Efficacy and safety of anti-obesity drugs in metabolic dysfunction-associated steatotic liver disease: An updated review

Abstract

Obesity is a major driver of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). As the global prevalence of obesity continues to rise, the burden of MASLD/MASH is increasing, posing significant challenges to healthcare systems. The use of anti-obesity medications (AOMs) in this population is complex due to altered hepatic metabolism, safety concerns, and potential hepatotoxicity. Recent advances in pharmacologic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), dual GLP-1/glucose-gastric inhibitory polypeptide (GIP) agonists, and triple GLP-1/GIP/glucagon agonists, have shown promising metabolic effects in the general population. Among these, GLP-1 RAs (e.g., liraglutide and semaglutide) consistently demonstrate hepatic benefits, including reductions in hepatic steatosis, improvements in liver enzyme profiles, and attenuation of fibrosis progression. Tirzepatide, a dual GLP-1/GIP agonist, has shown superior weight loss effects compared to GLP-1 receptor agonist monotherapy, with emerging but still limited data on hepatic outcomes in MASLD/MASH. Retatrutide, a triple agonist, has produced the most pronounced metabolic effects to date, although its impact on liver histology remains underexplored. Other AOMs, such as bupropion-naltrexone and phentermine-topiramate, require cautious use due to potential hepatotoxicity. Importantly, advanced MASLD may alter drug pharmacokinetics, underscoring the need for individualized therapy and close monitoring. This review provides an updated synthesis of the efficacy and safety of current and emerging AOMs in patients with MASLD/MASH and highlights the urgent need for further research to define optimal pharmacological strategies in this high-risk population.

Key Words: Obesity; Metabolic dysfunction-associated steatotic liver disease; Metabolic dysfunction-associated steatohepatitis; Glucagon-like peptide-1 receptor agonists; Tirzepatide; Retatrutide; Anti-obesity medications

Core Tip: Obesity is a leading modifiable risk factor for chronic liver disease, particularly metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis. Glucagon-like peptide-1 receptor agonists and emerging dual and triple incretin agonists offer promising metabolic and hepatic benefits. However, their use in advanced liver disease raises concerns due to altered pharmacokinetics and limited safety data. This review synthesizes current evidence on the efficacy and safety of anti-obesity medications in individuals with metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis and underscores the need for personalized treatment strategies and robust clinical trials.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver disease worldwide, affecting nearly 30% of the adult population[1]. Its clinical impact extends beyond hepatic injury, contributing substantially to cardiovascular disease, chronic kidney disease, and malignancies[2,3]. As a consequence of rising global obesity rates, the burden of MASLD is expected to escalate, straining healthcare systems across both high-income and low-income countries. Throughout this review, the term “MASLD” is used in alignment with the 2023 international consensus on updated nomenclature, which replaced the former term “non-alcoholic fatty liver disease”[4]. Likewise, “metabolic dysfunction-associated steatohepatitis” substitutes the previously used “non-alcoholic steatohepatitis”[5]. References to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) appear exclusively in the context of historical terminology or when citing original sources published before the nomenclature update. This approach ensures consistency, scientific accuracy, and inclusivity of earlier research findings. Despite increasing awareness, MASLD remains significantly underdiagnosed, particularly in primary care settings, due to its asymptomatic nature in early stages. To address this challenge, non-invasive diagnostic tools, such as vibration-controlled transient elastography (VCTE) and serum-based fibrosis scores like the fibrosis-4 (FIB-4) index and the NAFLD fibrosis score, have been developed to estimate fibrosis risk and reduce reliance on liver biopsy[6,7]. However, diagnostic accuracy varies, particularly in individuals with obesity or type 2 diabetes mellitus (T2DM)[8,9]. Obesity is recognized as the most powerful modifiable driver of MASLD, primarily via mechanisms involving insulin resistance (IR), adipose tissue dysfunction, and chronic low-grade inflammation[10]. Sustained weight loss has been shown to improve steatosis, inflammation, and even fibrosis, with clinical benefits observed from reductions as modest as 5%, and more profound histological improvement with ≥ 10% weight loss[10,11]. However, achieving and maintaining weight loss through lifestyle modification alone remains challenging for most patients. In this context, anti-obesity medications have emerged as a promising adjunct. These agents, which include incretin-based therapies, centrally acting agents, and novel multi-agonists, target various metabolic pathways to promote weight reduction, improve insulin sensitivity, and modulate lipid metabolism. Early clinical trials suggest that some anti-obesity medications may exert beneficial effects on hepatic outcomes in MASLD, though their role remains under investigation.

In parallel, alternative pharmacologic strategies - such as insulin sensitizers like pioglitazone - have shown histologic benefit in selected MASLD populations. However, concerns regarding side effects and long-term safety have limited their widespread adoption[12,13]. The evolving pharmacological landscape highlights the need for critical appraisal of efficacy, safety, and applicability of these agents across the MASLD spectrum. Importantly, significant knowledge gaps persist, particularly in advanced fibrosis and cirrhosis where altered pharmacokinetics and comorbidities complicate treatment. For instance, recent studies have reported changes in very-low-density lipoprotein composition and secretion in advanced disease stages, suggesting impaired hepatic synthetic function and altered lipid homeostasis[14]. These findings raise questions about the suitability of specific weight-centric therapies in late-stage MASLD. Therefore, the objective of this narrative review is to provide a comprehensive synthesis of current evidence on MASLD, including its etiology and pathophysiology, non-invasive diagnostic tools, and the efficacy and safety of anti-obesity pharmacotherapies across the disease spectrum. This work also aims to identify research gaps and propose future directions for improving care in this growing population.

LITERATURE REVIEW

A structured narrative review was conducted to assess the efficacy and safety of anti-obesity pharmacological agents in patients with MASLD. A comprehensive literature search was performed across five major databases (PubMed, Scopus, Web of Science, EMBASE, and SciELO) covering all publications up to June 30, 2025. The search strategy combined Medical Subject Headings terms and free-text keywords using Boolean operators as follows: (“anti-obesity drugs” AND “MASLD” OR “NAFLD”) AND (“efficacy” AND “safety”) AND (“GLP-1 receptor agonists” OR “tirzepatide” OR “orlistat” OR “semaglutide”). Although the term NAFLD was included in the search to ensure comprehensive retrieval of relevant literature, it is used herein to reflect the broader clinical spectrum now reclassified as MASLD, following updated nomenclature guidelines. Eligible studies included peer-reviewed articles published in English or Spanish, encompassing randomized controlled trials, cohort studies, meta-analyses, real-world evidence, and systematic reviews. The scope of this review focused on anti-obesity pharmacotherapies with primary or secondary approval for weight management, particularly those with emerging evidence in MASLD. Agents such as metformin and orlistat were considered during screening but ultimately excluded due to limited MASLD-specific evidence (e.g., metformin) or insufficient long-term weight loss efficacy in recent comparative trials (e.g., orlistat). Conference abstracts, non-peer-reviewed materials, and animal-only studies were excluded. No publication date limits were applied to capture both foundational and recent evidence. A total of 155 studies were included in this review, of which 50 (35.5%) were published within the last five years, reflecting the integration of the most up-to-date therapeutic developments.

ETIOLOGY AND PATHOPHYSIOLOGY OF MASLD

Role of IR, lipotoxicity, and inflammation

IR, lipotoxicity, oxidative stress, and inflammation form a pathophysiological continuum that drives the development and progression of MASLD. IR impairs glucose uptake and increases adipose tissue lipolysis, leading to an increased flux of free fatty acids (FFAs) to the liver (Figure 1)[5,15,16]. These FFAs exceed the hepatocyte’s capacity to safely store or oxidize lipids, resulting in lipotoxic intermediate accumulation, mitochondrial dysfunction, and endoplasmic reticulum stress. This cascade generates reactive oxygen species (ROS), which induce lipid peroxidation and damage mitochondrial DNA, proteins, and membranes[17,18]. ROS also initiate inflammatory pathways and activate damage-associated molecular patterns, intensifying hepatocellular injury[18,19]. Injured hepatocytes release cytokines and chemokines [e.g., tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β], which recruit and activate hepatic macrophages (Kupffer cells) and circulating monocytes[19-22]. This self-amplifying inflammatory loop not only perpetuates liver injury but also plays a key role in activating hepatic stellate cells (HSCs), thus linking metabolic dysfunction to fibrogenesis[20-22].

Figure 1 Mechanisms of obesity and liver disease. Insulin resistance leads to elevated free fatty acids, hepatic lipid accumulation, oxidative stress, and inflammation. These processes activate hepatic stellate cells and promote liver fibrosis. Image adapted from Servier Medical ART (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/Licenses/by/4.0/). Glu: Glucose; FFA: Free fatty acids; IL: Interleukin; TNF: Tumor necrosis factor.

Activation of HSCs

Under normal physiological conditions, HSCs remain in a quiescent state. However, in response to inflammatory cytokines, ROS, and damage-associated molecular patterns released by injured hepatocytes and activated immune cells, HSCs transdifferentiate into proliferative, contractile myofibroblasts[17,20,23]. These activated cells produce large quantities of extracellular matrix proteins, particularly type I collagen, and directly contribute to hepatic fibrosis. Beyond their fibrogenic activity, HSCs also secrete proinflammatory mediators and chemokines, amplifying immune cell recruitment and sustaining hepatic inflammation[20,23]. The reciprocal interaction between HSCs and hepatic macrophages is central to the orchestration of both fibrogenesis and inflammation in MASLD[20]. Moreover, HSC activation has been linked to mitochondrial dysfunction and worsening of systemic IR[23].

Progression from steatosis to fibrosis

The development of MASLD from simple steatosis to steatohepatitis and ultimately fibrosis involves a multifactorial pathogenic cascade. Hepatic steatosis, defined by excessive triglyceride accumulation in hepatocytes, represents the initial step in this spectrum. It results primarily from IR and adipose tissue dysfunction, which drive increased FFA delivery to the liver and upregulated de novo lipogenesis[15,24]. Progression to MASLD is marked by hepatocellular stress, triggering local immune responses and oxidative injury. Resident liver immune cells detect this stress and release proinflammatory mediators such as IL-17A, which in turn promote the recruitment of myeloid-derived inflammatory cells that secrete cytokines including TNF, transforming growth factor beta, and IL-1β[25]. This sustained inflammation activates HSCs, initiating fibrogenesis through deposition of collagen and other extracellular matrix components[17]. Fibrosis is further driven by oxidative stress, mitochondrial damage, and inflammasome activation - complications of lipotoxicity and excess FFAs[15]. Moreover, genetic and epigenetic predispositions, along with alterations in the gut-liver axis, modulate the pace and severity of fibrotic progression[15,26]. Understanding the multifactorial etiology and complex pathophysiology of MASLD highlights the importance of early and accurate detection. Given its often silent progression, particularly in individuals with metabolic risk factors, timely diagnosis is essential to prevent irreversible liver damage. Many diagnostic tools are specifically designed to detect the downstream consequences of these underlying mechanisms - such as hepatic steatosis, inflammation, and fibrosis - through surrogate metabolic markers, imaging techniques, and fibrosis scoring systems. The following section outlines current strategies for identifying MASLD, including non-invasive tests (NITs).

DIAGNOSIS OF MASLD AND METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS

The diagnosis of MASLD and metabolic dysfunction-associated steatohepatitis (MASH) relies on a combination of clinical evaluation, laboratory markers, imaging techniques, and, in select cases, liver biopsy. Accurate fibrosis staging is critical for risk stratification and therapeutic decision-making.

VCTE

VCTE, commonly known as transient elastography, is a non-invasive imaging technique used to assess liver stiffness, which correlates with fibrosis in MASLD. VCTE, commonly performed with the FibroScan device, is the most validated method for assessing fibrosis in MASLD. It measures liver stiffness by calculating the velocity of a shear wave through hepatic tissue. A liver stiffness measurement (LSM) < 8.0 kPa effectively excludes advanced fibrosis, while values ≥ 8.0 kPa indicate increased risk and warrant further evaluation. LSM between 8 and 12 kPa suggest fibrotic. MASLD, and values > 12 kPa indicate advanced fibrosis, though the positive predictive value is limited[27,28]. Other elastography techniques, such as two-dimensional shear wave elastography and magnetic resonance elastography, offer comparable or superior diagnostic accuracy, but are less widely available. VCTE remains the first-line, non-invasive tool for fibrosis risk stratification and prognostic assessment in MASLD[29-31].

Non-invasive scoring systems

NITs are crucial for fibrosis risk stratification in MASLD. The FIB-4 index and the NAFLD fibrosis score are the most validated and widely endorsed scoring systems. Both rely on readily available clinical and laboratory data to estimate the likelihood of advanced fibrosis (Figures 2 and 3). The FIB-4 index, which incorporates age, aspartate transaminase, alanine transaminase (ALT), and platelet count, is recommended as the first-line NIT due to its simplicity and high negative predictive value. A FIB-4 score of < 1.3 (for adults aged < 65 years) effectively rules out advanced fibrosis, while a score of ≥ 1.3 indicates the need for further evaluation, such as the LSM or the enhanced liver fibrosis (ELF) test. For adults aged ≥ 65 years, a higher cutoff (1.9-2.0) improves specificity. FIB-4 is not validated in pediatric populations or adults aged < 35 years (Figure 2)[8,27,32]. The NAFLD fibrosis score, which includes age, body mass index, impaired fasting glucose or diabetes, aspartate transaminase/ALT ratio, platelet count, and albumin, is effective for both ruling out (low cutoff: < -1.455) and confirming (high cutoff: > 0.675) advanced fibrosis. However, it has an indeterminate range, requiring further testing in some cases (Figure 3)[9,28,33]. The FIB-4 is commonly used to assess advanced fibrosis risk, although it performs worse than the VCTE, a more direct and validated imaging-based method. Many patients with elevated LSM values (≥ 8 kPa) show normal scores, leading to false negatives and underdiagnosis, particularly in those with diabetes, obesity, or older age[8,9]. In individuals with multiple metabolic risk factors, false-negative rates may exceed 30%[9]. Its performance is age-dependent, with reduced sensitivity in younger adults and reduced specificity in the elderly[33]. Although its negative predictive value is high (particularly with cutoffs of < 1.3), the score has a low positive predictive value and a high rate of indeterminate results[28,34,35]. It performs worse than VCTE or direct serum biomarkers like the Hepascore[36-38]. Guidelines recommend starting with FIB-4, followed by confirmatory testing (e.g., VCTE, ELF) in high-risk patients. The sequential use of NAFLD fibrosis score after FIB-4 is generally discouraged[8,27].

Figure 2 Fibrosis-4 score: Components and interpretation flowchart. Flowchart illustrating the calculation and interpretation of the fibrosis-4 score, a non-invasive marker for advanced fibrosis in metabolic dysfunction-associated steatotic liver disease. The formula incorporates age, aspartate aminotransferase, alanine aminotransferase, and platelet count. Cut-off values are stratified to classify risk: < 1.3 indicates low risk, 1.3-2.67 is indeterminate, and > 2.67 suggests high risk, warranting further evaluation with vibration-controlled transient elastography or enhanced liver fibrosis testing. FIB-4: Fibrosis-4; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; VCTE: Vibration-controlled transient elastography; ELF: Enhanced liver fibrosis.

Figure 3 Non-alcoholic fatty liver disease fibrosis score: Components and interpretation flowchart. Flowchart summarizing the non-alcoholic fatty liver disease fibrosis score, which incorporates age, body mass index, fasting glucose or diabetes status, aspartate aminotransferase/alanine aminotransferase ratio, platelet count, and serum albumin. This tool stratifies patients by fibrosis risk: Values < -1.455 suggest low risk, > 0.675 indicate high risk, and intermediate values require further evaluation. The non-alcoholic fatty liver disease fibrosis score is widely used for non-invasive fibrosis screening in metabolic dysfunction-associated steatotic liver disease, especially in primary care. NAFLD: Non-alcoholic fatty liver disease; BMI: Body mass index; IFG: Impaired fasting glucose; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.

Magnetic resonance imaging-proton density fat fraction and its role in quantifying hepatic steatosis

Magnetic resonance imaging (MRI)-proton density fat fraction (PDFF) is a non-invasive and reliable method for quantifying liver fat content, with reproducibility that makes it valuable both for diagnosis and for monitoring treatment response. Studies have shown that reductions in liver fat content measured by MRI-PDFF correlate with histological improvements in steatohepatitis, notably when liver fat decreases by at least 30%[35,36]. MRI-based assessments are beneficial in clinical trials and treatment monitoring, as they provide a non-invasive means to evaluate the efficacy of interventions to reduce liver fat. For example, pharmacologic interventions have been shown to reduce liver fat content measured by MRI, although the impact on liver fibrosis may be limited[36]. MRI also enables tracking of hepatic fat reduction following lifestyle or bariatric interventions, where significant reductions in liver fat content have been observed[37,38].

Liver biopsy

Liver biopsy remains the gold standard for diagnosing and staging MASLD, though its use has become more selective with the advent of validated noninvasive diagnostic methods. Indications for liver biopsy include: (1) Diagnostic uncertainty when NITs yield inconclusive results; (2) Suspicion of advanced fibrosis or cirrhosis with equivocal noninvasive assessment; (3) Evaluation of suspected coexisting liver diseases; and (4) When biopsy can impact management decisions, such as clinical trial inclusion or advanced therapies[28,39-41]. Histological evaluation from biopsy provides detailed information on steatosis, inflammation, hepatocellular ballooning, fibrosis, and architectural changes, which can have prognostic value[28,41]. It is particularly crucial for distinguishing steatohepatitis from simple steatosis and for identifying rare histological patterns, especially in pediatric populations[40]. Despite its importance, liver biopsy has significant limitations. It is invasive, carries risks such as pain and bleeding, and can suffer from sampling and interobserver variability. Furthermore, it is not feasible for routine screening or long-term monitoring. Consequently, noninvasive biomarkers and imaging techniques, such as elastography and serum fibrosis panels (e.g., FIB-4, NAFLD fibrosis score, aspartate aminotransferase to platelet ratio index, or ELF), are prioritized for initial risk stratification and monitoring, such as inclusion in clinical trials or confirmation of non-invasive fibrosis scores and panels (e.g., FIB-4, NAFLD fibrosis score, aspartate aminotransferase to platelet ratio index, ELF)[28,42].

NON-PHARMACOLOGICAL TREATMENT FOR MASLD

Non-pharmacological management constitutes the cornerstone of treatment for MASLD. The primary interventions are lifestyle modification, including dietary changes, increased physical activity, and weight loss, with bariatric surgery considered in select cases[28,43].

Dietary modification

The most robust evidence supports a Mediterranean eating pattern, which emphasizes high intake of vegetables, fruits, whole grains, legumes, nuts, olive oil, and fish, while limiting saturated fats, refined carbohydrates, and added sugars. Caloric restriction to induce weight loss is essential, with a minimum target of 5% total body weight reduction to improve hepatic steatosis, and ≥ 10% weight loss is associated with greater histological improvement, including potential fibrosis regression. Reducing fructose and added sugars is recommended explicitly due to their association with hepatic fat accumulation and fibrosis progression. Diets should also limit saturated fat and starch, and focus on high fiber and unsaturated fats for additional cardiometabolic benefit[8,9,27,28,44].

Physical activity

Both aerobic and resistance exercise independently reduce hepatic steatosis and improve insulin sensitivity, with benefits observed even in the absence of significant weight loss. Exercise regimens should be individualized and structured, as higher engagement and intensity correlate with greater improvements in liver outcomes. Vigorous exercise may further limit progression to steatohepatitis[27,28,45].

Weight loss

Sustained weight reduction is the most effective non-pharmacological intervention for MASLD. Weight loss of at least 5% is necessary for improvement in steatosis, while ≥ 7%-10% is associated with resolution of liver steatosis and regression of fibrosis in a significant proportion of patients. Structured, individualized weight loss programs are more effective than standard counseling[8,46].

Bariatric surgery

For patients with obesity who meet established criteria for metabolic surgery, bariatric procedures (e.g., sleeve gastrectomy, Roux-en-Y gastric bypass) can result in substantial and sustained weight loss, resolution of MASLD and MASH, and improvement in fibrosis. Bariatric surgery is not recommended in decompensated cirrhosis and should be used with caution in compensated cirrhosis[8,36,47].

Alcohol and other lifestyle factors

Alcohol intake should be minimized, and complete abstinence is recommended in patients with clinically significant fibrosis (≥ F2), as alcohol is a cofactor for disease progression. Smoking cessation and management of other cardiometabolic risk factors are also important[28,36]. The foundation of MASLD management relies on comprehensive lifestyle intervention - caloric restriction with a Mediterranean-style diet, regular aerobic and resistance exercise, and weight loss of at least 5%-10%. Bariatric surgery is an option for eligible patients with obesity. These interventions not only improve liver histology but also address the high burden of cardiovascular and metabolic comorbidities in this population[43-45].

CURRENT PHARMACOLOGICAL TREATMENT FOR MASLD

GLP-1 RAs: Mechanisms and therapeutic benefits in MASLD

GLP-1 RAs promote weight loss and have demonstrated reductions in liver steatosis and inflammation in MASLD patients[42-46]. Additionally, GLP-1 RAs are associated with a reduced risk of major cardiovascular events, clinically significant portal hypertension, and all-cause mortality in patients with MASLD[48-50]. A meta-analysis of observational studies further supports an association between GLP-1 RA use and decreased risk of serious hepatic adverse outcomes, hepatic decompensation, and hepatocellular carcinoma in individuals with T2DM[51]. These agents act by modulating the satiety center in the brain, inhibiting glucagon secretion from pancreatic α-cells, and stimulating insulin production from β-cells through activation of the GLP-1 receptor. These key mechanisms are illustrated in Figure 4, highlighting their role in improving glycemic control and hepatic steatosis. Clinically relevant dosing and average weight loss effects for liraglutide and semaglutide are summarized in Table 1. In addition, hepatic outcomes such as ALT/gamma-glutamyl transpeptidase (GGT) reductions and histological resolution are detailed in Table 2[42-46]. Beyond their systemic metabolic benefits, GLP-1 RAs may exert direct intrahepatic actions that recalibrate the fibrotic and lipogenic machinery of the liver. Preclinical studies have demonstrated that these agents dampen HSC activation, a central engine of fibrosis, by silencing profibrotic signaling pathways such as transforming growth factor beta/smooth muscle actin and mad related family and curbing the expression of α-smooth muscle actin and collagen type I - molecular hallmarks of fibrogenic transformation[52]. In parallel, GLP-1 RAs have been shown to suppress the hepatic lipogenic program, notably through downregulation of sterol regulatory element-binding protein-1c and its enzymatic targets, acetyl-coenzyme A carboxylase and fatty acid synthase. This dual action not only restricts de novo lipid synthesis, but also mitigates intracellular triglyceride accumulation - an effect that unfolds independently of systemic insulin sensitivity or weight loss[53]. While the direct expression of GLP-1 RAs in hepatocytes remains a subject of debate, emerging evidence suggests a paracrine interplay involving non-parenchymal liver cells, including Kupffer cells and HSCs, which may act as intermediaries of these hepatotropic effects[54]. These findings broaden the mechanistic landscape of GLP-1 RAs, positioning them not merely as metabolic regulators, but as molecular circuit breakers capable of directly modulating hepatic injury and fibrosis in MASLD.

Figure 4 Mechanisms of action of glucagon-like peptide-1 receptor agonists. Glucagon-like peptide-1 receptor agonists exert their effects by acting on the hypothalamus to increase satiety and reduce appetite, delaying gastric emptying, stimulating insulin secretion from pancreatic β-cells, and suppressing glucagon release from α-cells. These mechanisms contribute to improved glycemic control and reduced hepatic steatosis. Image adapted from Servier Medical ART (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/Licenses/by/4.0/). GLP-1 RA: Glucagon-like peptide-1 receptor agonists; MASLD: Metabolic dysfunction-associated steatotic liver disease; TNF: Tumor necrosis factor; IL: Interleukin.

Table 1 Overview of anti-obesity drug classes, mechanisms of action, and weight loss effects in metabolic dysfunction-associated steatotic liver disease.

Class	Drug	Dosage	Mechanism of action	Effect on body weight
GLP-1 RAs	Liraglutide	3.0 mg/day	GLP-1 receptor activation: Satiety, gastric emptying (↓)	8%-10%
GLP-1 RAs	Semaglutide	2.4 mg/week	GLP-1 receptor activation: Satiety, gastric emptying (↓)	10%-15%
Dual GLP-1/GIP agonists	Tirzepatide	5-15 mg/week	Combined GLP-1 and GIP receptor agonism	15%-20%
Triple GLP-1/GIP/glucagon agonists	Retatrutide	8-12 mg/week (in trials)	GLP-1, GIP, and glucagon receptor agonist	Up to 24%
FGF-21 analogs	Efruxifermin	28-70 mg/week (in trials)	FGF21 receptor agonist	Approximately 10%
CNS agents	Phentermine/topiramate	7.5/46 mg/day to 15/92 mg/day	Central appetite suppression via sympathomimetic + GABA modulation	7%-9%
CNS agents	Naltrexone/bupropion	8/90 mg BID	Opioid antagonist and dopamine/norepinephrine reuptake inhibitor	5%-6%

This table summarizes pharmacologic agents currently used or under investigation for weight management in patients with metabolic dysfunction-associated steatotic liver disease. It includes the drug class, name, dosage range, primary mechanism of action, and average weight loss percentages reported in clinical trials. This table supports treatment individualization based on therapeutic goals. GLP-1 RAs: Glucagon-like peptide-1 receptor agonists; GLP-1: Glucagon-like peptide-1; GIP: Glucose-dependent insulinotropic polypeptide; FGF-21: Fibroblast growth factor 21; CNS: Central nervous system; BID: Twice daily; GABA: Gamma-aminobutyric acid.

Table 2 Efficacy and hepatic outcomes of anti-obesity drugs in metabolic dysfunction-associated steatotic liver disease.

Class	Drug	ALT	GGT	Histological improvement	Effect on fibrosis	MASLD-specific efficacy	Safety profile	Approval (FDA/EMA)
GLP-1 RAs	Liraglutide	Decrease	Decrease	NASH resolution (LEAN trial)	No significant improvement	Histological and biochemical improvement in NASH patients	GI side effects; contraindicated in MTC or gastroparesis	Approved
GLP-1 RAs	Semaglutide	Decrease	Decrease	Steatohepatitis resolution (2021 phase 2)	No fibrosis improvement	Decrease hepatic fat and steatohepatitis resolution	Well tolerated; GI effects most common	Approved
Dual GLP-1/GIP agonist	Tirzepatide	Decrease	Decrease	No biopsy data	Not assessed	Decrease liver fat (MRI-PDFF); improved insulin sensitivity	GI symptoms; minimal hypoglycemia	FDA approved
Triple GLP-1/GIP/glucagon agonist	Retatrutide	Decrease	Decrease	No biopsy data	Not assessed	Decrease marked in hepatic fat in early-phase studies	GI adverse events; not tested in cirrhotics	Investigational
FGF-21 analog	Efruxifermin	Decrease	Decrease	↓Steatosis and ballooning (phase 2 MASH)	Yes (F2-F3 patients)	Biopsy-confirmed improvement in steatosis and fibrosis	Well tolerated; long-term safety under investigation	Investigational
CNS agent	Phentermine/topiramate	Unclear	Unclear	None	None	Presumed via weight loss; no liver-specific trials	Neurocognitive side effects; teratogenicity	Approved (for obesity)
CNS agent	Naltrexone/bupropion	Unclear	Unclear	None	None	No liver-specific data	Neuropsychiatric side effects; caution in seizures	Approved (for obesity)

Summary of drug-specific effects on hepatic biomarkers, histological outcomes, and safety profiles. ALT: Alanine aminotransferase; GGT: Gamma-glutamyl transferase; MASLD: Metabolic dysfunction-associated steatotic liver disease; FDA: Food and Drug Administration; EMA: European Medicines Agency; GLP-1 RAs: Glucagon-like peptide-1 receptor agonists; GLP-1: Glucagon-like peptide-1; FGF-21: Fibroblast growth factor 21; CNS: Central nervous system; NASH: Non-alcoholic steatohepatitis; LEAN: Liraglutide efficacy and action in non-alcoholic steatohepatitis; MASH: Metabolic dysfunction-associated steatohepatitis; MRI: Magnetic resonance imaging; PDFF: Proton density fat fraction; GI: Gastrointestinal; MTC: Medullary thyroid carcinoma.

Liraglutide: Evidence-based outcomes in liver disease

Liraglutide, a GLP-1 RA from the incretin class, was initially approved for the treatment of T2DM and later for weight management. It has also been shown to reduce cardiovascular risk and mortality[47]. As mentioned in the clinical practice guideline of the American Association of Clinical Endocrinology, liraglutide has also demonstrated beneficial effects in patients with NAFLD[13]. The “Liraglutide Efficacy and Action in NASH” trial demonstrated resolution of MASLD after 48 weeks of treatment, with no progression of liver fibrosis observed in 9 of 23 patients evaluated histologically[55]. In addition, liraglutide improved liver histology and significantly reduced serum levels of ALT, GGT, and other markers of hepatocellular injury[55]. As shown in Table 2, liraglutide has demonstrated resolution of MASH with improvements in ALT and GGT, although no significant impact on fibrosis was reported.

Semaglutide (approved): Therapeutic effects and clinical evidence

Semaglutide is a GLP-1 RAs primarily used for treating obesity and T2DM. In MASLD, semaglutide effectively reduces hepatic fat accumulation, improves insulin sensitivity, and decreases liver inflammation through specific mechanisms of action[56]. Clinical trials have reported significant benefits, including steatohepatitis resolution and improvements in hepatic fibrosis[57]. Gradual dose escalation is recommended to minimize gastrointestinal side effects, with liver-specific benefits observed at doses ranging from 0.1 mg to 0.4 mg daily in phase 2 studies and up to 2.4 mg weekly in phase 3 trials[57,58]. In patients with obesity and/or T2DM, semaglutide significantly reduced ALT and high-sensitivity C-reactive protein levels. Preclinical murine models of diet-induced steatotic liver disease demonstrated decreased expression of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6[59]. These findings reinforce semaglutide’s therapeutic potential in MASLD management. According to Table 2, semaglutide led to resolution of steatohepatitis and a reduction in hepatic fat content, with good tolerability and minimal hepatic safety concerns.

GLP-1 RAs in cirrhosis: Safety considerations and contraindications

GLP-1 RAs have shown a favorable hepatic safety profile in patients with compensated cirrhosis (Child-Pugh A), with studies reporting reductions in hepatic decompensation (48%) and hepatocellular carcinoma (53%) compared to non-users[56,60]. A recent review confirmed these agents reduce hepatic complications in compensated cirrhosis without increasing all-cause mortality[61]. However, use in advanced cirrhosis (Child-Pugh B/C) requires caution due to limited direct evidence. One cohort study reported benefits in decompensated cirrhosis, but lacked Child-Pugh score specification, limiting conclusions[57]. Key concerns in advanced disease include: (1) Potential worsening of malnutrition via delayed gastric emptying; (2) Scarce pharmacokinetic data; and (3) Theoretical risks related to portal hypertension[60,62]. GLP-1 RAs are contraindicated in patients with a history of medullary thyroid carcinoma (boxed warning) or severe gastroparesis[42,62]. Gastrointestinal side effects (nausea, vomiting, diarrhea) occur in 20%-40% of patients, but are usually transient and dose-dependent. Regarding pancreatitis risk, extensive cohort studies and meta-analyses have found no significant association, although caution is advised in patients with a history of severe or idiopathic pancreatitis[63]. A multidisciplinary approach is strongly recommended for patients with advanced disease, including gradual dose titration and close monitoring during the first 12 weeks to optimize tolerability[57,60,62].

While GLP-1 RAs have shown a favorable short-term hepatic safety profile in patients with compensated cirrhosis, real-world data beyond two years of continuous use remain scarce. Significantly, the potential nutritional consequences of sustained GLP-1 RA therapy in this population - particularly unintended sarcopenia due to excessive or rapid weight loss - are underexplored. Although short-duration studies suggest reductions in hepatic decompensation and liver-related mortality[60-62], long-term cohort studies assessing body composition dynamics, nutrient absorption, and muscle mass preservation are lacking. This gap is particularly relevant for cirrhotic patients, whose nutritional reserve is often fragile and easily perturbed. Thus, caution is warranted when extrapolating short-term benefits to chronic use, and future prospective studies should evaluate the longitudinal impact of GLP-1 RAs on sarcopenia and functional status in this vulnerable subgroup.

Dual incretin agonists (GLP-1/GIP): Mechanisms and therapeutic potential

Dual incretin agonists targeting both GLP-1 and GIP receptors represent an emerging class of treatments for obesity and T2DM, improving postprandial metabolic regulation[42,64-67]. GLP-1 inhibits glucagon secretion at elevated glucose levels, while GIP enhances glucagon release at low glucose levels. Activating both receptors improves glycemic control and weight loss in T2DM[67,68]. Beyond glycemic regulation, these agents have been to exert beneficial hepatic effects through enhanced insulin sensitivity, reduction of hepatic fat accumulation by decreasing de novo lipogenesis and promoting fatty acid oxidation, as well as anti-inflammatory and antifibrotic actions. These combined effects contribute to improvements in liver histology and function observed in MASLD patients receiving dual incretin therapy[64-67]. While GLP-1 RAs have demonstrated hepatic benefits primarily through systemic metabolic improvements, the direct hepatic effects of incretin-based therapies remain under investigation. Notably, hepatocytes do not consistently express GLP-1 receptors, and single-cell transcriptomic studies have failed to detect meaningful GLP-1 RA expression in hepatic parenchymal cells[64,69]. This supports the view that most hepatic benefits are mediated indirectly, via improved insulin sensitivity, reduced systemic inflammation, and paracrine signaling from non-parenchymal cells such as Kupffer cells and HSCs[69]. The activation of GIP and glucagon receptors, unique to dual and triple incretin agonists, introduces additional mechanisms. GIP-1 RA improves adipose tissue function and nutrient partitioning. In contrast, glucagon receptor agonism enhances hepatic β-oxidation, reduces de novo lipogenesis, and increases energy expenditure - mechanisms that reduce intrahepatic lipid accumulation and inflammatory signaling[64,70].

In MASLD models, incretin agonists have shown the capacity to reduce HSC activation indirectly, likely by attenuating circulating cytokines (e.g., TNF-α, IL-6), lowering leptin signaling, and reducing oxidative stress[15,69]. Experimental studies have reported decreased α-smooth muscle actin and collagen type I expression in liver tissue following GLP-1 RA or dual agonist therapy. However, direct receptor-mediated antifibrotic effects on HSCs remain unconfirmed[69]. Comparatively, retatrutide, a triple GLP-1/GIP/glucagon receptor agonist, has demonstrated superior weight loss outcomes (up to 24%) relative to GLP-1 or dual agonists[71,72]. However, no biopsy-confirmed data on fibrosis regression have been published to date, and its hepatic effects have only been assessed through MRI-PDFF in early-phase studies[73]. Although weight loss of ≥ 10% has been associated with fibrosis improvement in MASLD[10], it remains unclear whether this benefit extends proportionally with greater weight loss or whether ceiling effects exist. Furthermore, triple agonists have not yet been studied in patients with advanced fibrosis or cirrhosis, limiting their clinical applicability in high-risk MASLD cohorts[74]. In summary, while incretin-based therapies exert compelling indirect metabolic and hepatic benefits, current evidence does not support a direct antifibrotic mechanism, particularly in patients with advanced disease. Further trials with biopsy-based endpoints are needed to establish the long-term hepatic outcomes of dual and triple incretin agonists[71-75].

Tirzepatide (approved): Efficacy and impact on metabolic and hepatic outcomes

Tirzepatide is a dual GIP and GLP-1 RA that regulates carbohydrate metabolism and appetite by increasing insulin secretion, reducing serum glucagon, suppressing food intake, and delaying gastric emptying, thereby improving glucose control and inducing weight loss[64,76-78]. It also enhances insulin signaling and lipolysis[70]. Clinical trials have demonstrated tirzepatide’s superiority over GLP-1 RAs in reducing glycated hemoglobin A1c (HbA1c) (> 2%) and body weight (> 15%)[79,80]. Gastrointestinal adverse effects are common, but it does not increase hypoglycemia risk[81].

The SURMOUNT trials evaluated tirzepatide’s efficacy and safety in adults with obesity or overweight, with or without T2DM[82]. Phase 3 studies (SURMOUNT-1 to SURMOUNT-4) focused on weight reduction and quality of life[82]. SURMOUNT-1 showed significant weight loss and quality-of-life improvement in obese adults[83]. The SURPASS-3 trial provided liver-specific evidence, demonstrating tirzepatide’s efficacy and safety[84,85]. MRI-PDFF data confirmed fat reduction. Tirzepatide also reduced visceral and hepatic fat, while slightly increasing abdominal subcutaneous fat, indicating a favorable redistribution of adipose tissue[86]. These findings underscore tirzepatide’s potential to improve hepatic and visceral fat profiles alongside weight reduction. Table 1 outlines its dual agonism mechanism and robust weight loss profile, while Table 2 shows its hepatic effects, including liver fat reduction and improved insulin sensitivity, although no biopsy data are yet available.

Other approved agents

Phentermine/topiramate: Appetite suppression (approved for obesity) and emerging liver implications: Phentermine is a sympathomimetic agent that increases norepinephrine release in the hypothalamus by both stimulating its release and inhibiting its reuptake, thereby enhancing synaptic availability. This mechanism suppresses appetite via β-2 adrenergic receptor activation[87]. Topiramate, primarily approved for epilepsy, contributes to weight loss by modulating sodium and calcium channels, enhancing γ-aminobutyric acid type a receptor activity, and inhibiting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/kainate receptor at the hypothalamic level[88,89]. Although current evidence for these agents in MASLD is limited, extrapolation from studies in the general obese population should be interpreted with caution until MASLD-specific clinical trials are available.

The combination of phentermine and topiramate has been associated with moderate weight loss (5%-9%), and clinical studies indicate that their co-administration improves tolerability by reducing individual drug concentrations while enhancing therapeutic efficacy. Lifestyle modifications are often recommended alongside pharmacotherapy to optimize outcomes[90]. Several long-term studies suggest that weight loss exceeding 10 kg can be achieved and maintained over several years[91]. In comparative analyses, this combination has demonstrated superior efficacy in achieving a ≥ 5% body weight reduction within six months compared to other therapies[92]. Although data specific to MASLD are scarce, this combination appears promising due to its capacity for significant weight loss and has shown encouraging outcomes in patients with hepatic impairment[93]. Nevertheless, as with topiramate monotherapy, concerns remain regarding teratogenic effects and a persistent risk of neurodevelopmental disorders, particularly intellectual disability, as reported in clinical trials[87,94].

Naltrexone/bupropion (approved for obesity): Reward circuit modulation and weight reduction: Naltrexone is an opioid receptor antagonist that blocks the orexigenic effect of β-endorphin via mu-opioid receptor antagonism. Bupropion, a norepinephrine and dopamine reuptake inhibitor, acts at the hypothalamic level by stimulating the proopiomelanocortin pathway, thereby enhancing dopaminergic signaling and suppressing appetite. Together, these agents produce synergistic appetite suppression, with naltrexone potentiating bupropion’s effect[95]. Through dopaminergic and noradrenergic modulation, this combination helps reduce food-related reward signaling, supporting better adherence to dietary interventions and contributing to clinically relevant weight loss[95,96]. No clinical trials to date have evaluated the efficacy of naltrexone/bupropion specifically in MASLD patients. Existing evidence is limited to populations with overweight or general obesity, underscoring the need for future studies assessing safety and therapeutic efficacy in MASLD contexts[97-99].

INTEGRATING NON-PHARMACOLOGICAL AND PHARMACOLOGICAL STRATEGIES IN MASLD MANAGEMENT

Current management of MASLD is fundamentally based on the integration of non-pharmacological and pharmacological interventions, which are considered complementary and synergistic rather than mutually exclusive. Lifestyle modification - including dietary changes, increased physical activity, and behavioral interventions - remains the cornerstone of MASLD therapy and is recommended for all patients regardless of pharmacological treatment status[28,100,101]. These interventions target the underlying metabolic derangements and are associated with improvements in hepatic steatosis, liver enzymes, and cardiometabolic risk factors. Pharmacological therapy is considered in patients who do not achieve sufficient benefit from lifestyle modification alone, particularly those with established steatohepatitis (MASH), significant fibrosis, or high-risk metabolic comorbidities such as T2DM or obesity[102,103]. In summary, current consensus in the medical literature is that pharmacological and non-pharmacological treatments for MASLD should be implemented in a complementary fashion, with lifestyle modification as the foundation and pharmacotherapy individualized based on disease severity, comorbidities, and response to non-pharmacological measures[102,103].

EMERGING CONCEPTS AND INVESTIGATIONAL THERAPIES

MASLD evidence

MASLD is a common condition marked by hepatic steatosis in the context of metabolic risk factors such as obesity, T2DM, hypertension, and dyslipidemia[96]. Its spectrum ranges from simple steatosis to MASLD, fibrosis, cirrhosis, and hepatocellular carcinoma[104-106]. Recent studies reveal distinct phenotypes driven by liver-specific genetic variants and cardiometabolic traits, contributing to increased cardiovascular risk[107,108]. This heterogeneity underscores the need for personalized therapeutic approaches. Lipidomics analyses have demonstrated significant alterations in hepatic lipid composition correlated with disease progression from MASLD to MASH[108,109]. Additionally, metabolomic studies have identified unique metabolic signatures, such as changes in lysophosphatidylcholines and xanthine levels, which are associated with inflammation and IR[110]. Genetic variants, particularly in patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2, confer susceptibility to MASLD and may inform precision medicine approaches[111].

Retatrutide: A triple agonist targeting GIP, GLP-1, and glucagon receptors

Retatrutide is a novel triple agonist targeting the GIP, glucagon, and GLP-1 receptors. It is currently under investigation for the treatment of obesity and T2DM, and has shown promising results in phase 2 clinical trials. These studies reported substantial reductions in body weight and improved glycemic control. In a phase 2 obesity trial, retatrutide achieved up to 24.2% weight loss over 48 weeks at a dose of 12 mg, compared to a 2.1% reduction in the placebo group[71]. In patients with T2DM, it significantly improved HbA1c levels, outperforming dulaglutide, another GLP-1 RA[72]. Retatrutide has also been associated with notable reductions in liver fat in MASLD patients[73]. However, gastrointestinal side effects are common, as expected with this class of medications[71,72,75]. Clinical applicability: Phase 2 trials predominantly included patients with early-stage fibrosis (F1-F2), and the effects on fibrosis regression or histological endpoints such as steatosis resolution remain preliminary. Ongoing phase 3 trials are expected to provide crucial data on its impact on advanced fibrosis and cirrhosis, and potential regulatory submissions are anticipated within the next few years[74,75]. While triple agonists offer substantial weight loss and liver fat reduction, current evidence derives from early-phase trials in general obesity cohorts. There is no published histological data confirming benefits on inflammation or fibrosis, and safety in cirrhotic or high-risk MASLD patients remains unknown[71-75]. As summarized in Table 2, retatrutide has shown substantial hepatic fat reduction in early trials, though its histological effects and cirrhosis safety profile remain untested.

GLP-1 and fibroblast growth factor-21 combinations: Fibrosis regression and metabolic benefits

Pegbelfermin and efruxifermin: Pegbelfermin and efruxifermin are analogs of fibroblast growth factor (FGF)-21, which are being investigated for MASLD and related liver diseases. They differ in pharmacological design, clinical progression, and outcomes[112]. Efruxifermin is an engineered Fc-FGF-21 fusion protein with enhanced pharmacokinetics, including a prolonged half-life and improved receptor selectivity. It activates FGF-R1c, FGF-R2c, and FGF-R3c, but not FGF-R4, thus avoiding elevations in low-density lipoproteins cholesterol[113,114]. Clinical trials indicate that efruxifermin is safe and well-tolerated, with mainly mild to moderate gastrointestinal side effects[113]. Clinical applicability: Efruxifermin has shown significant efficacy in reducing liver fat, improving fibrosis scores, and enhancing metabolic parameters in patients with MASLD and compensated cirrhosis. It has demonstrated fibrosis regression in F2-F3 patients. However, data on cirrhosis patients are still limited, and ongoing phase 3 trials, several limitations restrict the current applicability of FGF-21 analogs in MASLD. While efruxifermin has demonstrated encouraging reductions in liver fat and improvements in fibrosis scores, biopsy-confirmed outcomes remain short-term and may vary significantly depending on baseline disease severity and metabolic comorbidities[115,116]. Moreover, pharmacokinetic profiles in patients with hepatic impairment are poorly understood, raising concerns about altered drug metabolism, potential accumulation, and reduced therapeutic efficacy[117]. Although gastrointestinal adverse events are the most commonly reported, long-term safety remains uncertain - particularly in populations with portal hypertension or decompensated liver function[115,117]. Pegozafermin, another FGF-21 analog, has shown similar antifibrotic activity in phase 2 trials, but direct comparisons and cirrhosis-specific data are lacking[97,116]. Further research is needed to clarify optimal patient selection, safety margins, and the positioning of these agents within MASLD treatment pathways. Table 2 highlights its ability to improve steatosis and fibrosis in F2-F3 patients, supported by biopsy-confirmed outcomes in phase 2 trials.

Oral GLP-1 agents: Orforglipron and danuglipron are oral, nonpeptide GLP-1 RAs that have demonstrated meaningful reductions in HbA1c (up to 1.3%) and body weight (up to 9.9%), with an acceptable safety profile in patients with obesity and T2DM[118]. In a phase 2 trial, danuglipron significantly reduced HbA1c, fasting glucose, and body weight in adults with T2DM, although gastrointestinal adverse effects led to treatment discontinuation in some patients[119]. Danuglipron research in MASLD is limited, and one study was terminated as the sponsor opted to focus on patients with obesity and T2DM without active liver disease[120]. Orforglipron has shown efficacy and safety comparable to injectable GLP-1 RAs, offering a potentially more accessible oral alternative. However, its effects on liver disease have not been studied[121]. Clinical applicability: Orforglipron and danuglipron are promising oral alternatives to injectable GLP-1 RAs, with comparable efficacy in weight loss and IR improvement. However, their impact on liver disease has not yet been extensively studied[122,123]. Studies specifically addressing MASLD are still in early stages, and current data on their hepatic benefits remain lacking. Ongoing trials are needed to assess their effectiveness in liver-related metabolic diseases, and regulatory progress is expected soon[124,125].

Amylin analogs (cagrilintide and semaglutide)

CagriSema, a co-formulation of cagrilintide (a long-acting amylin analog) and semaglutide (a GLP-1 RA), exerts synergistic effects on glycemic control and weight loss, likely through complementary mechanisms[99,126]. Although several studies highlight its benefits for obesity and diabetes, no evidence currently supports its use in MASLD or MASH[127-129]. Recent systematic reviews have reported that CagriSema outperforms semaglutide alone in weight reduction and glycemic control, but with a higher incidence of gastrointestinal side effects, particularly vomiting[130]. To date, no clinical trials or guidelines include CagriSema as a treatment option for MASLD. Although not yet approved for MASLD, CagriSema’s synergistic action and clinical potential are outlined in Table 1[131]. Clinical applicability: Although effective for weight reduction and glycemic control, CagriSema has not been investigated explicitly in MASLD or MASH patients, and no clinical trials have included it as a treatment option for these conditions. Its gastrointestinal side effects, particularly vomiting, also raise concerns regarding its clinical application in MASLD.

Novel molecular targets: FGF-21, amylin, leptin, mitochondrial uncouplers

Recent compounds - including SR4, CZ5, OPC-163493, compound 6j, BAM15, HU6, and MB-X01Y03 - demonstrate potential for treating obesity, T2DM, and liver-related metabolic diseases, with reduced toxicity and tissue-specific action compared to classical uncouplers like 2,4-dinitrophenol[132]. Leptin analogs, such as metreleptin, have improved metabolic parameters in congenital leptin deficiency and relative leptin deficiency in MASLD; however, they have not shown sufficient efficacy to support approval for MASLD treatment[133-135].

FUTURE DIRECTIONS AND UNMET NEEDS

Lack of long-term outcome data

A critical limitation in MASLD research is the scarcity of long-term data on pharmacologic interventions, particularly concerning liver safety in patients with stage F2-F3 fibrosis and advanced disease[136,137]. Most available studies are of short or medium duration, which restricts the extrapolation of findings to chronic treatment scenarios[138]. There is an urgent need for long-term studies that assess both the sustained efficacy and safety of emerging therapies over time.

Absence of validated clinical endpoints

Recent investigations, such as the randomized phase 2a trial of retatrutide, a triple hormone receptor agonist, have shown promising reductions in liver fat and improved metabolic parameters in patients with MASLD[139]. These results suggest potential benefits in liver disease management. However, the trial also emphasized the lack of validated clinical endpoints, as long-term safety and histologic efficacy remain unknown. Moreover, the optimal balance of receptor agonism remains unclear[140]. Although incretin-based therapies have demonstrated indirect hepatic benefits through weight reduction and improved IR, their direct effects on hepatocytes and HSCs remain debated[69]. Some evidence suggests these agents may not act directly on liver parenchymal cells, further complicating endpoint validation. In summary, despite encouraging metabolic and hepatic responses to triple agonists such as retatrutide, comprehensive data on durability, safety, and mechanistic action are lacking. Future research should aim to clarify the mechanisms of action on liver tissue, identify the patient populations most likely to benefit, and establish standardized, validated clinical endpoints[141,142].

Need for combination therapy trials

Combination therapy represents a promising approach for complex metabolic conditions like MASLD. Agents such as retatrutide and CagriSema have shown synergistic effects in obesity and T2DM, yet evidence for their role in MASLD is limited, particularly in advanced disease[121,143]. Ongoing trials with efruxifermin and GLP-1 + farnesoid X receptor/FGF-21 combinations offer potential as multifaceted therapies for MASLD and deserve further investigation[144].

Priorities for future phase 3/phase 4 trials

Several late-phase clinical trials are actively evaluating new pharmacologic strategies for MASLD, with a focus on both steatosis resolution and fibrosis regression. The MAESTRO-NASH trial assessed resmetirom, a selective thyroid hormone receptor-β agonist, in patients with MASLD. While MRI-PDFF showed significant reductions in liver fat, histologic response was limited in participants who failed to achieve ≥ 30% fat reduction, highlighting the need for biomarker-based thresholds[26]. The REGENERATE study investigated obeticholic acid in patients with MASLD and fibrosis, reporting improvements in NITs and fibrosis stage, suggesting NITs may serve as surrogates for biopsy in clinical trials[104]. A recent network meta-analysis compared novel agents and found that resmetirom was most effective in reducing liver steatosis, while pegozafermin, an FGF-21 analog, produced the most significant improvements in fibrosis[108]. These findings emphasize the promise of dual-acting therapies, but also underscore the need for long-term data to validate their safety and durability.

MASLD TREATMENT ACCESS

The global burden of MASLD is significant, with new pharmacotherapies offering promising options. However, these advances raise ethical and practical concerns related to cost-effectiveness, access, and equity, particularly in low-resource settings. The high cost of novel therapies, coupled with rapid price escalation, limits access for populations with limited healthcare resources or inadequate insurance coverage. MASLD disproportionately affects individuals with diabetes and obesity, conditions more prevalent in socioeconomically disadvantaged groups, making it harder for those most in need of treatment to access it. This exacerbates existing health disparities[145]. Ethical and policy challenges arise when expensive medications such as GLP-1 RAs become the standard of care without equitable frameworks for access. In many low-income and middle-income countries, these therapies are not included in national formularies or public insurance schemes, rendering them inaccessible to a large proportion of the population. This exclusion may worsen clinical outcomes and increase long-term healthcare costs associated with liver failure, transplantation, and cardiovascular events[146,147]. To address these disparities, health systems should consider implementing tiered access strategies based on clinical severity. Risk stratification tools such as FIB-4, ELF, or VCTE could be employed to prioritize high-risk MASLD patients for advanced therapies[148]. Moreover, integration of MASLD treatment into existing chronic disease programs - such as diabetes and cardiovascular disease management - can enhance cost-efficiency and improve outcomes[149].

Policymakers should also evaluate the inclusion of high-cost therapies like GLP-1 RAs into national essential medicines lists when sufficient evidence supports their long-term cost-effectiveness[150]. Price negotiations, public-private partnerships, and outcome-based reimbursement models may reduce acquisition costs and promote broader access[151]. Additionally, global health initiatives, such as pooled procurement mechanisms or support from international organizations (e.g., World Health Organization Essential Medicines), could facilitate access to these therapies in low-income and middle-income countries[152]. Research funding and clinical trial representation must also prioritize under-resourced populations to ensure generalizability of evidence and equitable innovation[153]. Ethically, equitable access to MASLD treatments is critical, as expensive therapies and advanced diagnostics create barriers for patients in low-resource settings. While non-invasive diagnostic options are emerging, their widespread use is delayed by the need for further validation and regulatory approval, which hinders their adoption in clinical practice and trials[145]. Cost-effectiveness analyses are crucial for informing policy, particularly in resource-constrained environments, suggesting that optimized screening and treatment strategies could enhance access and outcomes. However, these strategies must be explicitly tailored to local contexts to avoid deepening existing global health inequities. Addressing these issues requires multisectoral collaboration aimed at developing scalable, affordable, and culturally appropriate models of care for MASLD[149,152].

LIMITATIONS AND GAPS

Assessment of evidence quality using Grading of Recommendations Assessment, Development and Evaluation

Although this is a narrative review, the quality of the evidence was appraised using the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to guide a structured qualitative analysis[154]. Studies on GLP-1 RAs (liraglutide, semaglutide) demonstrated moderate quality, primarily due to consistent results across studies[13,55]. However, certain limitations, such as small sample sizes and short follow-up durations, were noted. In contrast, studies on tirzepatide and retatrutide were rated as low and very low quality, respectively, owing to the absence of long-term data and uncertainty regarding their hepatic effects. Evidence for other treatments, such as naltrexone-bupropion and phentermine-topiramate, remains limited, resulting in a low rating overall[87,88,118].

Recommendations based on GRADE

In line with the GRADE assessment, recommendations for the use of GLP-1 RAs in MASLD are considered moderate, supported by their positive effects in reducing hepatic steatosis and fibrosis[154]. However, for tirzepatide and retatrutide, recommendations must remain cautious due to the lack of robust long-term safety data[121-123]. A significant limitation in the available evidence is the absence of randomized clinical trials specifically focused on MASLD for several anti-obesity treatments. Drugs like phentermine/topiramate and naltrexone/bupropion have proven effective in weight loss; however, studies specifically targeting MASLD are sparse[87,88,118]. Most existing research includes general populations of patients with obesity or diabetes, but few studies focus on the specific impact of these treatments on liver pathology associated with MASLD. This gap in targeted evidence limits the ability to draw firm conclusions regarding the use of these agents in this patient group.

Heterogeneity of MASLD and its implications

The heterogeneity of MASLD represents another challenge when evaluating treatment efficacy and safety. MASLD manifests diversely across individuals, with some patients affected by diabetes and others not, as well as variations in fibrosis severity (e.g., early vs advanced fibrosis). This variability directly influences treatment outcomes, as patients with advanced fibrosis or cirrhosis may respond differently compared to those in the earlier stages of the disease. Furthermore, patients with diabetes may experience differential responses due to IR and other metabolic factors, which impact the efficacy of treatment. This heterogeneity highlights the need for more personalized approaches and underscores the necessity of conducting clinical trials that focus on distinct patient subgroups[154].

Exclusion of cirrhosis patients in clinical trials

An essential aspect that limits the applicability of clinical trial results to real-world clinical practice is the systematic exclusion of patients with cirrhosis from many studies. Most clinical trials investigating treatments for MASLD do not include patients with compensated or decompensated cirrhosis, creating a significant gap in our understanding of how these treatments may affect this vulnerable population. Given that MASLD can progress to cirrhosis, the lack of data regarding drug use in this patient group restricts the generalization of results and hampers clinical decision-making for cirrhosis patients in everyday settings[141]. A significant limitation of the available evidence is the systematic exclusion of patients with advanced fibrosis or cirrhosis from most clinical trials, which significantly limits the external validity and applicability of findings to real-world populations. Additionally, many studies were of short duration, typically ranging from 12 weeks to 72 weeks, which impairs our ability to draw firm conclusions about long-term safety, durability of hepatic outcomes, and progression of fibrosis. While emerging agents such as tirzepatide and retatrutide have demonstrated substantial reductions in hepatic fat content measured by MRI-PDFF, data on histologic endpoints such as inflammation and fibrosis regression remain scarce. This gap is especially relevant for informing treatment decisions in patients with advanced disease stages. Furthermore, several of the included studies were sponsored by pharmaceutical companies, which may introduce reporting bias. Independent studies and longer-term follow-up are needed to validate these findings and better define the hepatic impact of these therapies across the MASLD spectrum.

CONCLUSION

Pharmacological treatments for MASLD, particularly GLP-1 RAs and emerging incretin-based therapies, have shown promising benefits in reducing hepatic steatosis and improving metabolic health, especially in early stages. However, their role in advanced or compensated cirrhosis remains uncertain due to limited data on safety and efficacy. Future research should prioritize long-term studies including real-world populations with metabolic comorbidities to define clinical outcomes better and guide personalized treatment. Current evidence is moderate for GLP-1 RAs, but remains low for newer agents like tirzepatide and retatrutide.