INTRODUCTION
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), is the most prevalent liver disease in the USA [1], and has an estimated global prevalence of 30% [2,3]. Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), represents a more severe form of MASLD and is the leading indication for liver transplantation among women and individuals over 65 years old [4]. MASLD is linked to other metabolic conditions such as obesity, type 2 diabetes mellitus (T2DM), hypertension, and dyslipidemia, and it poses a substantial burden on both patient health and worldwide healthcare systems [5]. Moreover, the growing prevalence of MASLD imposes significant clinical, economic, and societal challenges [6]. Until recently, given the lack of approved therapies, therapeutic strategies have primarily focused on lifestyle modifications and optimization of comorbidities. While lifestyle interventions can be effective, they are challenging to maintain, which limits their overall impact [7]. Therefore, as fibrosis improvement is crucial to bend the arc of disease progression, and sustained weight loss through lifestyle intervention is achieved by only a minority, pharmacological therapies are needed to meaningfully impact liver-related outcomes. After decades of research, the Food and Drug Administration (FDA) approved the first treatment for MASH in March 2024, resmetirom, a thyroid hormone receptor-β (THR-β) agonist [8]. Several drug candidates are currently in the pipeline to enrich the armamentarium of treatment for MASH. In this review, we will focus on the identification of the appropriate target population and outline the current treatment landscape for drugs in development.
PATHOPHYSIOLOGY OF MASLD
The pathogenesis of MASLD is multifactorial, encompassing genetic predisposition, insulin resistance, impaired lipid and carbohydrate metabolism, oxidative stress, inflammation, and apoptosis [9]. Environmental factors, such as diet and physical inactivity, primarily increase the risk of hepatic steatosis. Excessive caloric intake beyond metabolic demand results in adipose tissue fat overload, promoting inflammation and insulin resistance in adipose tissue [10]. Insulin resistance impairs lipolysis regulation in adipose tissue, resulting in an increased hepatic fatty acid influx [11]. Positive energy balance also triggers hepatic de novo lipogenesis, resulting in carbohydrate-derived hepatic lipid accumulation [12]. Hepatic fatty acids undergo either mitochondrial β-oxidation or triglyceride synthesis via re-esterification. Overwhelmed fatty acid disposal mechanisms lead to lipotoxic species formation, triggering endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, and inflammasome activation, ultimately driving the MASH phenotype characterized by hepatocellular injury, inflammation, and fibrosis [9]. Moreover, dysbiosis of the gut microbiota compromises intestinal barrier integrity and increases permeability, facilitating the translocation of lipopolysaccharides and pro-inflammatory factors into the portal circulation, thereby promoting hepatic inflammation and injury. Furthermore, dysbiosis disrupts bile acid metabolism, exacerbating hepatic inflammation and oxidative stress [13]. Additionally, genetic factors, such as variations in the PNPLA3, TM6SF2, and HSD167B13 genes, have been identified as key risk factors that increase susceptibility to MASLD and progression to advanced liver disease and hepatocellular carcinoma [14]. These factors collectively serve as crucial risk factors, or “multiple hits”, that trigger the onset of hepatic steatosis and drive its progression to inflammation and fibrosis [9], while the sustained low-grade systemic inflammation promotes cardiovascular disease [15] and tumor development [16]. The aforementioned mechanisms serve as potential targets for pharmacological intervention (Fig. 1). Approaches targeting insulin sensitivity, free fatty acid metabolism, mitochondrial function, inflammation, fibrosis, and gut-liver axis signaling hold therapeutic potential.
LIFESTYLE MODIFICATION
Lifestyle modifications, particularly weight reduction through dietary adjustments and increased physical activity, remain the foundational strategy in the management of MASLD [17] and have been the only available options for several years prior to the approval of the first pharmacological therapy, resmetirom, in 2024. Even small amounts of weight loss (<5%) can improve liver enzymes though more substantial weight loss is needed to resolve steatohepatitis (approximately 7%) and >10% is needed to improve fibrosis [18]. While several studies have supported this concept, the impact of weight loss varies between individuals and can be impacted by many factors, including genetic polymorphisms [19,20]. Unfortunately, the sustainability of weight loss in patients is limited due to the challenge of lifestyle modification maintenance throughout the years [7]. While bariatric surgery has been shown to induce MASH regres-sion, attenuate hepatic fibrosis progression, and promote sustained weight reduction [21], its applicability is restricted to a subset of patients meeting specific criteria (body mass index ≥40 kg/m2 regardless of metabolic comorbidities or a body mass index ≥35 kg/m2 with metabolic comorbidities). Given these limitations, pharmacological treatments remain indispensable for the effective management of MASLD population.
PHARMACOLOGICAL AGENTS
Pharmacological agents should be tailored according to individual patient profile and may include liver directed therapy (resmetirom) and/or therapies to control metabolic comorbidities, such as T2DM, dyslipidemia, and obesity [22].
Resmetirom – the only drug conditionally approved by the FDA for MASH
Resmetirom, an oral, once-daily, liver-targeted THR-β selective agonist, is the first and currently the only drug to have received, on 14 March 2024, accelerated FDA approval in the USA for treating non-cirrhotic MASH with moderate-to-advanced liver fibrosis (corresponding to F2–F3 fibrosis stages) [8]. THR-β is predominantly expressed in the liver and plays a key role in regulating hepatic lipid metabolism through inducing fatty acid oxidation, mitophagy, lipol-ysis, and cholesterol clearance in the liver [23]. In the interim analysis of the registration trial, MAESTRO-NASH, which included 966 patients with biopsy proven MASH and significant fibrosis (F2–F3), both doses of resmetirom demonstrated statistical significance on the dual primary surrogate histological endpoints after 52 weeks of treatment [24]. Fibrosis improvement (at least 1 stage) with no worsening of NAFLD activity score (NAS) was achieved in 24% and 26% of patients in resmetirom 80 mg and 100 mg groups, respectively, versus 14% in the placebo group (P<0.001). MASH resolution with no worsening of fibrosis was achieved in a significantly higher proportion in the resmetirom 80 mg and 100 mg groups (26% and 30%, respectively) compared to the placebo group (10%, P<0.001). Resmetirom also met its key secondary endpoint and showed a significant decrease in low-density lipoprotein cholesterol in the resmetirom 80 mg and 100 mg groups (–14% and −16%, respectively) compared to a slight increase in the placebo group (+0.1%). Resmetirom was also associated with significant reduction in the hepatic fat fraction (magnetic resonance imaging-derived proton density fat fraction [MRI-PDFF]) with a relative change from baseline of −35% and −47% in patients treated by resmetirom 80 mg and 100 mg, respectively, versus −9% in the placebo group. The reduction in hepatic fat fraction was predictive of histological response as 88% of patients with fibrosis improvement and 96% of patients with MASH resolution had a relative reduction of at least 30% on MRI-PDFF. Resmetirom demonstrated an acceptable safety/tolerability profile with minimal impact on central and peripheral thyroid hormones. Serious adverse events were rare and comparable across all treatment groups, with the most common adverse events being mild and transient nausea, vomiting, and diarrhea. MAESTRONASH, together with additional phase 3 trials, are still ongoing to assess the progression to major adverse liver outcomes in MASH patients with and without cirrhosis. Resmetirom was granted conditional approval by the FDA under the accelerated approval pathway, permitting its market availability while its long-term clinical efficacy is being evaluated in ongoing trials. The final approval remains dependent on the demonstration of clinical benefit in these studies, and approval may be rescinded if the trials fail to meet their predefined endpoints.
Glucagon-like peptide-1 receptor agonists and dual agonists – FDA-approved drugs for obesity and/or T2DM
Semaglutide
Glucagon-like peptide-1 receptor agonists (GLP-1 Ras) promote insulin release from pancreatic β cells after food ingestion. They also delay gastric emptying, reduce appetite, and contribute to a decrease in hepatic steatosis [25]. Semaglutide, a GLP-1 RA approved by the FDA for treating T2DM and/or obesity, has been shown to promote weight loss and improve glycemic control in individuals with these conditions [26]. Since insulin resistance is a common feature of both T2DM and obesity, and a key driver in the pathogenesis of MASH, semaglutide has been studied as a treatment option for MASH. In November 2024, semaglutide met its primary endpoint in the ongoing phase 3 registrational trial, ESSENCE, which enrolled 1,200 patients with biopsy-proven MASH and significant fibrosis (F2–F3) [27]. At 72 weeks, an interim analysis of the first 800 randomized participants with biopsy results demonstrated that a significantly higher proportion of patients achieved at least 1 stage improvement in fibrosis with no worsening of MASH in the once-weekly subcutaneous semaglutide 2.4 mg group (37%) compared to the placebo group (23%, P<0.0001). MASH resolution with no worsening of fibrosis was achieved in 63% of patients treated with semaglutide versus 34% in the placebo group (P<0.0001). Semaglutide had a significant weight loss benefit with a relative weight decrease of 11% in the semaglutide group versus 2% in the placebo group. As previously shown, semaglutide was also associated with significant benefit for glucose and lipid control. In addition to the benefits observed in this MASH registration trial, the cardiovascular efficacy of semaglutide has been shown in outcomes trials conducted in the T2DM population [28] The safety/tolerability profile of this drug candidate has been widely investigated in the context of a high cardiovascular risk profile population and has been demonstrated to be safe and well tolerated. Common adverse events are gastrointestinal disorders such as nausea, diarrhea, constipation, and vomiting.
A recent study using a USA claims database demonstrated that MASLD cirrhosis patients with T2DM who received GLP-1 RAs had a reduced risk of long-term major adverse liver outcomes compared to those not receiving GLP-1 RAs [29]. Similarly, a Swedish registry suggested that GLP-1 RAs reduce the risk of major adverse liver outcomes in patients with chronic liver disease and T2DM [30]. The ongoing ESSENCE trial will further characterize the potential benefit of semaglutide to prevent major adverse liver outcomes in MASH patients with F2–F3 fibrosis.
Other GLP-1-based therapies
Several additional drug candidates are in development, such as dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP)-RAs (tirzepatide [31]) or dual GLP-1/glucagon RAs (survodutide [32]) and have shown promising phase 2b results (Table 1). GIP, another incretin regulating postprandial glucose and lipid metabolism, can further stimulate insulin secretion, reduce food intake via central nervous system modulation, and enhance perfusion in subcutaneous white adipose tissue, thereby improving postprandial triglyceride clearance and increasing insulin sensitivity [33]. Given that tirzepatide, a dual GIP and GLP-1 RA recently approved for T2DM, has demonstrated superior glycemic control and weight loss compared to a GLP-1 RA [34], its ability to reduce hepatic fat and visceral adipose tissue further underscores its potential advantage in treating MASH over GLP-1 RAs [35]. Though the role of GIP agonism in MASH therapy, independent of body weight loss, is not well understood, a phase 2b trial involving participants with MASH and moderate to severe fibrosis showed that once-weekly subcutaneous tirzepatide administered for 52 weeks was significantly more effective than placebo in achieving MASH resolution without worsening of fibrosis (44% with tirzepatide 5 mg, 56% with tirzepatide 10 mg, 62% with tirzepatide 15 mg vs. 10% with placebo; P<0.001 for all) [31]. Glucagon receptor activation reduces hepatic glycogen levels, increases gluconeogenesis, decreases hepatic lipogenesis, and boosts mitochondrial turnover and oxidative function in the liver, thereby increasing energy expenditure [36]. In phase 2b trials, once-weekly subcutaneous injections of survodutide, a dual GLP-1/glucagon RA, for 48 weeks were superior to placebo in improving MASH without worsening of fibrosis and in reducing hepatic fat content. The safety profile was generally tolerable, with gastrointestinal side effects commonly observed, similar to other GLP-1 RAs [32].
Pharmacotherapies with positive phase 2b data
Several additional drug candidates have completed their phase 2b and have either already started their phase 3 program or are pending phase 3 initiation. Among this potential armamentarium of drugs, the subcutaneous fibroblast growth factor 21 (FGF21) analogs, including efruxifermin [37] and pegozafermin [38], appear appealing. FGF21 directly inhibits de novo lipogenesis and lipotoxicity, enhances fatty acid oxidation, and reduces inflammation and fibrosis in the liver. Moreover, FGF21 stimulates adiponectin production in adipocytes, potentially augmenting its metabolic, anti-inflammatory, and antifibrotic properties [39]. Efruxifermin, a long-acting Fc-FGF21 fusion protein with a half-life of approximately 3 days, improved fibrosis without worsening of MASH in 30% and 49% of patients receiving 28 mg and 50 mg, respectively, compared to 19% in the placebo group, according to a recent analysis of sequential liver biopsy data from the 96-week phase 2b HARMONY trial. MASH resolution without fibrosis worsening was achieved in 40% and 37% of patients in the 28 mg and 50 mg efruxifermin groups, respectively, versus 19% in the placebo group [40]. In the 96-week phase 2b SYMMETRY trial involving patients with compensated cirrhosis (F4), 39% of patients in the efruxifermin 50mg group (P=0.009) demonstrated significant improvement in fibrosis by ≥1 stage without worsening of MASH at week 96, compared to 29% in the efruxifermin 28 mg group and 15% in the placebo group [41]. Pegozafermin, a long-acting glyco-pegylated recombinant analogue of FGF21, significantly improved fibrosis and MASH resolution in patients with stage 2–3 fibrosis, along with a notable reduction in liver fat content in a phase 2b trial. It also enhanced insulin sensitivity and provided benefits for lipid metabolism. While nonclinical and early clinical studies have suggested potential bone effects with FGF21 analogues, this trial detected no evidence of reduced bone density or fractures; however, longer-term studies are warranted [38]. Efimosfermin alfa (BOS-580), a long-acting, once-monthly Fc-FGF21 fusion protein, demonstrated encouraging outcomes in a 24-week study. It improved fibrosis without worsening of MASH (45% vs. 21%, P=0.038) and resolved MASH without worsening of fibrosis (68% vs. 29%, P=0.002). Beyond these histological improvements, efimosfermin significantly improved fibrosis biomarkers, reduced non-invasive markers of hepatic injury and hepatic fat, and enhanced glycemic control. The study also confirmed its favorable tolerability profile, with adverse events mostly limited to mild to moderate gastrointestinal symptoms [42].
Peroxisome proliferator-activated receptors (PPARs), a subfamily of nuclear hormone receptors, act as ligand-activated transcription factors and include three isoforms: PPARα, PPARβ/δ, and PPARγ. PPARα, mainly expressed in the liver, regulates hepatic fatty acid metabolism, plasma lipoprotein levels, and FGF21 secretion, while PPARβ/δ, found in skeletal muscle and adipose tissue, influences fatty acid oxidation and insulin sensitivity. PPARγ, predominantly in adipose tissue, plays a key role in regulating lipid metabolism, insulin resistance, immune function, and adipocyte differentiation [43,44]. Lanifibranor, an oral pan-PPAR agonist, demonstrated superior efficacy in achieving MASH resolution without fibrosis worsening (49% vs. 22%, P<0.01) and improving fibrosis by at least one stage without MASH worsening (48% vs. 29%, P<0.05), despite potential safety concerns, including weight gain, hemoglobin decrease, bone fractures, and vesical cancer [45].
Denifanstat (TVB-02640), an oral fatty acid synthase inhibitor, prevents steatosis by blocking de novo lipogenesis in hepatocytes, reduces inflammation by inhibiting immune cell activation, and prevents fibrosis by reducing de novo lipogenesis in stellate cells, thereby blocking stellate cell activation [46]. The 52-week phase 2b trial of once-daily oral denifanstat demonstrated statistically significant and clinically meaningful benefits, including resolution of MASH without fibrosis progression (38% vs. 16%, P<0.01) and improvement in fibrosis without worsening of MASH (41% vs. 18%, P<0.01), as confirmed by paired liver biopsy results [47]. PXL065, a novel oral agent that retains the efficacy of pioglitazone while lacking PPARγ activity, inhibits mitochondrial pyruvate carrier and long-chain acyl-CoA synthetase 4. In a phase 2b trial, it demonstrated fibrosis improvement by ≥1 stage without worsening of MASH following 36 weeks of treatment (38% [7.5 mg], 50% [15 mg, P=0.06], and 31% [22.5 mg] vs. 17% for placebo) [48]. Icosabutate, an oral, structurally enhanced fatty acid that targets free-fatty acid receptor 1 and 4, which are highly expressed in Kupffer cells, demonstrated histological improvements along with enhanced insulin sensitivity and lipid-related benefits in a phase 2b trial, despite not meeting its primary endpoint (Table 1) [49].
Careful consideration is required when interpreting the results of clinical trials. First, participants in MASH trials are typically non-cirrhotic MASH patients, either F1–F3 or F2–F3, with a NAS of ≥4. These criteria have led to significant variability in MASH activity and fibrosis stages among enrolled patients [50]. The impact of disease heterogeneity on the response to MASH therapies remains unclear, but drug efficacy may vary across individuals and disease stages. Second, histological surrogate endpoints have been established in clinical trials for MASH because the slow progression of the disease makes long-term observation of liver-related clinical outcomes impractical. For accelerated FDA approval, at least one of the following histologic endpoints must be met: (1) MASH resolution without worsening of liver fibrosis, or (2) fibrosis improvement without worsening of MASH [51]. However, MASH activity alone has limited prognostic value for clinical outcomes [52]. Moreover, liver biopsy is subject to sampling variability, which limits comprehensive liver assessment and may lead to inaccurate evaluations of treatment efficacy [53]. Additionally, inter- and intraobserver inconsistencies further complicate the reliable assessment of drug efficacy in MASH trials [54].
NON-INVASIVE IDENTIFICATION OF MASH PATIENTS WITH F2–F3 FIBROSIS
The introduction of approved MASH therapy is considerably transforming the clinical management of MASLD patients and should bring additional real-world evidence on this patient population, especially on the non-invasive diagnosis and follow-up of patients. Although pivotal clinical trials for resmetirom relied on histologic diagnosis, liver biopsy is not practical for routine clinical use [55]. Fortunately, the current FDA label does not mandate liver biopsy as a diagnostic criterion. However, careful attention is required to ensure the accurate selection of the target population. Based on the baseline characteristics of patients included in the phase 3 registration trials of resmetirom, an expert panel has published their recommendations for patient selection and follow-up [56]. After excluding alternate diagnoses through comprehensive history-taking and additional testing, which may occasionally require a liver biopsy, non-invasive biomarkers can effectively identify the population eligible for resmetirom treatment. To select presumed MASH, steatosis assessment using vibration-controlled transient elastography (VCTE)-controlled attenuation parameter (CAP) score (≥280 dB/m) or MRI-PDFF (≥5%), along with elevated aspartate aminotransferase (AST) (>17 IU/L for females and >20 IU/L for males), is recommended as an initial screening approach. As outlined in Figure 2, MASH F2–F3 patients may present with a liver stiffness measurement (LSM) of 10–15 kPa via VCTE or 3.3–4.2 kPa via magnetic resonance elastography (MRE). The threshold recommended by the expert panel is based on the interquartile range from the MAESTRO-NASH trial data. To avoid overtreatment in patients at the lower end of the spectrum, the panel set a lower threshold of 10 kPa for VCTE, considering the reduced specificity of VCTE values in individuals with obesity.
More recently, the American Association for the Study of Liver Diseases (AASLD) released guidance for clinicians on the use of resmetirom, including updated non-invasive criteria for patient selection [57]. The AASLD guidance suggests broader eligibility criteria, recommending LSM values of 8–15 kPa by VCTE or 3.1–4.4 kPa by MRE. This expansion reflects findings from the MAESTRO-NASH trial, in which approximately half of the participants had LSM by VCTE outside the interquartile range of 10–15 kPa. Ultimately, the assessment of a patient’s fibrosis status remains at the discretion of the prescribing clinician, who must integrate both expert opinion and AASLD guidance to make an informed treatment decision.
Higher liver stiffness suggests more advanced fibrosis, and such patients should be approached with caution or excluded. As a single non-invasive test (NIT) is insufficient, the expert panel suggests performing several NITs and considering the entire patient profile before making any decisions. It is of paramount importance to exclude patients with potential cirrhosis, which may be indicated by several lab parameters and/or signs of portal hypertension.
Laboratory safety parameters should be assessed after three months of treatment, then NITs may confirm improvements after 6–12 months of treatment. The application of NITs in the assessment of treatment response is an emerging area of interest. Substantial evidence has established the association between improvements in NITs and changes in fibrosis stage in MASH [58]. A systematic review and meta-analysis of participants from NASH clinical trials identified the combination of MRI-PDFF and alanine aminotransferase (ALT) response as a predictor of histological response [59]. In addition, a decline in VCTE stiffness has been suggested to correlate with histologic response [60]. In the MAESTRO-NASH trial, a reduction of at least 20% in liver stiffness, measured by MRE, was associated with improvements in histologic fibrosis, while a ≥30% decrease in hepatic steatosis, measured by MRI-PDFF, was linked to more favorable histologic outcomes compared to placebo. In contrast, ALT, CAP, and VCTE demonstrated weaker correlations with histopathological responses [61]. However, more robust data are needed to establish NITs as reliable surrogates for histologic improvement following MASH pharmacotherapy.
From a clinical perspective, it is essential not only to stratify patients by fibrosis severity and MASH activity but also to identify those most vulnerable to disease-related adverse clinical outcomes. Substantial additional evidence is being developed, testifying to a collective effort to link NITs to major adverse liver outcomes. Recently, Lin and colleagues [62] demonstrated the high accuracy of VCTE-based scores in predicting major adverse liver outcomes in clinical practice, based on data from over 16,000 patients. Future analyses of data from MASH clinical trials may offer further insights into the role of NITs in treatment monitoring and predicting clinical outcomes.
CHALLENGES IN THE APPLICATION TO REAL CLINICAL PRACTICE
While the introduction of new therapeutic drugs for MASLD represents progress, it also comes with challenges. Firstly, a recent consensus process involving multiple scientific societies has established new terminology, replacing NAFLD with MASLD [2]. Nevertheless, the differential definitions of NAFLD and MASLD could potentially lead to uncertainty in clinical applications. From the perspective of incorporating the new MASLD nomenclature criteria into existing clinical data from patients with biopsy-proven NAFLD, the results remain relevant, as reflected in the strong concordance between traditional NAFLD and the newly defined MASLD [63,64]. However, the dynamic nature of metabolic risk factors and alcohol intake must be considered as they influence the definition of MASLD. Further research is needed to extrapolate clinical trial results to current MASLD patients. On the other hand, MASLD diagnosis is based on affirmative criteria rather than exclusion, with relatively simple and widely used parameters defining MASLD, facilitating earlier identification of at-risk patients [2]. Moreover, refining diagnostic criteria and patient classification will be beneficial for achieving favorable clinical trial outcomes and tailoring therapeutic approaches. Additionally, the newly introduced definition of metabolic alcohol-associated liver disease (MetALD) represents an overlap of MASLD with significant alcohol use and was frequently excluded from clinical trials under the previous NAFLD definition. Given the lack of evidence on dedicated treatment approaches and interventions for this patient group, careful consideration is needed when applying MASLD-based clinical trial results to MetALD patients. To establish evidence-based treatment strategies, specialized clinical trials focusing on the MetALD population are urgently needed.
Second, many standard NITs focus on the detection of advanced fibrosis and exhibit suboptimal performance with an area under the receiver operating characteristic curve <0.8 in identifying at-risk MASH [65]. Diagnosing at-risk MASH is challenging as it requires assessing hepatic steatosis, fibrosis, and inflammation. The most promising NITs for this purpose include FibroScan AST score, MRI-AST score, MRE combined with fibrosis-4 index, and MRI using iron-corrected T1, with further optimization ongoing [58]. However, these NITs also lack mechanistic biomarkers that account for biological variations among patients and the wide range of MASLD phenotypes. Therefore, circulating microRNAs (miRs) and proteomics-based biomarkers are increasingly recognized as promising candidates for clinical application. Recent evidence suggests that specific miRs exhibit significant alterations in the sera of patients with atrisk MASH and hold promise as early biomarkers for diagnosing and predicting MASLD progression [66]. The NIS4® and its modified version, NIS2+TM, comprise serum biomarkers, including miR-34a, demonstrating good performance in identifying at-risk MASH [67]. In addition, a proteomics-based signature has been identified for detecting at-risk MASH and monitoring therapy-induced histological changes [68]. Ongoing research in this field presents promising opportunities for advancing personalized treatment approaches and refining diagnostic tools.
Third, the economic impact of MASH therapies requires thorough consideration as these treatments become integrated into clinical practice. Although resmetirom may introduce additional financial burdens for patients, including drug costs, it also has the potential to slow or even reverse disease progression. The progression of MASH is a significant driver of healthcare costs, with expenses rising exponentially as the disease advances [69]. In a simulated cohort with an average life expectancy of about 21 years, a medical intervention for MASLD was considered cost-effective in reducing liver fibrosis and mortality only if the annual drug cost remained below $12,000 [70]. Another early economic evaluation suggested that resmetirom could be cost-effective for treating MASH and fibrosis compared to a placebo, assuming a willingness-to-pay threshold of US $100,000 per quality-adjusted life year [71]. A recent budget impact analysis from the perspective of USA private insurers assessed the financial implications of incorporating resmetirom for adults with non-cirrhotic MASH and moderate-to-advanced liver fibrosis [72]. While its inclusion in the formulary led to a moderate budget increase over three years, primarily driven by drug costs, it also contributed to reducing expenses related to disease progression. However, the limited time frame constrains the evaluation of long-term benefits, such as cost savings from slowed disease progression and the impact of future treatment competition. To fully evaluate the financial and clinical sustainability of resmetirom, long-term cost-effectiveness analyses are necessary.
Early trials suggest that many MASH therapies not only improve liver health but also provide metabolic and cardiovascular advantages, since metabolic dysfunction is fundamentally linked to the pathophysiology of MASH. Given that cardiac disease continues to be the primary cause of mortality in individuals with MASLD, treatments that enhance cardiovascular disease profiles are of particular interest. However, the cost and accessibility of these therapies will play a crucial role in their widespread adoption. Given its high cost, several strategies could improve the affordability and accessibility of resmetirom, similar to approaches used to lower the prices of human immunodeficiency virus and hepatitis C virus medicines [73]. Pricing strategies include tiered pricing models (implementing region-specific pricing based on economic status), value-based pricing (pricing based on real-world effectiveness in improving liver outcomes), and subscription-based models (implementing a flat-rate pricing model). Additional approaches include expanding insurance coverage, patient assistance programs, voluntary licensing agreements for generic production, and research into alternative dosing regimens to reduce costs while maintaining efficacy.
FUTURE DIRECTIONS
The therapeutic efficacy of monotherapy remains suboptimal, as evidenced by clinical investigations demonstrating that approximately 60% of subjects exhibit insufficient treatment response or fail to achieve predetermined primary endpoints [74]. Considering the sophisticated pathophysiology of MASH involving various contributing pathways and the complex cross-talk among target molecules within different signaling networks, combination therapy is likely to become the standard of care in this disease, similar to T2DM and hypertension. Combination approaches offer potential advantages, such as boosting biological potency, enhancing clinical efficacy, and optimizing side effect profiles by targeting converging pathways, which can strengthen biological responses, counter compensatory mechanisms, and address both upstream and downstream pathogenic drivers [75]. Including treatment regimens with verified extrahepatic clinical benefits, such as significant weight loss, achieved with GLP-1 RAs [27], adds an additional advantage to combination therapy, as weight loss may further enhance therapeutic response. Achieving an optimal combination therapy may necessitate the integration of two or more pharmacotherapies with complementary mechanisms of action. Several potential therapeutic combination options are under investigation [76]. However, substantial challenges remain in developing combination approaches, as early clinical trial data have been negative. The efficacy of each drug in combination therapy has yet to be fully established. Identifying two optimal synergistic pathways among various interconnected mechanisms, navigating complex regulatory requirements, determining optimal dosing, managing an increased risk of side effects, and enrolling a large number of patients all present significant clinical and translational hurdles [77].
Among potential combinations, adding GLP-1 RAs to THR-β agonists appears physiologically promising, as it may enhance antifibrotic effects through additional metabolic benefits such as weight loss and improved glucose control. Adding an FGF21 agonist to resmetirom could increase glucose uptake by adipose tissue while simultaneously preventing its release through lipolysis. Given the potent effects of FGF21 and the limitation of its subcutaneous administration, an induction regimen with FGF21 followed by long-term oral resmetirom therapy may offer a viable treatment strategy [78]. In real-world applications of combination therapy, GLP-1 RAs will serve as the backbone, as they are already widely prescribed for T2DM and obesity, which are common in patients with MASH [77]. The combination of FGF21 analogs and GLP-1 RA presents an intriguing possibility by potentiating the insulin-sensitizing effect of FGF21 [78] with the insulin-secretion effect of GLP-1 [25]. which would likely improve glycemic and lipid control. The combined administration of efruxifermin (an FGF21 analogue) and GLP-1 RA demonstrated superior efficacy to GLP-1 RA monotherapy in patients with MASH and T2DM. This dual therapy significantly reduced hepatic fat content and enhanced multiple clinical parameters, including markers of liver injury, fibrosis, glucose metabolism, and lipid profiles, while maintaining a safety and tolerability profile comparable to GLP-1 RA alone [79]. A phase 2 trial combining semaglutide (GLP-1 RA) with firsocostat (acetyl-CoA carboxylase inhibitor) and/or cilofexor (farnesoid X receptor agonist) successfully achieved its primary endpoints, demonstrating greater relative liver fat reduction, improvement in liver biochemistry and non-invasive fibrosis markers, and a favorable safety profile [80]. Large-scale, late-phase clinical trials with long-term follow-up are needed to validate these promising findings. Further mechanistic studies are essential to understand the drug-drug interactions and potential synergistic effects before this therapeutic approach can be incorporated into clinical practice. It remains unclear whether combination therapy should be used during the initial induction phase, followed by monotherapy for maintenance, or reserved only for patients who do not respond to monotherapy.
Despite the recent development of new drugs, a significant proportion of patients have not responded to therapy, with response rates of only 20% to 30% in clinical trials demonstrating MASH resolution and fibrosis regression [24,45,81]. Considering that MASLD is collectively influenced by genetic, metabolic, and environmental factors, contributing to its heterogeneity [9], precision medicine is gaining interest in optimizing individual patient care. Genomic and metabolomic technologies provide insights into individual patient variations, allowing for more targeted therapeutic approaches based on predicted treatment responses. To select the most effective combination therapy, it is crucial to adopt a personalized strategy that includes non-invasive testing, metabolic evaluations, and genetic analysis to tailor treatment to the patient’s unique characteristics [82].
CONCLUSION
Given the global burden of MASLD and MASH, along with their associated morbidity and mortality, these conditions remain a substantial and growing public health concern. The establishment of targeted pharmacological therapies is crucial for addressing the ongoing health challenge and improving outcomes for affected individuals. Resmetirom is the first FDA-approved therapy targeting MASH, showing effectiveness in reversing liver fibrosis and steatohepatitis, in addition to lipid benefits. Incretin-based therapies, such as GLP-1 and dual receptor agonists, also show promise for addressing MASH with fibrosis. Several agents in late-phase 2 or phase 3 trials appear promising but still require additional validation. Using NITs with high discriminatory ability to identify patients with at-risk MASH and significant fibrosis can help select those most likely to benefit from MASH pharmacotherapy, and guide treatment response monitoring. In the near future, MASH treatment is anticipated to undergo a paradigm shift, likely involving combination therapies and precision medicine that specifically target the primary drivers of each patient’s condition.
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