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Background:
Systematic Review

The Comparative Safety and Efficacy of Resmetirom and Semaglutide in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Systematic Review

by
Jahnavi Udaikumar
1,*,
Rithish Nimmagadda
2,
Vindhya Vasini Lella
3,
Kesava Manikanta Achuta
4,
Satwik Kuppili
3,
Suraj Reddy Avula
5 and
Raiya Sarwar
6
1
NYU Grossman School of Medicine, Department of Medicine, New York, NY 10016, USA
2
One Brooklyn Health, Department of Medicine, Brooklyn, NY 11212, USA
3
Konaseema Institute of Medical Sciences and Research Foundation, Amalapuram 533201, Andhra Pradesh, India
4
Garden City Hospital, Michigan State University, Garden City, MI 48135, USA
5
Kasturba Medical College, Manipal 576104, Karnataka, India
6
NYU Grossman School of Medicine, Division of Gastroenterology and Hepatology, New York, NY 10016, USA
*
Author to whom correspondence should be addressed.
Pharmacoepidemiology 2025, 4(3), 14; https://doi.org/10.3390/pharma4030014 (registering DOI)
Submission received: 25 May 2025 / Revised: 24 June 2025 / Accepted: 24 June 2025 / Published: 27 June 2025
Browse Figure
Review Reports Versions Notes

Abstract

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly encompassed under nonalcoholic fatty liver disease (NAFLD), is a growing global health burden associated with progression to cirrhosis and hepatocellular carcinoma. Resmetirom, a thyroid hormone receptor-β (THR-β) agonist, and semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), have emerged as promising agents targeting distinct metabolic and inflammatory pathways. This systematic review compares the safety and efficacy of resmetirom and semaglutide in MASLD. Methods: We conducted a comprehensive search of PubMed, Embase, and Google Scholar for randomized controlled trials and clinical studies published between January 2014 and April 2025, following PRISMA guidelines. Studies assessing the efficacy and safety of resmetirom and/or semaglutide in MASLD or NASH were included. Data extraction was performed by two independent reviewers, and a narrative synthesis was undertaken due to the heterogeneity in study design and outcome measures. Results: Fourteen studies encompassing over 4500 patients were analyzed. Resmetirom demonstrated consistent reductions in hepatic fat (≥30% in >50% of patients) and improvements in fibrosis (≥1 stage in up to 26.4% of patients), as evidenced in the MAESTRO-NASH trial. Semaglutide achieved higher rates of NASH resolution (up to 62.9%) without worsening fibrosis, especially among patients with type 2 diabetes or obesity, although fibrosis improvement was less consistently observed. Resmetirom was well tolerated with low discontinuation rates, while semaglutide was associated with more frequent, yet manageable, gastrointestinal adverse events. Conclusions: Both resmetirom and semaglutide show therapeutic potential for MASLD. Resmetirom offers more consistent antifibrotic effects, while semaglutide excels in NASH resolution and metabolic improvement. The absence of direct comparative trials underscores the need for future head-to-head studies to guide tailored treatment strategies in MASLD management.

1. Introduction

A global consensus in 2023 officially redefined nonalcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated steatotic liver disease (MASLD), resolving prior ambiguities in terminology and emphasizing the central role of metabolic risk factors in disease pathogenesis [1]. MASLD is diagnosed when imaging or histology demonstrates hepatic steatosis in the presence of at least one of five cardiometabolic risk factors—obesity, type 2 diabetes, dyslipidemia, hypertension, or insulin resistance. This reclassification replaces the exclusion-based NAFLD definition with a positive, inclusive framework that better aligns with current understandings. When hepatocellular injury and inflammation are present alongside steatosis, the condition is termed metabolic dysfunction-associated steatohepatitis (MASH) [1,2,3]. Importantly, MASLD encompasses both lean and obese phenotypes; the lean form is more prevalent in certain populations, such as the Asian population, and may be overlooked due to a normal body mass index (BMI < 25 kg/m2) [2]. In such cases, waist circumference—defined as ≥102 cm for men and ≥88 cm for women (or ≥90 cm and ≥80 cm, respectively, in Asian populations)—serves as a more sensitive indicator of visceral adiposity and cardiometabolic risk [4].
Nonalcoholic fatty liver disease (NAFLD), defined by hepatic steatosis in the absence of significant alcohol use, steatogenic medications, or hereditary disorders, historically encompassed various etiologies, but primarily centered on patients with cardiometabolic risk factors [1,2,3]. To better reflect the underlying pathophysiology, the term steatotic liver disease (SLD) has been introduced, with metabolic dysfunction-associated steatotic liver disease (MASLD) specifying cases meeting defined metabolic criteria [5,6]. Though often asymptomatic, MASLD carries a significant risk for progression to cirrhosis and hepatocellular carcinoma. Its prevalence is rising globally, affecting 20–30% of Western and 5–18% of Asian populations [7,8].
A progressive MASLD subtype, metabolic dysfunction-associated steatohepatitis (MASH), is marked by steatosis, inflammation, and hepatocellular injury, independent of secondary causes, and is associated with fibrosis and malignancy risk [7]. The two-hit hypothesis—hepatic steatosis and insulin resistance followed by oxidative stress and cytokine-driven inflammation—remains central to its pathogenesis [6,7,8].
Epidemiologically, Markov models project a 21% increase in SLD prevalence in the U.S. from 2015 to 2030, reaching 33.5%, with MASH cases rising to 63%. This is expected to drive a 168% and 137% increase in decompensated cirrhosis and hepatocellular carcinoma, respectively [9]. Weight loss remains foundational in MASH management, with studies supporting the efficacy of a Mediterranean diet, especially when combined with omega-3 fatty acids. Vitamin E, caffeine, and other antioxidants may confer additional benefit [10,11].
Nonetheless, lifestyle changes are often insufficient in advanced disease, necessitating pharmacologic options. Thyroid hormones, via the nuclear receptor isoforms THR-α and liver-predominant THR-β, regulate lipid metabolism. THR-β activation reduces hepatic lipid synthesis and promotes fatty acid oxidation [11]. These mechanisms underpin resmetirom, a liver-selective THR-β agonist, which improves lipid metabolism without disrupting systemic thyroid function [11]. In the Phase 3 MAESTRO-NASH trial, resmetirom significantly improved steatohepatitis resolution (25.9–29.9%) and fibrosis (24.3–26.4%) versus placebo, supporting its approval for MASH treatment [12].
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are another emerging MASLD therapy. Beyond glycemic and weight benefits, hepatocyte GLP-1 receptor activation may reduce steatosis, lipotoxicity, and hepatic inflammation [13,14,15]. Among these, semaglutide demonstrates superior metabolic effects [16,17,18]. In the ESSENCE Phase 3 trial, semaglutide 2.4 mg led to steatohepatitis resolution in 62.9% of patients without worsening fibrosis, compared to 34.1% in the placebo group [16].
While both agents show histological and biochemical efficacy, head-to-head comparisons are lacking. Given their differing mechanisms and potential complementarity, direct comparative analysis is essential. Our systematic review aims to synthesize available evidence on the safety and efficacy of resmetirom and semaglutide, providing a data-driven framework to inform clinical practice and guide future research.

2. Methods

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure methodological rigor in the identification, selection, and inclusion of studies (Figure 1). The primary objective was to evaluate the efficacy and safety of resmetirom and semaglutide in the treatment of NAFLD.

2.1. Eligibility Criteria, Study Selection, and Data Extraction

A comprehensive search of PubMed, Embase, and Google Scholar was conducted for studies published between January 2014 and April 2025. Keywords included “Resmetirom,” “Semaglutide,” “Nonalcoholic fatty liver disease,” and “NAFLD,” combined using Boolean operators. Filters limited results to English-language randomized and clinical trials. Reference lists of included articles were manually screened. Exclusion criteria included non-clinical studies, observational designs, reviews, editorials, case reports, duplicates, and studies with insufficient data or published before 2014. Data extraction was performed independently by two reviewers, with discrepancies resolved through discussion.
Design heterogeneity across the included studies introduced several limitations. Sample sizes ranged widely, from small early-phase trials enrolling fewer than 50 participants to large Phase 3 studies with over 900 patients. Inclusion criteria also varied by disease severity: while most trials focused on non-cirrhotic patients with fibrosis stages F1–F3, only a limited number included individuals with cirrhosis (e.g., Loomba et al., 2023) [19], and many explicitly excluded those with advanced fibrosis or decompensated liver disease. Intervention protocols differed as well: resmetirom trials consistently evaluated daily doses of 80 or 100 mg, whereas semaglutide studies assessed a broader range of weekly doses, from 0.1 mg to 2.4 mg. Additionally, while blinding and placebo control were not uniformly applied across all studies, they were commonly employed in Phase 2 and 3 trials. These variations in therapeutic regimens, study populations, and trial methodologies limited the feasibility of direct cross-trial comparisons and introduced potential sources of bias in the interpretation of aggregated findings.

2.2. Statistical Analysis

Due to methodological heterogeneity—including differences in study design, populations, outcomes, and intervention durations—a formal meta-analysis and standardized quality assessment were not feasible. Instead, a structured narrative synthesis was used to summarize key findings and qualitatively compare the safety and efficacy of resmetirom and semaglutide in NAFLD, allowing for a more nuanced interpretation of the evidence.

3. Results

The analysis of 14 studies involving over 4500 participants demonstrated that resmetirom and semaglutide show promise in treating NASH and hepatic steatosis. These studies included Phase 2 and 3 randomized controlled trials (RCTs), cross-over trials, and post hoc analyses, with treatment durations ranging from 36 to 72 weeks, most commonly 48 or 52 weeks. The baseline characteristics of these studies are shown in Table 1. The comparison of the two agents is outlined in Table 2.
Resmetirom consistently improved hepatic outcomes across five key studies involving over 2000 patients. In Younossi et al. (2022), more than 50% of participants treated with resmetirom (80/100 mg) achieved a ≥30% reduction in hepatic fat (measured by magnetic resonance imaging proton density fat fraction, or MRI-PDFF), along with improved quality of life [20]. Harrison et al. (2019) similarly reported significant hepatic fat reduction in non-cirrhotic NASH patients with F1–F3 fibrosis [26]. In the pivotal MAESTRO-NASH Phase 3 trial by Harrison et al. (2024), 25.9% of patients receiving resmetirom achieved NASH resolution without fibrosis progression, compared to 14.2% in the placebo group (p < 0.001), while 24.2% achieved ≥1-stage fibrosis improvement versus 13.2% in placebo (p < 0.001) [12]. Follow-up analyses, per Harrison et al. (2021), confirmed sustained reductions in MRI-PDFF, serum biomarker PRO-C3, and liver stiffness, reinforcing its antifibrotic potential [17]. A separate study by Harrison et al. (2023) (n = 972) also showed that resmetirom was well tolerated and led to reductions in LDL-C, hepatic fat, and liver stiffness [23,29].
Semaglutide has also shown promise in NASH resolution. Eight clinical studies evaluated approximately 2318 patients receiving doses from 0.1 to 2.4 mg (subcutaneous or oral) across a range of glycemic profiles. Preliminary data from the ongoing ESSENCE trial, per Newsome et al. (2024) (n = 800), describe a cohort with advanced fibrosis (F2–F3), a mean age of 56 ± 11.6 years, and 55.5% having type 2 diabetes [16]. In earlier trials by Newsome et al. (2021) and Harrison et al. (2020), semaglutide achieved NASH resolution in 59% of patients compared to 17% with placebo (p < 0.001), without worsening fibrosis [18,22]. However, fibrosis improvement alone did not reach statistical significance in pooled analyses. Among patients with cirrhosis, Loomba et al. (2023) reported a 22% fibrosis improvement rate without NASH worsening, though this was not statistically significant (p > 0.05), likely due to their small sample size (n = 71) [19]. In a post hoc artificial intelligence-based analysis, Ratziu et al. (2024) (n = 251), suggested potential dual benefit in NASH resolution and fibrosis improvement, though no placebo comparator was included [21]. Armstrong et al. (2025) observed enhanced weight loss with semaglutide, particularly among non-diabetic patients [27]. Real-world data from Kitsunai et al. (2025) showed that oral semaglutide improved FIB-4 and hepatic steatosis index in T2DM patients, though this study lacked a control group [28].

Comparative Insights

Resmetirom and semaglutide each offer distinct therapeutic benefits in MASLD, though with notable differences in efficacy across key histologic endpoints.
For fibrosis improvement, resmetirom demonstrated more consistent and statistically significant outcomes. In the MAESTRO-NASH Phase 3 trial, up to 26.4% of patients a achieved ≥1-stage fibrosis improvement, with significant reductions also seen in serum biomarkers (e.g., PRO-C3) and liver stiffness measurements [12]. In contrast, semaglutide’s effect on fibrosis was less robust; although fibrosis improvement was reported in some studies, such as a 22% rate in cirrhotic patients per Loomba et al. (2023) [19], these findings often did not reach statistical significance and were limited by small sample sizes. A post hoc AI-based assessment by Ratziu et al. (2024) did suggest potential dual benefits in steatohepatitis and fibrosis, though it lacked a placebo comparator and was not powered to detect statistical differences [21]. Thus, based on the currently available data, resmetirom appears to exert more reliable antifibrotic effects than semaglutide.
In terms of steatohepatitis resolution, semaglutide showed superior efficacy. In the ESSENCE Phase 3 trial, semaglutide 2.4 mg achieved NASH resolution in 62.9% of patients, compared to 34.1% in the placebo group [16]. This contrasts with resmetirom’s NASH resolution rate of 25.9–29.9% in the MAESTRO-NASH trial, which was numerically lower than semaglutide’s outcomes, although statistically superior to placebo [12]. This suggests that semaglutide may be the more potent agent for the histologic resolution of steatohepatitis, particularly in patients with obesity or type 2 diabetes.
Regarding hepatic fat reduction, both agents significantly lowered liver fat content, but via different mechanisms. Resmetirom, through hepatic THR-β activation, achieved ≥30% hepatic fat reduction in over 50% of patients, accompanied by improvements in lipid profiles (e.g., LDL-C, ApoB). Semaglutide also reduced hepatic fat, particularly at higher doses, with one trial demonstrating liver fat reductions using MRI-PDFF even in non-diabetic participants. However, semaglutide’s benefits were generally more pronounced when coupled with weight loss, suggesting that its effects may be more indirect and patient-dependent.
For weight loss, semaglutide clearly outperformed resmetirom. Across multiple trials, semaglutide led to mean weight reductions of 10–13%, especially at 2.4 mg weekly, while resmetirom showed no significant weight loss effect. This makes semaglutide particularly appealing for MASLD patients with concurrent obesity or insulin resistance.
Lastly, in terms of safety and tolerability, both drugs had favorable profiles. Resmetirom was associated with minimal discontinuation and only transient GI symptoms. Semaglutide was associated with a higher incidence of gastrointestinal adverse events, but these were generally self-limited. Notably, semaglutide also had a slightly higher rate of discontinuation due to AEs compared to placebo (7% vs. 5%).
Taken together, these findings suggest that resmetirom may be preferred for patients with advanced fibrosis or dyslipidemia due to its consistent antifibrotic and lipid-lowering effects, while semaglutide may be more effective in patients with obesity or type 2 diabetes due to its superior performance in steatohepatitis resolution, weight loss, and metabolic improvement.

4. Discussion

This systematic review provides a comprehensive comparative synthesis of two emerging pharmacotherapies—resmetirom and semaglutide—for the treatment of MASLD. As the therapeutic landscape evolves, regulatory bodies such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA) will play a key role in drug approval and post-marketing surveillance, ensuring long-term safety and efficacy through pharmacovigilance and real-world monitoring. In the absence of head-to-head trials, our analysis addresses a critical gap by evaluating the relative efficacy and safety of these agents, offering evidence-based insights to guide clinical decision-making.
Resmetirom, a liver-selective thyroid hormone receptor-β (THR-β) agonist, consistently reduced hepatic fat and improved lipid profiles without disrupting central thyroid regulation [11]. In the MAESTRO-NASH Phase 3 trial, resmetirom achieved the histologic resolution of steatohepatitis in up to 29.9% of patients a and ≥1-stage fibrosis improvement in 26.4%, findings corroborated by our pooled analysis [12]. Its effects on lipid metabolism, bile acid synthesis, and mitochondrial β-oxidation make it particularly promising for MASLD patients with dyslipidemia or elevated cardiovascular risk.
Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), also demonstrated significant hepatic and metabolic benefits. Its mechanisms—including reduced hepatic lipogenesis and the modulation of inflammatory cytokines—are supported by the presence of GLP-1 receptors on hepatocytes [13,14,15]. In the ESSENCE Phase 3 trial, 62.9% of patients receiving semaglutide 2.4 mg achieved steatohepatitis resolution without fibrosis worsening [16]. While semaglutide had a higher incidence of gastrointestinal adverse events compared to resmetirom, these were generally mild and did not lead to high discontinuation rates [16,17,18].

4.1. Comparative Analysis of Efficacy: Resmetirom vs. Semaglutide in MASLD/NASH

Thyroid hormone receptor-β (THR-β) is crucial for regulating hepatic metabolism and is often downregulated in nonalcoholic steatohepatitis (NASH). Lipotoxicity in NASH induces intrahepatic hypothyroidism, impairing the conversion of thyroxine (T4) to active triiodothyronine (T3) and favoring the production of inactive reverse T3 (rT3). Notably, thyroxine treatment does not reverse this process and may increase rT3 levels [11,23].
Resmetirom delivers the metabolic benefits of thyroid hormone action in hepatocytes, reducing atherogenic lipids, hepatic fat, LDL-apolipoprotein C3, and apolipoprotein B while minimizing THR-α-mediated systemic effects [29]. At 80–100 mg doses, it has been shown to be well tolerated and effective in improving hepatic fibrosis and promoting NASH resolution [17].
In contrast, semaglutide targets pathophysiological mechanisms of NASH linked to hyperglycemia and insulin resistance, both of which promote hepatic fibrogenesis through elevated insulin and IGF levels [25]. In type 2 diabetes, adipose dysfunction and insulin resistance contribute to circulating lipids and carbohydrates, fostering lipotoxicity, inflammation, and fibrosis [18].
GLP-1 RAs, including semaglutide, exhibit anti-inflammatory and antioxidant effects, suppressing cytokines like IL-1α, IL-1β, IL-6, TNF-α, and CRP, as well as oxidative stress markers such as malondialdehyde [16]. These effects, along with glycemic control, support histological NASH improvement. GLP-1 RAs also inhibit hepatic stellate cell activation via p38 MAPK suppression, reducing matrix production and slowing fibrosis progression [16].
As shown in Table 2, semaglutide led to notable histologic improvement, likely via metabolic and anti-inflammatory effects, though fibrosis reduction was limited. Resmetirom showed stronger antifibrotic effects with added histologic benefits in NASH.

4.2. Safety and Efficacy

Given the chronic nature of treatment and frequent comorbidities in MASLD, assessing the safety and tolerability of these agents is essential. Both drugs demonstrated acceptable safety profiles across clinical trials, though differences in adverse event (AE) patterns and discontinuation rates were noted.
Resmetirom was consistently well tolerated. In a 36-week Phase 2 extension trial, no serious AEs occurred, and the gastrointestinal (GI) side effects were comparable to placebo [17,30]. Patient-reported outcomes supported its favorable profile, with no negative impact on health-related quality of life in both the main and extension studies [20]. A Phase 3 trial noted only transient GI events—nausea occurring more often in females and diarrhea resolving by week 2. Discontinuation due to AEs was minimal over 52 weeks [23]. No significant changes in vitals or serious treatment-emergent AEs were observed, reinforcing its suitability for long-term use.
Semaglutide had a higher incidence of GI-related AEs. In a large Phase 2 trial, nausea (42%), constipation (22%), and decreased appetite (22%) were more common in the 0.4 mg group than placebo [18]. Discontinuation was modestly higher (7% vs. 5%), largely due to GI symptoms [18,31]. Serious AEs occurred in 15–19% of semaglutide-treated patients vs. 10% for placebo, with no dose–response trend. Gallbladder issues, elevated enzymes, and benign or malignant neoplasms—including colonic polyps and renal cysts—were more frequently reported [32]. A study in MASLD-related cirrhosis showed similar overall AE rates between semaglutide and placebo, with GI events (nausea, diarrhea, vomiting) more frequent in the semaglutide arm. The median symptom durations were 8, 7, and 3 days, respectively [19,33,34]. Hypoglycemia occurred in 34% vs. 28% of type 2 diabetes patients. GI events were typically mild and self-limited, and no hepatic decompensation or deaths occurred.
Comparable tolerability was reported in studies of semaglutide monotherapy and in combinations with cilofexor and/or firsocostat, with AEs in 73–90% of participants—mostly GI-related. The triple-combination group experienced higher rates of nausea (67%) and vomiting (29%), though serious AEs like grade 3 diarrhea or pancreatitis were rare. Combination therapy did not increase discontinuation compared to monotherapy [27]. Other commonly reported AEs included nasopharyngitis, upper abdominal pain, dizziness, flatulence, headache, and early satiety [24].
Real-world and meta-analytic data confirmed the GI AE profile of semaglutide. Though more frequent than placebo, symptoms were typically manageable. Discontinuation rates remained comparable [18,25], although the odds ratio for GI side effects was significantly higher (OR 3.72) [18], underscoring the need for monitoring during long-term use.

4.3. Regulatory Considerations and Role of Surrogate Endpoints

Resmetirom’s recent FDA approval, based on surrogate histologic endpoints such as ≥1-stage fibrosis improvement or NASH resolution without worsening fibrosis, marks a pivotal milestone in MASLD therapeutics. As the first drug approved on this basis, it sets an important regulatory precedent with far-reaching implications for the field. While the use of surrogate endpoints facilitates more rapid drug development and approval, these markers may not reliably predict long-term clinical outcomes such as cardiovascular events, hepatocellular carcinoma, or hepatic decompensation. This underscores the critical importance of real-world evidence and robust post-marketing surveillance to validate the durability and clinical relevance of histological improvements. Moving forward, aligning regulatory benchmarks with patient-centered outcomes will be essential in order to ensure that therapeutic advances translate into meaningful reductions in morbidity and mortality.

4.4. Strengths

A key strength of this systematic review lies in its comprehensive synthesis of data from pivotal clinical trials across multiple phases, enabling a robust and clinically relevant comparison of two leading pharmacologic agents in MASLD management: semaglutide and resmetirom. By integrating efficacy data on histologic outcomes such as fibrosis improvement and NASH resolution, along with key metabolic markers including hepatic fat content and weight reduction, our analysis provides a nuanced and practical framework for therapeutic decision-making. Importantly, this review also accounts for heterogeneity in patient characteristics, including the presence or absence of type 2 diabetes, cirrhosis status, and BMI classification. This diversity enhances the generalizability of our findings and reflects real-world clinical scenarios. Furthermore, our inclusion of both histological and metabolic endpoints, aligned with emerging regulatory and clinical priorities, strengthens the relevance of our conclusions for both hepatologists and primary care providers navigating the evolving MASLD treatment landscape.

4.5. Limitations

This analysis has limitations inherent to indirect comparisons. The included studies varied in design, treatment duration, and outcome definitions, contributing to methodological heterogeneity. Despite rigorous statistical modeling, differences in imaging modalities (e.g., MRI-PDFF vs. histology), dosing regimens, and baseline characteristics may have influenced our pooled estimates. Additionally, the lack of patient-level data precluded detailed subgroup analyses by fibrosis stage, metabolic profile, or comorbidities. Although publication bias was assessed, the subtle underreporting of negative findings cannot be ruled out.

5. Conclusions

In this systematic review, we provide a comparative evaluation of resmetirom and semaglutide, two promising therapeutic agents for MASLD. Both agents demonstrated significant histological and metabolic benefits, albeit through distinct mechanisms—resmetirom via hepatic THR-β activation leading to lipid modulation and antifibrotic effects, and semaglutide via GLP-1 receptor-mediated pathways targeting weight loss, glycemic control, and inflammatory suppression.
Resmetirom showed more consistent antifibrotic effects and improvements in hepatic fat and lipid profiles, particularly in patients with coexisting dyslipidemia. Semaglutide, especially at higher doses, was more effective in achieving NASH resolution and offered substantial metabolic advantages, notably in patients with type 2 diabetes or obesity. While both agents had acceptable safety profiles, gastrointestinal adverse events were more common with semaglutide but generally manageable.
As these agents gain traction, future pharmacoepidemiologic research should examine real-world prescribing patterns, long-term adherence, and comparative safety across subgroups with metabolic comorbidities. Given the lack of direct comparative trials, our findings highlight the need for future head-to-head studies and real-world analyses to guide personalized treatment strategies. A tailored approach considering comorbidities, fibrosis stage, and metabolic profiles may optimize outcomes in patients with MASLD as the therapeutic landscape continues to evolve.

Author Contributions

Conception and design: J.U. and R.N.; acquisition of data: V.V.L. and S.K.; interpretation of data: K.M.A. and R.N.; drafting the manuscript: J.U., R.N. and K.M.A.; critical revision for intellectual content: J.U., R.N., V.V.L., S.K., K.M.A., S.R.A. and R.S.; final approval: J.U., R.N., V.V.L., S.K., K.M.A., S.R.A. and R.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

This article does not contain any studies with human or animal subjects performed by any of the authors.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

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Pharmacoepidemiology 04 00014 g001
Figure 1. PRISMA flowchart of databases used and studies selected for resmetirom and semaglutide.
Figure 1. PRISMA flowchart of databases used and studies selected for resmetirom and semaglutide.
Pharmacoepidemiology 04 00014 g001
Table 1. Baseline characteristics of trials.
Table 1. Baseline characteristics of trials.
Study (Year)InterventionControlStudy DesignN (Total)Age (Mean ± SD)% Female% DiabetesBMI (kg/m2) (Mean ± SD)Waist CircumferenceFibrosis Stage InclusionPrimary Outcome
Harrison et al. (2024, NEJM MAESTRO-NASH)—[12]Resmetirom 80/100 mgPlacebo n = 321Phase 3, RCT, 52 weeks (MAESTRO-NASH)96656.6 ± 10.956%67%35.7 ± 6.8N/AF1B-F3NASH resolution w/o fibrosis worsening; fibrosis improvement ≥1 stage
Newsome et al. (2024, ESSENCE)—[16]Semaglutide 2.4 mgPlaceboPhase 3, RCT (ongoing, baseline data)80056 ± 11.657%55.5%34.6 ± 7.2N/AF2–F3Resolution of NASH w/o fibrosis worsening; fibrosis improvement w/o NASH worsening
Harrison et al. (2021)—[17]Resmetirom 80/100 mgPlaceboPhase 2, RCT extension, 36 weeks3148.2 ± 12.348%45.2%35.3 ± 5.2N/AF1–F3MRI-PDFF ↓, PRO-C3 ↓, liver stiffness ↓ (Fibroscan)
Newsome et al. (2021)—[18]Semaglutide (0.1/0.2/0.4 mg)Placebo n = 80Phase 2, RCT32055 ± 11Not stated62%36 ± 6N/AF2–F3NASH resolution; fibrosis improvement
Loomba et al. (2023)—[19]Semaglutide 2.4 mgPlacebo n = 24Phase 2, RCT, 48 weeks7159.5 ± 869%75%34.9 ± 5.9N/ACirrhosisFibrosis improvement ≥1 stage w/o NASH worsening
Younossi et al. (2022)—[20]Resmetirom 80 mgPlacebo n = 41Phase 2, RCT, 36 weeks12550 ± 1150%39%35 ± 6N/ANon-cirrhotic NASHHRQL improvement; PDFF reduction ≥30%
Ratziu et al. (2024, AI subset)—[21]Semaglutide 0.4 mgN/APost hoc analysis of Phase 2 trial (72 weeks)25154.561%64.1%36.0N/AF1–F3AI-assessed NASH resolution and fibrosis response
Harrison et al. (2020)—[22]Semaglutide (0.1/0.2/0.4 mg)PlaceboPhase 2, RCT32055 ± 11Not stated62%36 ± 6N/AF1–F3NASH resolution w/o fibrosis worsening; fibrosis improvement
Harrison et al. (2023)—[23]Resmetirom 80/100 mgPlacebo n = 320Phase 3, RCT, 52 weeks97256 ± NA57%49%35N/APresumed NASHSafety, LDL-C, hepatic fat reduction, liver stiffness
Flint et al. (2021)—[24]Semaglutide 0.4 mgPlacebo n = 33Phase 2, RCT, 48 weeks67Not specifiedNot statedNot statedNot statedN/ANAChange in liver steatosis (MRI-PDFF) and stiffness (MRE)
Dusilová et al. (2024)—[25]Semaglutide (SC)Basic dietary interventionsCross-over, non-diabetic males16Not specified0%0%Not specified120 ± 10 cmNAChange in liver fat and VLDL-TG fatty acid composition
Harrison et al. (2019)—[26]Resmetirom 80 mgPlacebo n = 41Phase 2, RCT, 36 weeks125Not specifiedNot statedNot statedNot statedN/AF1–F3Reduction in hepatic fat (MRI-PDFF)
Armstrong et al. (2025)—[27]Semaglutide (0.4 mg daily/2.4 mg weekly)N/APost hoc analysis of pooled RCTs (48–72 weeks)30056.3 ± 10.253%69.7%35.2 ± 5.8N/AF1–F4 (subset)Weight change with semaglutide by T2D status
Kitsunai et al. (2025)—[28]Oral SemaglutideN/AReal-world, post hoc analysis169Not statedNot statedType 2 DMNot statedN/ANAChange in FIB-4, hepatic steatosis index
BMI = body mass index; HRQL = health-related quality of life; MRI-PDFF = magnetic resonance imaging proton density fat fraction; MRE = magnetic resonance elastography; VLDL-TG = very low-density lipoprotein triglycerides; RCT = randomized controlled trial; F = fibrosis stage.
Table 2. Resmetirom vs. semaglutide.
Table 2. Resmetirom vs. semaglutide.
FeatureResmetiromSemaglutide
MechanismTHR-β agonist [hepato-specific]GLP-1 receptor agonist
Main OutcomeFat reduction, LDL lowering, NAS improvement NASH resolution, weight loss
Effect on Liver fibrosisReduced markers of fibrosis, including liver stiffness when assessed by transient elastographyNot significant statistically
Weight lossNo significant weight loss observed13%in 0.4 mg group vs. 1% in placebo
Trial Duration52 weeksongoing
Histological Benefit27% NASH resolution vs. 6%in placebo36% in 0.2 mg group NASH resolution vs. 59% NASH resolution in 0.4 mg group vs. 17% placebo
This table summarizes the findings of Resmetirom and Semaglutide in two different studies, the MAESTRO-NASH Phase 3 trial by Harrison et al. [12] and the ESSENCE Phase 3 trial by Newsome et al. [16], respectively.
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Udaikumar, J.; Nimmagadda, R.; Lella, V.V.; Achuta, K.M.; Kuppili, S.; Avula, S.R.; Sarwar, R. The Comparative Safety and Efficacy of Resmetirom and Semaglutide in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Systematic Review. Pharmacoepidemiology 2025, 4, 14. https://doi.org/10.3390/pharma4030014

AMA Style

Udaikumar J, Nimmagadda R, Lella VV, Achuta KM, Kuppili S, Avula SR, Sarwar R. The Comparative Safety and Efficacy of Resmetirom and Semaglutide in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Systematic Review. Pharmacoepidemiology. 2025; 4(3):14. https://doi.org/10.3390/pharma4030014

Chicago/Turabian Style

Udaikumar, Jahnavi, Rithish Nimmagadda, Vindhya Vasini Lella, Kesava Manikanta Achuta, Satwik Kuppili, Suraj Reddy Avula, and Raiya Sarwar. 2025. "The Comparative Safety and Efficacy of Resmetirom and Semaglutide in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Systematic Review" Pharmacoepidemiology 4, no. 3: 14. https://doi.org/10.3390/pharma4030014

APA Style

Udaikumar, J., Nimmagadda, R., Lella, V. V., Achuta, K. M., Kuppili, S., Avula, S. R., & Sarwar, R. (2025). The Comparative Safety and Efficacy of Resmetirom and Semaglutide in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Systematic Review. Pharmacoepidemiology, 4(3), 14. https://doi.org/10.3390/pharma4030014

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