

The Nomenclature Evolution

Historically, liver conditions characterized by steatosis with inflammation were labeled as NASH, with the broader term Non‐alcoholic Fatty Liver Disease (NAFLD) covering the entire spectrum. However, as research increasingly implicated metabolic abnormalities—such as insulin resistance, dyslipidemia, and obesity—as key drivers of liver injury, experts recognized that the term ‘nonalcoholic’ was both misleading and insufficient. In response, a consensus emerged to rename the condition

• MASLD (Metabolic Dysfunction–Associated Steatotic Liver Disease): This umbrella term encompasses the entire spectrum of fatty liver disease where metabolic dysfunction is the primary instigator. 
• MASH: This refers specifically to the inflammatory and progressive stage of MASLD, where hepatocellular injury and fibrosis are prominent.

This change aligns with the mounting evidence that the metabolic milieu—not merely the absence of alcohol—is crucial in driving liver pathology. It also emphasizes that patients with obesity, diabetes, and metabolic syndrome are at the highest risk, a fact that is driving both diagnostic and therapeutic innovations.

Obesity-targeted Therapies and Their Impact on MASH

Given the tight link between metabolic syndrome and liver injury, obesity-targeted drugs have emerged as promising candidates for treating MASH. Medications initially created for diabetes and weight loss are now being repurposed to help reduce liver fat buildup, inflammation, and fibrosis.

GLP‑1 Receptor Agonists: Agents such as semaglutide improve insulin sensitivity, suppress appetite, and reduce de novo lipogenesis, thereby reducing liver fat and inflammation.

Dual/Triple Receptor Agonists: Tirzepatide (a GLP‑1/GIP dual agonist) and emerging candidates like efinopegdutide and survodutide target multiple receptors to produce synergistic metabolic effects.

SGLT2 Inhibitors: Originally designed for glycemic control, these drugs also show potential in reducing hepatic steatosis and inflammation.

Together, these therapies represent a multifaceted approach to counteracting the metabolic drivers of liver disease, potentially halting—or even reversing—fibrosis progression.

Comparative Efficacy of Semaglutide and Tirzepatide in Managing Obesity-Driven MASLD

Both semaglutide and tirzepatide have emerged as potent obesity therapies with significant implications for managing MASH. Their robust weight loss effects—an essential driver in improving liver histology in MASLD—reflect distinct mechanisms and clinical outcomes.

Novo Nordisk and Eli Lilly are pushing the boundaries in the MASLD treatment space by investigating these two transformative obesity drugs for their potential to reverse liver injury in MASH.

Novo Nordisk is currently evaluating semaglutide in the Phase III ESSENCE trial (NCT04822181), a 240-week double-blind study in 1,200 adults with MASH and moderate to advanced liver fibrosis (Stage II or III). In Part 1 of the trial, liver biopsy data from the first 800 randomized patients at Week 72 revealed that once-weekly semaglutide 2.4 mg produced statistically significant histological improvements: 37.0% of patients experienced an improvement in liver fibrosis without worsening steatohepatitis, compared with 22.5% on placebo, while 62.9% achieved resolution of steatohepatitis without fibrosis worsening versus 34.1% on placebo. Semaglutide’s safety profile was consistent with earlier studies, with no new concerns arising, and its promise was underscored in August 2020 when the US FDA granted it BTD for NASH. The trial successfully met its primary endpoints, showing a statistically significant and superior improvement in liver fibrosis without worsening steatohepatitis. Additionally, it achieved steatohepatitis resolution with no deterioration in liver fibrosis. Novo Nordisk plans to seek regulatory approvals in the US and EU in the first half of 2025.

In parallel, Eli Lilly’s tirzepatide—approved as MOUNJARO for type 2 diabetes and as ZEPBOUND for obesity—was assessed in the Phase II SYNERGY-NASH trial (NCT04166773). This multicenter, double-blind, placebo-controlled study enrolled adults with biopsy-confirmed MASH and Stage II or III fibrosis. At Week 52, the trial’s primary endpoint, MASH resolution without worsening fibrosis, was achieved by 51.8%, 62.8%, and 73.3% of patients receiving tirzepatide at doses of 5 mg, 10 mg, and 15 mg, respectively, compared to only 13.2% in the placebo group. For the secondary endpoint—fibrosis improvement without worsening MASH—response rates were 59.1%, 53.3%, and 54.2% at the respective doses versus 32.8% with the placebo. Significant improvements in body weight, liver injury markers, and metabolic parameters accompanied these robust efficacy signals. Importantly, tirzepatide’s safety profile mirrored that observed in previous trials (such as SURMOUNT and SURPASS), with adverse gastrointestinal events (nausea, diarrhea, decreased appetite, and constipation) remaining mild to moderate.

Taken together, these studies underscore a paradigm shift; while both semaglutide and tirzepatide demonstrate promise in improving liver fibrosis, tirzepatide’s dual receptor agonism appears to confer even greater benefits in terms of weight loss and metabolic improvement. As further data emerge, these agents may well redefine MASLD management—offering not only a means to address obesity and metabolic dysfunction but also to directly ameliorate liver pathology, thereby reducing the long-term burden of this increasingly prevalent disease.

Early Clinical Data 

Survodutide (BI 456906) is a novel dual agonist targeting both GLP-1 and glucagon receptors, developed collaboratively by Boehringer Ingelheim and Zealand Pharma. In a Phase II NASH clinical trial involving adults with MASH, up to 83% of participants treated with survodutide achieved significant histological improvement in MASH without worsening fibrosis, compared to 18.2% in the placebo group. Additionally, survodutide demonstrated substantial reductions in liver fat content and fibrosis markers, with up to 64.5% of patients with fibrosis Stages F2 and F3 showing improvement without MASH progression versus 25.9% with placebo. These findings suggest that survodutide holds promise as an effective treatment for MASH, addressing both liver inflammation and fibrosis.

Efinopegdutide (MK-6024) is an investigational dual agonist targeting both GLP-1 and glucagon receptors, developed by Merck & Co. in collaboration with Hanmi Pharmaceutical. In a Phase IIa clinical trial involving patients with NAFLD, efinopegdutide 10 mg weekly led to a 72.7% reduction in liver fat content over 24 weeks, significantly outperforming semaglutide 1 mg weekly, which achieved a 42.3% reduction. These results highlight efinopegdutide’s potential as an effective treatment for NAFLD and its more severe form, NASH, warranting further investigation in larger clinical trials.

Altimmune’s Pemvidutide is emerging as another promising therapeutic candidate in the fight against MASH. This investigational drug is a balanced dual agonist that targets both the GLP-1 and glucagon receptors. Its unique design incorporates a glycolipid surfactant conjugation, which extends its half-life and permits once‐weekly dosing. Preclinical studies in mouse models of MASH demonstrated impressive efficacy—with marked reductions in liver fat content and liver volume—and these promising findings have translated into early clinical success. In a recent Phase Ib study involving patients with NAFLD, Pemvidutide achieved an approximate 75% reduction in liver fat content over 6 months, suggesting potent anti-steatotic and potentially anti-inflammatory effects.

Building on these encouraging results, Altimmune has advanced pemvidutide into a Phase IIb study—the IMPACT NASH trial (NCT05989711)—which is evaluating histological endpoints in approximately 190 MASH patients. This study will help determine whether Pemvidutide can not only reduce liver fat but also improve fibrosis and resolve steatohepatitis. If successful, Pemvidutide could represent a vital addition to the emerging therapeutic landscape for MASH, complementing agents like semaglutide and tirzepatide by offering another mechanism to target both metabolic dysfunction and liver injury directly.  

Retatrutide is an investigational triple agonist targeting GIP, GLP-1, and glucagon receptors, developed by Eli Lilly. In a Phase II clinical trial involving adults with obesity and MASLD, retatrutide demonstrated a significant reduction in liver fat content. At 24 weeks, participants receiving the 12 mg dose experienced an 82.4% decrease in liver fat, compared to a 0.3% increase in the placebo group.

Strategic Shift: Efinopegdutide’s Development Focus from Obesity to MASH

Efinopegdutide is an investigational dual agonist targeting both GLP-1 and glucagon receptors, developed by Merck in collaboration with Hanmi Pharmaceutical, currently under clinical investigation for the treatment of NAFLD and NASH. In a Phase IIa study, efinopegdutide demonstrated a significant reduction in liver fat content compared to semaglutide, another GLP-1 receptor agonist, suggesting its potential efficacy in treating NASH. 

In earlier obesity clinical trials, efinopegdutide exhibited promising weight loss results. However, these studies reported a relatively high incidence of adverse gastrointestinal events, leading to a notable discontinuation rate among participants. Specifically, 24.5% of participants in a Phase II obesity trial discontinued efinopegdutide at a 10 mg dose due to adverse events. 

These safety concerns have contributed to a strategic shift in focus towards MASH, where efinopegdutide’s dual agonist mechanism may offer more targeted therapeutic benefits with a potentially improved risk-benefit profile.

The strategic prioritization of efinopegdutide’s development for MASH over obesity reflects a nuanced consideration of therapeutic potential and market dynamics. MASH represents a significant unmet medical need, with limited approved therapies and a growing patient population at risk of progressing to cirrhosis and liver-related complications. The robust efficacy signals observed in liver fat reduction position efinopegdutide as a promising candidate in this space. Conversely, the obesity treatment landscape has become increasingly competitive, with several GLP-1 receptor agonists already approved and demonstrating substantial efficacy. By focusing on MASH, companies can leverage efinopegdutide’s unique dual agonist properties to address a critical gap in treatment options, potentially expediting regulatory approvals and optimizing resource allocation. This strategic decision underscores a targeted approach to drug development, aligning clinical benefits with areas of highest unmet need.

KOL Perspective

The strong efficacy of survodutide in improving MASH and fibrosis underscores the growing role of glucagon receptor agonism in liver disease treatment. With an 83% response rate in a mid-stage trial, survodutide reinforces the hypothesis that glucagon’s ability to reduce liver fat is clinically meaningful. The competitive landscape is shifting, with dual and triple agonists like tirzepatide and retatrutide showing metabolic benefits. However, concerns over cardiovascular safety with retatrutide may give survodutide a strategic advantage, positioning it as a leading candidate in the evolving MASH market.

The convergence of obesity and diabetes therapeutics with MASH treatment is a paradigm shift in hepatology. The historical challenge in bringing MASH drugs to market stemmed from the complexity of liver disease progression and fibrosis reversal. However, the latest data from metabolic agents, particularly those achieving significant weight loss, are reshaping expectations. The correlation between ≥10% body weight reduction and fibrosis improvement highlights the metabolic foundation of MASH, reinforcing optimism that therapies originally designed for diabetes and obesity may finally deliver long-awaited solutions for liver disease.

Conclusion and Future Outlook of Liver Disease

The redefinition of liver disease—from NASH to MASH—has transformed therapeutic strategies. By addressing the metabolic underpinnings of liver injury, obesity-targeted pharmacotherapies are emerging as powerful tools in the fight against liver fibrosis and its sequelae. The integration of established agents like semaglutide and tirzepatide with a host of novel GLP‑1 receptor agonists and dual/triple agonists alongside FGF21 analogs represents a paradigm shift.

Ultimately, collaboration among pharmaceutical innovators, regulatory bodies, and clinical researchers will be crucial in shaping a more precise, effective, and patient-centered approach to managing one of today’s most pressing global health challenges.