Mechanistic rationale: resmetirom

Thyroid hormones play a crucial role in regulating energy expenditure, lipid turnover, and mitochondrial respiration. In hepatocytes, triiodothyronine (T3) binding to THR-β stimulates β-oxidation, increases LDL receptor expression, improves mitochondrial function in hepatic cells, boosts very-low-density lipoprotein (VLDL) secretion, and enhances reverse cholesterol transport, thereby reducing lipotoxicity and inflammation [3, 16]. Research on humans and rodents indicates that intrahepatic hypothyroidism (resulting from elevated deiodinase 3 activity or reduced THR-β expression) is a key factor in MASH. However, administering thyroid hormone systematically exposes to the risks of cardiotoxicity and bone loss mediated by THR-α before any hepatic benefits can be seen. Resmetirom (MGL-3196) addresses this issue by selectively activating THR-β with a 28-fold affinity compared to THR-α [16].

Structurally, resmetirom (MGL-3196) is a synthetic, non-iodinated small molecule that selectively targets THR-β. Its backbone consists of two substituted phenyl rings linked by an ether bridge, creating a compact, planar scaffold (Figure 1). Halogen substituents, one chlorine atom, a para-fluoro group, and a trifluoromethyl moiety, boost lipophilicity and metabolic stability. A terminal carboxylic acid side chain mimics the acidic tail of native thyroid hormones and anchors the ligand in the receptor pocket. Altogether, these features confer high THR-β affinity while supporting once-daily oral dosing. A phase III, randomized, controlled trial of resmetirom in biopsy-confirmed NASH patients with liver fibrosis was conducted. In this trial, 322 subjects received 80 mg of resmetirom, 323 subjects received 100 mg of resmetirom, and 321 subjects received a placebo once daily for 52 weeks. The study showed that the drug was highly effective in terms of NASH resolution and improvement of liver fibrosis [17].

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Figure 1. Chemical structures of Resmetirom (MGL-3196) and endogenous thyroid hormone triiodothyronine (T3). (A) Resmetirom, a synthetic, liver-targeted, selective thyroid-hormone-receptor-β (THR-β) agonist, consists of a tri-substituted benzyl ether core in which (i) two iodine atoms present in T3 are replaced by polar, non-halogen substituents (a trifluoromethyl group and a cyano group), and (ii) the hydrophobic phenolic ring of T3 is replaced by a 3,5-dichloro-4-(4-cyano)phenyl moiety. (B) T3 is the natural ligand for thyroid hormone receptors and features (i) a diphenyl ether backbone containing three iodine atoms at positions 3, 5, and 3’, (ii) an α-amino-propionic acid side chain conferring zwitterionic character, and (iii) a phenolic hydroxyl group essential for receptor binding. Molecular formulas, molecular weights, substance identifiers (SID), and CAS numbers for each substance are given.

Resmetirom also takes advantage of hepatic first-pass extraction to achieve a liver-to-plasma exposure ratio of approximately 8:1 [16, 18]. In animal studies, resmetirom increases the expression of genes involved in fatty acid oxidation (CPT1A, ACOX1), mitochondrial biogenesis (PPARGC1A), and cholesterol catabolism (CYP7A1), while reducing levels of lipogenic targets (SREBP-1c, FASN) [19–21]. These changes at the genetic level lead to a decrease in hepatic triglyceride levels, improved insulin sensitivity, and a reduction in inflammatory and fibrotic pathways related to NF-κB and transforming growth factor-β (TGF-β). Additionally, resmetirom lowers levels of circulating LDL-C (by 20% to 30%) and ApoB (by 15% to 25%), providing a dual benefit for individuals with atherogenic dyslipidemia. Overall, the metabolic impact of resmetirom can be likened to pharmacological simulation of mild hyperthyroidism localized to hepatocytes, thus avoiding any systemic complications from excess thyroid hormone [16].

In conclusion, the liver selectivity of resmetirom is achieved through two complementary design principles: (i) a 28-fold higher binding affinity for THR-β compared to THR-α [18], and (ii) preferential first-pass hepatic extraction that results in a favorable liver-to-plasma exposure ratio. This effectively protects extra-hepatic tissues from thyromimetic stimulation, demonstrating liver-specific action without causing systemic adverse effects [16, 18].

Mechanistic rationale: semaglutide

Semaglutide is a 31-amino-acid analogue of the human incretin hormone GLP-1 that has been strategically modified to boost its stability and half-life (Figure 2). At position 8, the native alanine is replaced by the protease-resistant amino acid α-aminoisobutyric acid (Aib). This substitution makes the peptide resistant to dipeptidyl-peptidase-4 (DPP-4), whereas the C18 fatty di-acid side chain attached to Lys26 ensures high-affinity, reversible albumin binding; together, these modifications extend the elimination half-life to ~160 h and allow once-weekly dosing [22, 23].

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Figure 2. Structure of semaglutide. The analog of human glucagon-like peptide-1 (GLP-1) is composed of 31 amino acids with the depicted sequence, which are numbered from 7–37 (according to the unprocessed GLP-1 protein). Compared to GLP-1, semaglutide carries a substitution of the alanine at position 8 with α-aminoisobutyric acid (Aib) and acylation of the lysine at position 26 with a fatty di-acid side chain for extended half-life, which is linked via a linker sequence. Moreover, it carries an amino acid substitution at position 34 (lysine to arginine), which prevents the C18 fatty acid binding moiety at the wrong site. Molecular formula, molecular weight, substance identifier (SID), and CAS number for semaglutide are given.

Furthermore, the ε-amine of the lysine at position 26 is acylated: via a glutamic acid linker, a C18 fatty di-acid (stearic acid derivative) is attached [4]. This hydrophobic side chain allows reversible binding to serum albumin, shielding the peptide from rapid renal clearance and enabling once-weekly dosing.

Apart from these substitutions, the sequence largely mirrors native GLP-1, so semaglutide retains potent agonism at the GLP-1 receptor while circulating far longer in the bloodstream, which allows for once-weekly subcutaneous or once-daily oral dosing options [4]. Originally developed for glycemic control, semaglutide promotes glucose-dependent insulin secretion, suppresses glucagon release, delays gastric emptying, and, most importantly for MASH, produces significant weight loss through the hypothalamic regulation of appetite and satiety.

In addition to calorie restriction, GLP-1 signaling has direct effects on the liver and other organs relevant to MASH. In laboratory studies, GLP-1 RAs decrease de novo lipogenesis by down-regulating SREBP-1c and up-regulating AMPK, enhance β-oxidation through PPAR-α activation, and reduce oxidative stress through cAMP-PKA-mediated pathways [21, 24]. Semaglutide also decreases endotoxemia-induced Kupffer cell activation and influences the gut-liver axis by changing bile acid pools and intestinal permeability. Moreover, semaglutide reduces appetite and increases satiety [25]. In rodent models, these cellular changes result in reduced steatosis, lobular inflammation, and ballooning. However, liver fibrosis regression is not consistently observed, suggesting that the antifibrotic effects are a result of metabolic improvement. Overall, the mechanisms of semaglutide action can be described as a systemic, weight-focused intervention that targets caloric overload, insulin resistance, and pro-inflammatory adipokine profiles, all of which contribute to the liver pathology of MASH.

Therapeutic efficacy: resmetirom

The pivotal phase II trial (MGL-3196-05, n = 125) randomized patients with biopsy-proven MASH to receive either 80 mg of resmetirom or a placebo for 36 weeks [26]. The primary endpoint, which was the relative reduction in magnetic resonance imaging-proton density fat fraction (MRI-PDFF) assessed hepatic fat, was achieved with a placebo-adjusted difference of –29%. Additionally, 32% of patients on resmetirom vs. 10% on placebo achieved a ≥ 2-point reduction in NAS without worsening fibrosis. Notably, histologic fibrosis stage improved by ≥ 1 point in 24% of patients on resmetirom compared to 10% on placebo, a signal that is not commonly seen with weight-neutral agents in such a short timeframe [26]. Moreover, LDL-C, triglycerides, ApoB, and Lp(a) all decreased significantly, highlighting cardiometabolic benefits of the compound.

Based on these findings, the double-blind phase III MAESTRO-NASH trial enrolled over 950 non-cirrhotic patients, stratified by fibrosis stage (F1–F3) and metabolic comorbidities [17]. After 52 weeks, 26% and 30% of participants who received 80 mg and 100 mg of resmetirom, respectively, achieved MASH resolution with no fibrosis worsening compared to 10% on placebo (p < 0.0001). Fibrosis improvement of ≥ 1 stage was seen in 24% (80 mg) and 26% (100 mg) compared to 14% in the placebo group (p < 0.005 for both doses) [17]. The lipid-lowering effects persisted, with LDL-C reductions of approximately 19% and ApoB by 16%. Pruritus, mostly mild, emerged as the main adverse event (see below). While 52 weeks may be considered too short to assess hard outcomes like cirrhosis or HCC incidence, the histologic improvements surpassed the traditional regulatory threshold for accelerated approval, positioning resmetirom as a frontrunner in the MASH pipeline.

Therapeutic efficacy: semaglutide

Efficacy data for semaglutide in MASH primarily come from a 72-week, dose-finding phase II RCT (n = 320) that compared 0.1, 0.2, and 0.4 mg subcutaneous semaglutide daily versus placebo [27]. The highest dose resulted in MASH resolution in 59% of patients compared to 17% on placebo (p < 0.001), a remarkable achievement not seen with previous pharmacotherapies. Median weight loss was 13%, and glycemic parameters improved in both the pre-diabetic and type 2 diabetic subgroups. However, the fibrosis endpoint (i.e., ≥ 1-stage improvement without worsening steatohepatitis) did not reach statistical significance (p = 0.10). Post-hoc analyses revealed that patients who lost more than 10% body weight experienced greater fibrosis regression, supporting the idea that weight loss, rather than a direct antifibrotic mechanism, plays a role in histologic repair with GLP-1 RA therapy [27].

In addition to liver histology, the impact of semaglutide on cardiovascular outcomes has been confirmed in large trials for diabetes (SUSTAIN-6, LEADER) and obesity (STEP-CVOT, ongoing), where major adverse cardiovascular events (MACE) were reduced by 21–26% [28–30]. Since cardiovascular disease is the leading cause of death in MASH, this additional benefit could be crucial even if the effect of semaglutide on hepatic fibrosis lags behind other medications. Furthermore, the availability of an oral formulation and once-weekly dosing increases adherence options compared to competitors.

Comparative efficacy

Semaglutide achieved the highest rate of histologic MASH resolution reported to date (59% at 0.4 mg/day), while resmetirom produced an early ≥ 1-stage fibrosis improvement within 36–52 weeks, an effect rarely seen with weight-neutral agents [31, 32]. Since the fibrosis stage is the strongest independent predictor of liver-related outcomes [33], this difference should guide treatment selection and the design of future combination studies. The complementary, yet distinct, mechanistic landscapes of the two agents are summarized in Figure 3. By visually contrasting resmetirom’s hepatocentric THR-β activation with semaglutide’s system-wide incretin signaling, the figure clarifies how each drug addresses different biological “pressure points” within the MASH spectrum, focusing on hepatic lipid disposal versus systemic caloric unloading and glyco-metabolic control. It also highlights downstream consequences (e.g., LDL-C reduction, weight loss, early fibrosis signals) and the non-overlapping adverse-event profiles that must be balanced when selecting or combining therapies.

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Figure 3. Complementary mechanistic pathways of resmetirom and semaglutide in the treatment of MASH. Resmetirom is administered as an oral tablet entering the portal circulation, accumulating in hepatocytes, and selectively activating nuclear THR-β. The downstream transcriptional effects include up-regulation of genes that govern β-oxidation, LDL-receptor expression, and bile-acid synthesis, along with the suppression of lipogenic (SREBP-1c) and profibrotic (TGF-β) pathways. The net therapeutic outcomes are a reduction of hepatic fat, early histologic fibrosis regression, and a significant lowering of LDL cholesterol (LDL-C) and apolipoprotein B (ApoB). In contrast, semaglutide is administered as a once-weekly s.c. injection. The albumin-bound drug engages GLP-1 receptors on multiple organs including the pancreas, hypothalamic centers, stomach, and adipose tissue. Both drugs have major extra-hepatic effects. Importantly, both drugs have the potential to evolve therapeutic synergy, as indicated by “hepatic lipid disposal/antifibrotic × systemic metabolic unloading/weight loss”. GI: gastrointestinal; GLP-1: glucagon-like peptide-1; GPCR: G-protein coupled receptor; LDL: low-density lipoprotein; MASH: metabolic dysfunction-associated steatohepatitis; MRI-PDFF: magnetic resonance imaging-proton density fat fraction; SREBP-1c: sterol regulatory element-binding protein-1c; t_1/2: half-life; TGF-β: transforming growth factor-β; THR-β: thyroid hormone receptor-β; s.c.: subcutaneous.

Safety and tolerability

Resmetirom has demonstrated a favorable safety profile so far. Gastrointestinal (GI) complaints (10–15%) and mild pruritus (15–20%) were more common than with placebo but rarely led to discontinuation (< 3%) [34]. Heart rate, blood pressure, and bone-mineral parameters remained stable, confirming hepatic selectivity. Transient decreases in thyroid-stimulating hormone (TSH) and modest increases in free T4 were observed but normalized without intervention, even in euthyroid patients. There is no evidence of arrhythmia, osteopenia, or thyroid neoplasia, although longer surveillance is required.

Semaglutide’s safety profile has been well characterized after > 10 million patient-years of exposure in diabetes and obesity [4, 35]. Nausea (20–40%), vomiting (5–15%), and diarrhea (10–20%) are typical GLP-1 RA class effects, usually transient and dose-dependent. Rare but significant concerns include gallstone disease (1–2%), especially in the context of rapid weight loss, and acute pancreatitis (< 0.3%). Signals for retinopathy progression in patients with pre-existing diabetic retinopathy have been observed (SUSTAIN-6) but not consistently replicated. It is important to note that semaglutide’s GI profile may overlap with the baseline dyspepsia and gastroparesis found in cirrhotics, necessitating careful titration in advanced liver disease. No hepatotoxicity or adverse lipid shifts have been reported, which is a notable contrast to some other anti-obesity agents.

It should be mentioned that there are other drugs targeting the GLP-1 RA (e.g., liraglutide, tirzepatide, and survodutide) on the market that have also shown highly encouraging results, often with higher rates of MASH resolution and fibrosis improvement [36]. Therefore, it will be essential in future studies to optimize drug regimens and identify patients most likely to benefit from one or the other of these drugs, considering the specific pathophysiological, pharmacokinetic, and pharmacodynamic differences of each population group [37]. Moreover, continuous evaluation of real-world data is critical to better define the optimal positioning of oral semaglutide along the T2DM trajectory and fully exploit its potential in everyday clinical practice [38].

Cost-effectiveness and access

Affordability and reimbursement will heavily influence real-world uptake. In the United States, the wholesale acquisition cost of weekly injectable semaglutide at anti-obesity doses exceeds USD 18,000 per year [42]. Without insurance, however, prices vary widely: compounded versions that do not carry FDA approval have been advertised for as little as USD 129 per monthly supply, whereas the on-label, FDA-approved product can cost USD 1,850 for the same time period [43]. By comparison, the annual wholesale acquisition cost of resmetirom has been set at USD 47,400; the Institute for Clinical and Economic Review (ICER) has calculated a health benefit price benchmark of USD 39,600–50,100 per year [44]. These figures exceed, by several-fold, the per-capita pharmaceutical budget in many health-care systems and underscore a critical, often overlooked question: not every individual with hepatic steatosis can, or should, receive high-cost pharmacotherapy. Cost-effectiveness analyses consistently show that drug treatment becomes economically attractive only in patients with at least stage F2 fibrosis or with high cardiovascular risk, whereas lifestyle modification and, in particular, physical activity that induces exercise-mediated anti-inflammatory effects and dietary changes are the preferred first-line options for early, uncomplicated disease [45–47]. Accordingly, payers and clinicians will need to implement risk-stratified algorithms, based on non-invasive fibrosis scores, metabolic comorbidities, and patient preferences, to decide who should be treated now, who can safely defer pharmacotherapy, and how limited resources can be deployed most equitably. Expanding coverage of anti-obesity interventions to eligible individuals could generate billions of budgetary savings to the Medicare budget [48].

Real-world adherence

Adherence patterns are likely to differ between a daily oral therapy (resmetirom) and a weekly injectable therapy (semaglutide) in an otherwise asymptomatic population. While a once-weekly injection reduces the dosing frequency, challenges such as needle aversion, refrigeration requirements, and refill visits can still impact persistence. On the other hand, a once-daily oral tablet may be easily forgotten among other medications in a population without symptoms. This underscores the importance of tailored adherence aids (such as smart pens, digital pillboxes, and mobile reminders) and shared decision-making to align dosing with individual lifestyle preferences and capabilities. Implementing effective screening procedures for NAFLD, utilizing molecular diagnostics, digital reminder systems, remote biomarker monitoring, promoting clinical guidelines, and pharmacy-led adherence programs could help prevent drop-off [49–51]. Conversely, GI side effects with GLP-1 RAs or mild itching with THR-β agonists could lead to discontinuation if not proactively managed through dose adjustments and patient education [52].

Both agents are positioned to address specific, partially overlapping niches in the emerging MASH treatment algorithm. Resmetirom, already approved by the FDA for adults with non-cirrhotic MASH and stage F2–F3 fibrosis, is ideal for lean or weight-stable patients with progressive fibrogenesis or atherogenic dyslipidemia. It offers significant reduction in hepatic fat, early fibrosis improvement, and lowering of LDL-C/ApoB without affecting weight. Conversely, semaglutide, with strong cardiovascular outcomes and weight-loss efficacy, may be better suited for individuals with obesity, T2DM, or high cardiometabolic risk, where it can improve histology and provide extra-hepatic benefits through calorie reduction and glycemic control.

In clinical practice, factors such as fibrosis stage, BMI level, metabolic comorbidities, tolerability (pruritus vs. GI symptoms), and insurance criteria will influence the initial choice of therapy. Future research will determine whether sequential or combination therapy can optimize long-term disease management.

However, general long-term outcome data for both agents are still scarce. Most current evidence is limited to 52–72 weeks of exposure [4]. Extended follow-up studies are therefore essential to determine whether the histologic improvements translate into durable reductions in cirrhosis, HCC, and all-cause mortality. Only multi-year trials and real-world registries will clarify the true clinical and economic benefits of semaglutide and resmetirom.

Looking ahead, NASH trials ought to incorporate a thorough evaluation of the systemic drivers, modifiers, and manifestations of the disease. This broader lens would enable a more holistic and impartial appraisal of investigational therapies, capturing cardiovascular, renal, and metabolic endpoints in addition to traditional histologic markers of liver injury, so that therapeutic value is not judged solely on liver-specific surrogates [53].

Moreover, several studies pinpoint that sex probably modulates the response to treatment [53–55]. Future research should explicitly examine sex-specific efficacy and safety profiles of resmetirom and semaglutide as part of precision-medicine efforts. In parallel, systematic evaluation of how genetic polymorphisms, environmental exposures, divergent metabolic stressors, variable susceptibility to hepatocyte lipotoxicity, and differences in tissue-repair capacity shape the actions of these drugs will be crucial for advancing truly personalized therapy [53].

Extra-hepatic complications

MASH confers excess risk not only for cardiovascular disease but also for chronic kidney disease (CKD) and several extra-hepatic malignancies [56, 57]. By improving atherogenic dyslipidaemia, resmetirom might secondarily attenuate cardio-renal progression, whereas semaglutide has already shown nephro-protective and potential anti-neoplastic signals in large T2DM trials [58, 59]. Follow-up studies and disease registries will be essential to determine whether such benefits translate into lower CKD progression rates or cancer incidence in MASH cohorts.

Sex-specific precision medicine

Mounting evidence indicates that both disease biology and drug responsiveness in MASH and fibrosis are sexually dimorphic: pre-menopausal women exhibit slower fibrosis progression but may respond differently to metabolic therapies [55, 60, 61]. Therefore, the upcoming phase III and post-marketing studies should stratify efficacy and safety endpoints by sex and menopausal status. This will enable precision algorithms to match individual profiles with the most suitable single-agent or combination regimen.