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Objective: To review the literature leading to the Food and Drug Administration (FDA) approval of the first medication, resmetirom, for the treatment of nonalcoholic steatohepatitis (NASH), including the pharmacology, pharmacokinetics, clinical studies, dosing, and adverse effects. Relevant data will be used to discuss how resmetirom impacts clinical practice. Data sources: A literature search was conducted using MEDLINE from database inception to May 12, 2024. Keywords included non-alcoholic steatohepatitis, nonalcoholic fatty liver disease, and resmetirom. Study selection, data extraction and all English-language studies involving the use of resmetirom for nonalcoholic fatty liver disease (NAFLD)/NASH were included. Data synthesis: Resmetirom, a thyroid hormone receptor agonist, is administered at daily doses of either 80 mg or 100 mg. The drug was shown to provide NASH resolution as assessed by the NAFLD activity score, 80 mg-24.2%, 100 mg-25.9% compared to 14.2% with the placebo group (P < 0.001). Resmetirom, improved liver fibrosis, 80 mg-25.9%, 100 mg-29.9% compared to 9.7% with the placebo group (P < 0.001). Resmetirom's ability to improve fibrosis in patients with F2-F3 fibrosis offers valuable benefit for patients at risk of progressing to cirrhosis. Relevance to patient care and clinical practice: Resmetirom expands the medication options available to treat patients with NASH which can be given alongside other medications to optimize metabolic factors such as glucagon-like peptide-1 and hydroxymethylglutaryl-coenzyme A reductase inhibitors. Resmetirom was well tolerated in studies. Conclusion: Resmetirom serves as an attractive option in patients diagnosed with NASH with evidence of advanced fibrosis (F2-F3) in combination with exercise, diet, and other multimodal therapies targeting metabolic risk factors. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease is the largest liver disease around the world and is a serious public health hazard， but there has always been a lack of drugs approved for treatment. On March 14， 2024， Resmetirom became the first drug approved by the US Food and Drug Administration for the treatment of metabolic dysfunction-associated steatohepatitis （MASH）. This article summarizes the mechanism of action of Resmetirom in the treatment of MASH， related clinical trial designs， and some research results and analyzes shortcomings and future prospects. Current data have shown that Resmetirom is effective in improving steatohepatitis and liver fibrosis， but there is still a large gap between Resmetirom and the ideal drug for the treatment of MASH， and it is expected to develop more effective drugs for MASH. [ABSTRACT FROM AUTHOR]

Obesity and associated insulin resistance induce a chronic metaboinflammatory state that lead to injury and dysfunction of multiple organs resulting in a cluster of noncommunicable diseases such as type 2 diabetes mellitus, hypertension, cardiovascular disease, chronic kidney disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). Metabolic dysfunction-associated steatohepatitis (MASH) is a histologically active form of MASLD and characterized by greater injury and inflammation and progresses to cirrhosis with greater certainty than steatosis alone. The progression to cirrhosis is characterized by increasing fibrosis. The goal of treatment of MASLD/MASH was to improve the metaboinflammatory state i.e., the root cause of the liver disease and to prevent fibrosis progression to cirrhosis whereas in those who already have cirrhosis need additional care to prevent portal hypertension-related outcomes. Fibrosis regression is thus a key objective of treatment. The recent approval of resmetirom for MASH with fibrosis and the use of glucagon-like peptide-1 receptor agonists for obesity and type 2 diabetes has increased awareness of these NCDs and resulted in the growing demand for liver assessment and care in obese individuals. Patients with MASLD also have multiple metabolic comorbidities which represent competing threats to life, and the care of the patient requires both assessment of the totality of the risk and a more holistic approach integrating the care of all of the threats to life. Here, we provide a pragmatic and easily implementable risk-based approach to the evaluation and management of MASLD. [ABSTRACT FROM AUTHOR]

This was a randomized, double-blind, placebo-controlled study to assess the effects of pemvidutide, a glucagon-like peptide-1 (GLP-1)/glucagon dual receptor agonist, on liver fat content (LFC) in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). Patients with a BMI ≥28.0 kg/m2 and LFC ≥10% by magnetic resonance imaging-proton density fat fraction were randomized 1:1:1:1 to pemvidutide at 1.2 mg, 1.8 mg, or 2.4 mg, or placebo administered subcutaneously once weekly for 12 weeks. Participants were stratified according to a diagnosis of type 2 diabetes mellitus. The primary efficacy endpoint was relative reduction (%) from baseline in LFC after 12 weeks of treatment. Ninety-four patients were randomized and dosed. Median baseline BMI and LFC across the study population were 36.2 kg/m2 and 20.6%; 29% of patients had type 2 diabetes mellitus. At week 12, relative reductions in LFC from baseline were 46.6% (95% CI -63.7 to -29.6), 68.5% (95% CI -84.4 to -52.5), and 57.1% (95% CI -76.1 to -38.1) for the pemvidutide 1.2 mg, 1.8 mg, and 2.4 mg groups, respectively, vs. 4.4% (95% CI -20.2 to 11.3) for the placebo group (p <0.001 vs. placebo, all treatment groups), with 94.4% and 72.2% of patients achieving 30% and 50% reductions in LFC and 55.6% achieving normalization (≤5% LFC) at the 1.8 mg dose. Maximal responses for weight loss (-4.3%; p <0.001), alanine aminotransferase (-13.8 IU/L; p = 0.029), and corrected cT1 (-75.9 ms; p = 0.002) were all observed at the 1.8 mg dose. Pemvidutide was well-tolerated at all doses with no severe or serious adverse events. In patients with MASLD, weekly pemvidutide treatment yielded significant reductions in LFC, markers of hepatic inflammation, and body weight compared to placebo. Metabolic dysfunction-associated steatotic liver disease, and its progressive form steatohepatitis, are strongly associated with overweight/obesity and it is believed that the excess liver fat associated with obesity is an important driver of these diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonists elicit weight loss through centrally and peripherally mediated effects on appetite. Unlike GLP-1R agonists, glucagon receptor agonists act directly on the liver to stimulate fatty acid oxidation and inhibit lipogenesis, potentially providing a more potent mechanism for liver fat content reduction than weight loss alone. This study demonstrated the ability of once-weekly treatment with pemvidutide, a dual GLP-1R/glucagon receptor agonist, to significantly reduce liver fat content, hepatic inflammatory activity, and body weight, suggesting that pemvidutide may be an effective treatment for both metabolic dysfunction-associated steatohepatitis and obesity. NCT05006885. [Display omitted] • Pemvidutide is a GLP-1/glucagon dual receptor agonist. • Pemvidutide treatment significantly reduced liver fat content compared to placebo. • Pemvidutide treatment significantly reduced non-invasive biomarkers of liver inflammation. • Pemvidutide treatment significantly reduced body weight. • Pemvidutide may be an effective treatment for MASH. [ABSTRACT FROM AUTHOR]

Metabolic-Associated Steatohepatitis-Related Liver Disease (MASLD) and, its progressive form, Metabolic-Associated Steatohepatitis (MASH) pose significant global health challenges. Current therapeutic strategies targeting metabolic abnormalities have shown promise but lack specificity for the liver. Thyroid hormones, particularly thyroid hormone receptor beta (THR-β) agonists like resmetirom, offer a targeted approach to liver-related pathways. A network meta-analysis (NMA) comparing different doses of resmetirom to placebo for MASLD and MASH was conducted. PubMed, Scopus, Cochrane, and Web of Science were searched for relevant randomized controlled trials (RCTs). Efficacy outcomes included histological, radiological, and biochemical parameters, while safety outcomes comprised adverse events and treatment discontinuation. Resmetirom demonstrated dose-dependent efficacy in histological and radiological assessments, with the 100 mg dose showing superior MASH resolution and hepatic fat reduction. Biochemical markers indicated improved liver function with resmetirom treatment. However, adverse events, particularly diarrhea and nausea, were more prevalent in the resmetirom group, leading to higher treatment discontinuation rates. Resmetirom shows promise as a therapeutic option for MASLD and MASH management, with significant improvements in liver health parameters. However, safety concerns warrant careful monitoring in clinical practice. Further research is needed to optimize its long-term safety and efficacy. [ABSTRACT FROM AUTHOR]

The FDA’s approval of resmetirom (Rezdiffra) marks a significant breakthrough in treating metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis, conditions linked to non-alcoholic fatty liver disease (NAFLD). MASH is a growing global health concern, and resmetirom offers a novel therapeutic option by targeting liver pathophysiology through thyroid hormone receptor-beta activation. This mechanism effectively reduces fibrosis markers, improves liver enzyme levels, and minimizes liver fat buildup. Clinical trials have shown that resmetirom has a favorable safety profile, with manageable side effects like diarrhea and nausea. Additionally, it may lower cardiovascular risks associated with MASH, enhancing patient outcomes and quality of life. As the first FDA-approved drug for MASH, resmetirom’s introduction fills a crucial treatment gap, providing new hope for millions of patients and representing a pivotal moment in hepatology.

Abstract Fatty liver disease is a commonly occurring disease resulting in hepatic and extrahepatic complications. To date, there have been few available treatments beyond conventional lifestyle modification. While lifestyle modifications resulting in weight loss >10% have shown to be beneficial for metabolic dysfunction‐associated steatohepatitis (MASH), for the majority of patients, this is difficult to achieve. The recent approval of resmetirom (a thyroid hormone receptor beta agonist) by the Food and Drug Administration following positive results for histological outcomes in a phase 3 trial has opened the door for new treatments for metabolic (dysfunction)‐associated fatty liver disease (MAFLD) and MASH. There are currently a number of phase 3 trials targeting a variety of signaling pathways involved in the pathogenesis of metabolic steatohepatitis that are also promising. This review focuses on the currently available treatments for MAFLD and MASH, ongoing phase 3 clinical trials, and unresolved controversies in clinical trials in this area.

The influence of thyroid hormone (TH) on liver metabolism has attracted the attention of pharmacologists seeking new treatments for metabolic dysfunction-associated steatotic liver disease (MASLD), an increasingly common metabolic disorder. In this context, the selective induction of autophagy by TH in preclinical models has been identified as a promising mechanism. In this process, TH clears intrahepatic fat through lipophagy while protecting against inflammation and mitochondrial damage in hepatocytes via mitophagy. Furthermore, TH-induced aggrephagy may represent a protective mechanism to mitigate the development of MASLD-associated hepatocellular carcinoma. Considering the defects in autophagy observed during the progression of human MASLD, the induction of autophagy by TH, its metabolites, and its analogs represent a novel strategy to combat hepatic damage across the MASLD spectrum.

The pharmacotherapy of metabolic dysfunction‐associated steatotic liver disease (MASLD) and its progressive form, the metabolic dysfunction‐associated steatohepatitis (MASH), remains a hot topic in research and a largely unmet need in clinical practice. As the first approval of a disease‐specific drug, resmetirom, was regarded as a milestone for the management of this common liver disease, this comprehensive and updated review aimed to highlight the importance of the hepatic thyroid hormone (TH) receptor (THR)‐β signalling for the treatment of MASH, with a special focus on resmetirom. First, the genomic and non‐genomic actions of the liver‐directed THR‐β mediated mechanisms are summarized. THR‐β has a key role in hepatic lipid and carbohydrate metabolism; disruption of THR‐β signalling leads to dysmetabolism, thus promoting MASLD and possibly its progression to MASH and cirrhosis. In the clinical setting, this is translated into a significant association between primary hypothyroidism and MASLD, as confirmed by recent meta‐analyses. An association between MASLD and subclinical intrahepatic hypothyroidism (i.e. a state of relatively low hepatic triiodothyronine concentrations, with circulating TH concentrations within the normal range) is also emerging and under investigation. In line with this, the favourable results of the phase 3 placebo‐controlled MAESTRO trials led to the recent conditional approval of resmetirom by the US FDA for treating adults with MASH and moderate‐to‐advanced fibrosis. This conditional approval of resmetirom opened a new window to the management of this common and burdensome liver disease, thus bringing the global scientific community in front of new perspectives and challenges. [ABSTRACT FROM AUTHOR]

Introduction: Studies have compared the group-averages of liver stiffness measures (LSMs) from multiple rib spaces by vibration-controlled transient elastography (VCTE) to stage liver fibrosis. No previous study has assessed within-individual liver stiffness variation from two rib spaces in individuals with metabolic-dysfunction associated steatotic liver disease (MASLD). Methods: We evaluated within-individual LSM variation according to body weight classification and its clinical implication. From October 2019 to March 2024, VCTE was performed on MASLD patients or those at high risk, in accordance with FibroScan guidelines. The LSMs were categorized into stages: <5 kPa (stage 0), 5–7.99 kPa (stage 1), 8–9.99 kPa (stage 2), 10–13.99 kPa (stage 3), and 14+ kPa (stage 4). Measurements with 10 values and IQR/median ≤ 0.30 were included, using SPSS V25.0 for analysis. Results: Among 1107 subjects (age 54.4 ± 13.9 years, 56.9% female), 7.7% were normal weight, 20.7% overweight, 28.9% class 1 obesity, 21.3% class 2 obesity, and 21.2% class 3 obesity. Significant within-individual variation was noted: 67% (0–2 kPa) variation, 23.4% (2.1–6 kPa), and 10% (≥6.1 kPa). Class 3 obese individuals had the maximum variation. Comparing the group-average of LSM at each ICS site showed that 95% of individuals were within one fibrosis stage. Conclusions: While LSM group-averages at different rib sites provides reliable fibrosis staging, significant within-individual variability exists especially in class 3 obesity. This should be considered when serial LSM assessments are used to assess medical therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Introduction: As of March 2024, resmetirom is the first and only therapy approved in the United States (US) for the treatment of adults with non-cirrhotic nonalcoholic steatohepatitis (NASH) with moderate-to-advanced liver fibrosis (MALF) consistent with stages F2/F3 fibrosis. Estimates of the diagnosed, treatment-eligible NASH population are poorly understood due to diagnostic variability. This study provides a contemporary estimate of the size of the US resmetirom treatment-eligible population. Methods: A dynamic population calculator was developed combining literature, screening guidelines, resmetirom study criteria, and analyses of the NHANES 2017–March 2020 cycle. It computes NASH prevalence, proportion non-cirrhotic NASH with MALF, Year 1 diagnosis, and new diagnoses in Years 2 and 3. NASH prevalence was estimated by applying the American Association of Clinical Endocrinology screening algorithm and recommended NIT cut-offs in the NHANES dataset. The proportion of non-cirrhotic NASH with MALF was informed by analyses of the Forian US integrated medical claims database using NASH and cirrhosis-specific ICD-10-CM codes and FIB-4 scores. NASH diagnosis rates were obtained from published estimates and NHANES responses. Treatment-eligible population growth was projected using published incidence data. Estimates were compared to a NASH budget-impact-analysis (BIA) from the Institute for Clinical and Economic Review (ICER). Results: In the base case, a NASH prevalence of 4.6% was modeled (range 1.3–14.2%). This value was multiplied by the proportion estimated to have non-cirrhotic MALF (i.e., 35%). Published analyses suggest a diagnosis rate of ~ 10% (range 3.3–14.3%) and ~ 16% year-over-year growth in the treatment-eligible population. Assuming a 1-million commercial-member population, the resmetirom treatment-eligible population was estimated as 1255–1699 in Years 1–3 following approval. Sensitivity analyses were conducted and comparison to the ICER BIA was influenced by different diagnosis rates. Conclusion: Estimation of the treatment-eligible population for resmetirom depends importantly on NASH diagnosis rates, which are predicted to be < 15% in the 3 years after drug approval. Plain Language Summary: Nonalcoholic steatohepatitis (NASH) is an advanced form of nonalcoholic fatty liver disease. Previously there were no treatments for NASH in the United States (US), but as of March 2024, the US Food and Drug Administration (FDA) approved resmetirom (REZDIFFRA™), a once-daily, oral therapy, in conjunction with diet and exercise, under accelerated approval for the treatment of adults (aged 18 years or older) with non-cirrhotic NASH with moderate-to-advanced liver fibrosis (MALF), consistent with stages F2–F3. It is not well understood how many diagnosed patients with NASH would be eligible for treatment with resmetirom; thus, this study aimed to estimate the size of the US resmetirom treatment-eligible population. To do so, we created a flexible population calculator that considers how many people have NASH, what proportion would be eligible for resmetirom treatment—i.e., have non-cirrhotic NASH with MALF—and of those how many people would be diagnosed. We used published literature, screening guidelines, resmetirom study criteria, and analyses of national surveys to inform our range of estimates. In the main analysis, we modeled a NASH prevalence of 4.6% (range 1.3–14.2%), which was then limited to the proportion estimated to have non-cirrhotic NASH with MALF (i.e., 35%) and diagnosed (i.e., 10%, range 3.3–14.3%). A year-over-year growth of approximately 16% in the treatment-eligible population was modeled in years following approval. Assuming a population of 1 million commercial insurance enrollees, the resmetirom treatment-eligible population was estimated to be 1255–1699 in Years 1–3 following approval. We assessed alternative scenarios and have compared our results to existing models. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL–EASD–EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as the fibrosis-4 index [FIB-4]) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification—including weight loss, dietary changes, physical exercise and discouraging alcohol consumption—as well as optimal management of comorbidities—including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for type 2 diabetes or obesity, if indicated—is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis. [ABSTRACT FROM AUTHOR]

Background and Aim: Metabolic dysfunction‐associated steatohepatitis (MASH) is a metabolic disorder with limited treatment options. The thyroid hormone receptor (THR)‐β agonist resmetirom/MGL‐3196 (MGL) increases liver fat oxidation and has been approved for treating adult MASH. However, over 60% of patients receiving MGL treatment do not achieve MASH resolution. Therefore, we investigated the potential for combination therapy of MGL with the mitochondrial uncoupler BAM15 to improve fatty liver disease outcomes in the GAN mouse model of MASH. Methods: C57BL/6J male mice were fed GAN diet for 38 weeks before stratification and randomization to treatments including MGL, BAM15, MGL + BAM15, or no drug control for 8 weeks. Treatments were admixed in diet and mice were pair‐fed to control for drug intake. Treatment effectiveness was assessed by body weight, body composition, energy expenditure, glucose tolerance, tissue lipid content, and histological analyses. Results: MGL + BAM15 treatment resulted in better efficacy versus GAN control mice than either monotherapy in the context of energy expenditure, liver fat loss, glucose control, and fatty liver disease activity score. Improvements in ALT, liver mass, and plasma cholesterol were primarily driven by MGL, while improvements in body fat were primarily driven by BAM15. No treatments altered liver fibrosis. Conclusions: MGL + BAM15 treatment had overall better efficacy to improve metabolic outcomes in mice fed GAN diet than either monotherapy alone. These data warrant further investigation into combination therapies of THR‐β agonists and mitochondrial uncouplers for the potential treatment of disorders related to fatty liver, obesity, and insulin resistance. [ABSTRACT FROM AUTHOR]

The influence of thyroid hormone (TH) on liver metabolism has attracted the attention of pharmacologists seeking new treatments for metabolic dysfunction-associated steatotic liver disease (MASLD), an increasingly common metabolic disorder. In this context, the selective induction of autophagy by TH in preclinical models has been identified as a promising mechanism. In this process, TH clears intrahepatic fat through lipophagy while protecting against inflammation and mitochondrial damage in hepatocytes via mitophagy. Furthermore, TH-induced aggrephagy may represent a protective mechanism to mitigate the development of MASLD-associated hepatocellular carcinoma. Considering the defects in autophagy observed during the progression of human MASLD, the induction of autophagy by TH, its metabolites, and its analogs represent a novel strategy to combat hepatic damage across the MASLD spectrum. [ABSTRACT FROM AUTHOR]

Background and Aim: The role of Resmetirom in non‐alcoholic steatohepatitis (NASH) represents a promising therapeutic approach in addressing the growing global burden of liver disease. With NASH emerging as a leading cause of liver‐related morbidity and mortality worldwide, there is an urgent need for effective treatments. Resmetirom, a selective thyroid hormone receptor‐β agonist, offers potential benefits in improving liver histology and metabolic parameters in patients with NASH. This review examines the current evidence surrounding Resmetirom's role in NASH management. Methods: A systematic review and meta‐analysis was done by searching in Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE (including MEDLINE InProcess) (OvidSP), Web of Science, Embase (OvidSP), and Scopus databases. ROB2 Cochrane tool was used for assessing risk of bias in randomized controlled trials (RCTs). In the analysis, we used RevMan Cochrane software. Results: The study showed that patients who were treated with Resmetirom had significantly lower low‐density lipoprotein‐cholesterol (LDL‐C) levels (mean difference [MD] −10.45; 95% confidence interval [CI] −15.86 to −5.83; P < 0.001) and alanine aminotransferase (ALT) levels (MD −7.18; 95% CI −12.67 to −1.68; P = 0.01) as compared with those in the placebo group. The risk of adverse events including diarrhea [risk ratio (RR) 1.81; 95% CI 1.40 to 2.35; P < 0.001] and nausea (RR 1.72; 95% CI 1.31 to 2.27; P < 0.001) was significantly increased for the Resmetirom group as compared with the placebo group. Conclusion: Resmetirom presents a promising therapeutic option for NASH, offering potential benefits in reducing liver fat content and improving histological outcomes. The encouraging results from clinical trials suggest that Resmetirom may address an unmet need in NASH management, providing hope for patients with this progressive liver disease. Further research and long‐term studies are warranted to validate its efficacy and safety profile in larger patient populations. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic-Dysfunction Associated Steatohepatitis (MASH) are linked to obesity, type 2 diabetes, and metabolic syndrome, increasing liver-related morbidity and cardiovascular risk. Recent therapies, including Resmetirom, FGF21 analogs, and GLP-1 agonists, have shown promise. This network meta-analysis evaluates their comparative efficacy and safety. Methods: A literature search was conducted across PubMed, Scopus, Web of Science, and Cochrane Library. Included clinical trials addressed MASLD or MASH with Resmetirom, FGF21 analogs, or GLP-1 agonists. Statistical analyses used a random-effects model, calculating mean differences (MD) and relative risks (RR), with heterogeneity assessed using τ2, I2, and Q statistics. Results: MASH resolution was significantly higher for FGF21 (RR 4.84, 95% CI: 2.59 to 9.03), Resmetirom showed the most significant reduction in MRI-PDFF (MD −18.41, 95% CI: −23.60 to −13.22) and >30% fat reduction (RR 3.56, 95% CI: 2.41 to 5.26). Resmetirom significantly reduced ALT (MD −15.71, 95% CI: −23.30 to −8.13), AST (MD −12.28, 95% CI: −21.07 to −3.49), and GGT (MD −19.56, 95% CI: −34.68 to −4.44). FGF21 and GLP-1 also reduced these markers. Adverse events were significantly higher with Resmetirom (RR 1.47, 95% CI: 1.24 to 1.74), while GLP-1 and FGF21 showed non-significant trends towards increased risk. Conclusions: Resmetirom and FGF21 show promise in treating MASLD and MASH, with Resmetirom particularly effective in reducing liver fat and improving liver enzymes. GLP-1 agonists also show benefits but to a lesser extent. Further long-term studies are needed to validate these findings and assess cost-effectiveness. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Non‐Alcoholic Steatohepatitis (NASH), a severe form of Non‐Alcoholic Fatty Liver Disease (NAFLD), is characterized by inflammation and fibrosis in the liver, often progressing to cirrhosis and hepatocellular carcinoma. Despite its rising prevalence and significant disease burden, effective pharmacological treatments have been limited to lifestyle modifications and surgical interventions. Recently, resmetirom, a thyroid hormone receptor‐β agonist, received FDA approval for treating NASH, offering new hope to patients. This review explores the current understanding of NASH and the role of resmetirom as a breakthrough therapeutic option. Methods This study is a comprehensive literature review analyzing peer‐reviewed articles, clinical trial data, and public health reports. No original analyses were conducted, and no statistical software was utilized in this review. Results Resmetirom demonstrated efficacy in resolving NASH without fibrosis progression and improving fibrosis scores in patients with biopsy‐confirmed NASH. In a randomized Phase 3 trial, significant histological improvements were observed in 25.9% and 29.9% of patients receiving 80 and 100 mg doses, respectively, compared to 9.7% in the placebo group. Similar trends were noted in fibrosis improvement, with 24.2% and 25.9% of patients showing ≥ 1 stage improvement compared to 14.2% in the placebo group. Adverse effects, including nausea and diarrhea, were reported more frequently in the treatment groups, but the rates of serious adverse events were comparable across groups. Conclusion The approval of resmetirom marks a significant advancement in the treatment of NASH, addressing the limitations of lifestyle‐based interventions. As the obesity epidemic drives the increasing prevalence of NASH, resmetirom provides a promising therapeutic option, paving the way for improved patient outcomes and future research.

DBI/ACBP is a phylogenetically ancient hormone that stimulates appetite and lipo-anabolism. In response to starvation, DBI/ACBP is secreted through a noncanonical, macroautophagy/autophagy-dependent pathway. The physiological hunger reflex involves starvation-induced secretion of DBI/ACBP from multiple cell types. DBI/ACBP concentrations subsequently increase in extracellular fluids to stimulate food intake. Recently, we observed that glucocorticoids, which are endogenous stress hormones as well as anti-inflammatory drugs, upregulate DBI/ACBP expression at the transcriptional level and stimulate autophagy in hepatocytes, thereby causing a surge in circulating DBI/ACBP levels. Prolonged increase in glucocorticoid concentrations causes an extreme form of metabolic syndrome, dubbed "Cushing syndrome", which is characterized by clinical features including hyperphagia, hyperdipsia, dyslipidemia, hyperinsulinemia, insulin resistance, lipodystrophy, visceral adiposity, steatosis, sarcopenia and osteoporosis. Mice and patients with Cushing syndrome exhibit supraphysiological DBI/ACBP plasma levels. Of note, neutralization of extracellular DBI/ACBP protein with antibodies or mutation of the DBI/ACBP receptor (i.e. the GABRG2 subunit of GABR [gamma-aminobutyric acid type A receptor]) renders mice resistant to the induction of Cushing syndrome. Similarly, knockout of Dbi/Acbp in hepatocytes suppresses the corticotherapy-induced surge in plasma DBI/ACBP concentrations and prevents the manifestation of most of the characteristics of Cushing syndrome. We conclude that autophagy-mediated secretion of DBI/ACBP by hepatocytes constitutes a critical step of the pathomechanism of Cushing syndrome. It is tempting to speculate that stress-induced chronic elevations of endogenous glucocorticoids also compromise human health due to the protracted augmentation of circulating DBI/ACBP concentrations. Abbreviations: DBI/ACBP: diazepam binding inhibitor, acyl-CoA binding protein; GABA: gamma-aminobutyric acid; GABAR: gamma-aminobutyric acid type A receptor; GABRG2: gamma-aminobutyric acid type A receptor subunit gamma2. [ABSTRACT FROM AUTHOR]

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important public health problem owing to its high prevalence and associated morbidity and mortality secondary to progressive liver disease and cardiovascular events. Resmetirom, a selective thyroid hormone receptor-β agonist has been developed as a therapeutic modality for MASLD. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of resmetirom compared to a placebo in the treatment of MASLD. Eligible studies were systematically identified by screening PubMed, Scopus, Web of Science, Cochrane library, Embase, and ClinicalTrials.gov from 2014 to 2024. Only randomized controlled trials comparing the efficacy and safety of resmetirom in the treatment of MASLD against placebo were included in the analysis. Meta-analysis was performed using RevMan 5.4 software. Four studies with low risk of bias and involving a total of 2359 participants were identified. The metanalysis included only three clinical trials with 2234 participants. A significant reduction in MRI-proton density fat fraction (MRI-PDFF) with 80 mg Resmetirom compared to that with placebo [SMD − 27.74 (95% CI − 32.05 to − 32.42), p

On March 14, 2024, after more than 25 years of intense research and a long series of failures, the Food and Drug Administration approved resmetirom as first drug for the treatment of non-alcoholic steatohepatitis (NASH) with fibrosis (now Metabolic-Associated Steatotic Liver Disease – MASLD). The present review covers this difficult process, finally providing a drug to complement lifestyle intervention, that has long been the sole approved therapeutic intervention. However, the availability of a drug shown to reduce disease progression in advanced stages of diseases opens a series of questions that deserve even more intense research. How to continue ongoing trials? How to generate an appropriate use of resmetirom in the community, limiting treatment according to predefined criteria and according to individual risk assessment? How to guarantee that both hepatic and non-hepatic comorbidities are appropriately targeted? How to define cost-effective strategies that might prevent the generation of unacceptable differences within the population, given the high costs of novel drugs and the extremely high numbers of candidates to treatment? Only a close surveillance of drug use in the real world, generated by insurance databases and national healthcare system registries, might provide adequate answers to these compelling questions. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important public health problem owing to its high prevalence and associated morbidity and mortality secondary to progressive liver disease and cardiovascular events. Resmetirom, a selective thyroid hormone receptor-β agonist has been developed as a therapeutic modality for MASLD. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of resmetirom compared to a placebo in the treatment of MASLD. Eligible studies were systematically identified by screening PubMed, Scopus, Web of Science, Cochrane library, Embase, and ClinicalTrials.gov from 2014 to 2024. Only randomized controlled trials comparing the efficacy and safety of resmetirom in the treatment of MASLD against placebo were included in the analysis. Meta-analysis was performed using RevMan 5.4 software. Four studies with low risk of bias and involving a total of 2359 participants were identified. The metanalysis included only three clinical trials with 2234 participants. A significant reduction in MRI-proton density fat fraction (MRI-PDFF) with 80 mg Resmetirom compared to that with placebo [SMD − 27.74 (95% CI − 32.05 to − 32.42), p < 0.00001] at 36–52 weeks as well as at 12–16 weeks [SMD − 30.92 (95% CI − 36.44 to − 25.40), p < 0.00001]. With Resmetirom 100 mg dose at 36–52 weeks [SMD − 36.05 (95% CI − 40.67 to − 31.43), p < 0.00001] and 12–16 weeks [SMD − 36.89 (95% CI − 40.73 to − 33.05), p < 0.00001] were observed. Resmetirom treatment was associated with a significant reduction in LDL-c triglyceride, lipoproteins. and liver enzymes. There was significant reduction FT4 and increase in SHBG and sex steroids with Resmetirom compared to placebo. There was no major difference in the overall treatment emergent adverse events at 80 mg [OR 1.55 (95% CI 0.84 to 2.87), and 100 mg [OR 1.13 (95% CI 0.78 to 1.63), doses of Resmetirom compared to placebo. However, gastrointestinal adverse events diarrhoea and nausea occurred in ≥ 10% in the Resmetirom group compared to placebo at < 12 week. Resmetirom treatment showed modest efficacy in treating MASLD with reduction in MRI-PDFF, LDL-c, triglyceride, lipoproteins, liver enzymes and NASH biomarkers without significant safety concerns. Larger and long-term RCTs may further confirm this promising outcomes of Resmetirom use in MASLD. [ABSTRACT FROM AUTHOR]

Affecting approximately 25% of the global population, steatotic liver disease (SLD) poses a significant health concern. SLD ranges from simple steatosis to metabolic dysfunction-associated steatohepatitis and fibrosis with a risk of severe liver complications such as cirrhosis and hepatocellular carcinoma. SLD is associated with obesity, atherogenic dyslipidaemia, and insulin resistance, increasing cardiovascular risks. As such, identifying SLD is vital for cardiovascular disease (CVD) prevention and treatment. Bile acids (BAs) have critical roles in lipid digestion and are signalling molecules regulating glucose and lipid metabolism and influencing gut microbiota balance. BAs have been identified as critical mediators in cardiovascular health, influencing vascular tone, cholesterol homeostasis, and inflammatory responses. The cardio-protective or harmful effects of BAs depend on their concentration and composition in circulation. The effects of certain BAs occur through the activation of a group of receptors, which reduce atherosclerosis and modulate cardiac functions. Thus, manipulating BA receptors could offer new avenues for treating not only liver diseases but also CVDs linked to metabolic dysfunctions. In conclusion, this review discusses the intricate interplay between BAs, metabolic pathways, and hepatic and extrahepatic diseases. We also highlight the necessity for further research to improve our understanding of how modifying BA characteristics affects or ameliorates disease. [ABSTRACT FROM AUTHOR]

Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in liver fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident and non-resident heterogeneous liver cell populations, ultimately leading to deposition of extracellular matrix and organ failure. Shifts in cell phenotypes and functions involve pronounced transcriptional and protein synthesis changes that require metabolic adaptations in cellular substrate metabolism, including glucose and lipid metabolism, resembling changes associated with the Warburg effect in cancer cells. Cell activation and metabolic changes are regulated by metabolic stress responses, including the unfolded protein response, endoplasmic reticulum stress, autophagy, ferroptosis, and nuclear receptor signaling. These metabolic adaptations are crucial for inflammatory and fibrogenic activation of macrophages, lymphoid cells, and hepatic stellate cells. Modulation of these pathways, therefore, offers opportunities for novel therapeutic approaches to halt or even reverse liver fibrosis progression. Horn and Tacke review how cellular adaptations in substrate metabolism, metabolic stress responses, and nuclear receptor signaling shape inflammatory and fibrogenic cell states in liver fibrosis. Our increasing understanding provides promising therapeutic avenues to halt or reverse liver disease progression. [ABSTRACT FROM AUTHOR]

Introduction: Studies have compared the group-averages of liver stiffness measures (LSMs) from multiple rib spaces by vibration-controlled transient elastography (VCTE) to stage liver fibrosis. No previous study has assessed within-individual liver stiffness variation from two rib spaces in individuals with metabolic-dysfunction associated steatotic liver disease (MASLD). Methods: We evaluated within-individual LSM variation according to body weight classification and its clinical implication. From October 2019 to March 2024, VCTE was performed on MASLD patients or those at high risk, in accordance with FibroScan guidelines. The LSMs were categorized into stages:

Introduction: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic-Dysfunction Associated Steatohepatitis (MASH) are linked to obesity, type 2 diabetes, and metabolic syndrome, increasing liver-related morbidity and cardiovascular risk. Recent therapies, including Resmetirom, FGF21 analogs, and GLP-1 agonists, have shown promise. This network meta-analysis evaluates their comparative efficacy and safety. Methods: A literature search was conducted across PubMed, Scopus, Web of Science, and Cochrane Library. Included clinical trials addressed MASLD or MASH with Resmetirom, FGF21 analogs, or GLP-1 agonists. Statistical analyses used a random-effects model, calculating mean differences (MD) and relative risks (RR), with heterogeneity assessed using τ2, I2, and Q statistics. Results: MASH resolution was significantly higher for FGF21 (RR 4.84, 95% CI: 2.59 to 9.03), Resmetirom showed the most significant reduction in MRI-PDFF (MD −18.41, 95% CI: −23.60 to −13.22) and >30% fat reduction (RR 3.56, 95% CI: 2.41 to 5.26). Resmetirom significantly reduced ALT (MD −15.71, 95% CI: −23.30 to −8.13), AST (MD −12.28, 95% CI: −21.07 to −3.49), and GGT (MD −19.56, 95% CI: −34.68 to −4.44). FGF21 and GLP-1 also reduced these markers. Adverse events were significantly higher with Resmetirom (RR 1.47, 95% CI: 1.24 to 1.74), while GLP-1 and FGF21 showed non-significant trends towards increased risk. Conclusions: Resmetirom and FGF21 show promise in treating MASLD and MASH, with Resmetirom particularly effective in reducing liver fat and improving liver enzymes. GLP-1 agonists also show benefits but to a lesser extent. Further long-term studies are needed to validate these findings and assess cost-effectiveness.

Thyroid hormones (THs) have a salutary metabolic effect but exert negative effects on the cardiovascular system and other extrahepatic tissues when used in euthyroid individuals. For targeting metabolic diseases, TH analogs with thyroid receptor ß selectivity and increased hepatic exposure have been designed. Several of these agents have shown possibility of benefit in nonalcoholic fatty liver disease and dyslipidemia with resmetirom being the most promising of the lot. In addition, the hepatomitogenic and neurotrophic role of thyromimetics is also promising. This narrative review looks back at the evidence that exists with these agents and also looks at their probable role in future. [ABSTRACT FROM AUTHOR]

Aims: This study assessed the budget impact of resmetirom as a treatment for adults with non-cirrhotic non-alcoholic steatohepatitis (NASH) with moderate-to-advanced liver fibrosis and estimated total costs for a hypothetical private payer in the United States. Materials and methods: A three-year budget impact analysis based on an open cohort state transition model was developed for a hypothetical one-million-member private health plan. The comparator was Standard of Care (SOC), defined as routine care for non-cirrhotic NASH patients with moderate-to-advanced liver fibrosis. Each year, the number of resmetirom treatment-eligible patients was estimated through prevalent, incident, and diagnostic rate estimates. Costs included resources incurred by the medical and pharmacy benefits of private payers, including resmetirom drug acquisition costs, diagnosis and monitoring, other medical and other prescription costs stratified by disease progression status (i.e. non-cirrhotic vs. cirrhotic/advanced liver diseases). Resmetirom adverse event management costs were included in sensitivity analysis. Drug costs were estimated based on the average wholesale acquisition cost as of March 2024. Other costs were based on published sources and inflated to 2023 US dollars. Budget impact outcomes were presented in aggregate, net, and on a per-member per-month (PMPM) basis. Results: Compared with a scenario without resmetirom, the introduction of resmetirom yielded results ranging from 50 to 238 treated patients, net budget impact of $2.2 to $9.5 million, and PMPM from $0.19 to $0.80 over years one and three. Net costs excluding resmetirom declined over time. In sensitivity analyses, results were most sensitive to diagnostic and epidemiologic inputs. Limitations: Market shares are based on internal forecasts, a short time horizon, average treatment effects, and other limitations common to BIMs. Conclusion: The adoption of resmetirom on the formulary for the treatment of non-cirrhotic NASH with moderate-to-advanced liver fibrosis resulted in a moderate increase in budget impact with declining costs related to NASH progression. PLAIN LANGUAGE SUMMARY: Non-alcoholic steatohepatitis (NASH) is a serious liver disease that can lead to significant liver damage, other health complications, and increased healthcare costs. As the disease progresses, patients typically experience worsening health outcomes. Until recently, there were no Food and Drug Administration (FDA) approved treatments for NASH in the United States. However, in March 2024, the FDA approved REZDIFFRA, a new drug specifically designed to treat NASH patients with moderate-to-advanced liver fibrosis (i.e. NASH with moderate-to-advanced scarring of the liver). Clinical trials have shown that REZDIFFRA can improve health outcomes in these patients. To identify patients who could benefit from REZDIFFRA and to estimate the associated costs, we developed a budget impact model. In this study, we detail the development of this model and present its findings. Our analysis revealed that, while REZDIFFRA is associated with higher overall costs, primarily due to the price of the drug itself, there are potential cost savings when considering the drug's ability to slow disease progression. [ABSTRACT FROM AUTHOR]

In the present narrative review, we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD). We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes. We then discuss how randomized–controlled trials are performed following guidance from regulatory agencies, including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency. Difficulties and hurdles related to limitations of liver biopsy, a large number of screening failures in recruiting patients, as well as unpredictable response rates in the placebo group are evaluated. Finally, we recapitulate the strategies employed for potential drug treatments of this orphan condition. The first is to repurpose drugs that originally targeted T2DM and/or obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide), multi-agonists (tirzepatide and retatrutide), and sodium-glucose transporter 2 inhibitors. The second is to develop drugs specifically targeting NAFLD/MASLD. Among those, we focused on resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, as they are currently in Phase 3 of their clinical trial development. While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past, it is likely that approval of the first treatments is near. As occurs in many chronic conditions, combination therapy might lead to better outcomes. In the case of non-alcoholic steatohepatitis, we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease, while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis. [ABSTRACT FROM AUTHOR]

Resmetirom, a liver-directed, orally active agonist of THR-β, could play a favorable role in treating NASH, but little is known about the underlying mechanism. A NASH cell model was established to test the preventive effect of resmetirom on this disease in vitro. RNA-seq was used for screening, and rescue experiments were performed to validate the target gene of the drug. A NASH mouse model was used to further elucidate the role and the underlying mechanism of resmetirom. Resmetirom effectively eliminated lipid accumulation and decreased triglyceride (TG) levels. In addition, repressed RGS5 in the NASH model could be recovered by resmetirom treatment. The silencing of RGS5 effectively impaired the role of resmetirom. In the NASH mouse model, obvious gray hepatization, liver fibrosis and inflammation, and increased macrophage infiltration were observed in liver tissues, while resmetirom almost returned them to normal conditions as observed in the control group. Pathological experimental data also confirmed that resmetirom has great potential in NASH treatment. Finally, RGS5 expression was suppressed in the NASH mouse model, but it was upregulated by resmetirom treatment, while the STAT3 and NF-κB signaling pathways were activated in NASH but inhibited by the agent. Resmetirom could improve NASH by recovering RGS5 expression and subsequently inactivating the STAT3 and NF-κB signaling pathways. [ABSTRACT FROM AUTHOR]

Introduction: Thyroid hormone receptor b (THR-b) plays a critical role in metabolism regulation and has become an attractive target for treating lipid metabolism disorders in recent years. Thus, in this study, we discovered CS271011, a novel THR-b agonist, and assessed the safety and efficiency of CS271011 compared to MGL-3196 in vitro and in vivo. Methods: We conducted luciferase reporter gene assays to assess the activation of THR-b and a in vitro. C57BL/6J mice were fed a high-fat diet for 12 weeks, CS271011 was administered by gavage at the dose of 1 mg/kg and 3 mg/kg, and MGL-3196 was administered at the dose of 3mg/kg for 10weeks.Body weight, food intake, serum and hepatic parameters, histological analysis, pharmacokinetic studies, RNA sequencing of the liver and heart, and expression of hepatic lipid-metabolic genes were determined to evaluate the safety and efficiency of CS271011. Results: Compared with MGL-3196, CS271011 showed higher THR-b activation in vitro. In the diet-induced obesity mice model, CS271011 demonstrated favourable pharmacokinetic properties in mice and was enriched in the liver. Finally, CS271011 improved dyslipidaemia and reduced liver steatosis in the diet-induced obesity murine model. Mechanistically, CS271011 and MGL-3196 showed potent regulation of lipid metabolism-related genes. Conclusions: CS271011 is a potent and liver-targeted THR-b agonist for treating lipid metabolism disorders. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects an ever-increasing part of the global population, affecting millions of individuals worldwide. Despite the progress in the treatment of other liver diseases, there is a scarcity of liver-specific drugs targeting MASLD. In light of that, research has focused both on pipeline drugs targeting multiple different receptors implicated in the pathogenesis of the disease, as well as medications already approved for other indications, that might exert beneficial effects on MASLD. The fact that MASLD is associated with an increased prevalence of obesity and type 2 diabetes mellitus (T2DM) establishes a possible pathway with respect to already available pharmaceutical interventions for this group of patients, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT2-is). Thus, the hitherto at hand, along with the upcoming members of these families, provide much-needed options for our arsenal. This review attempts to explore old and novel dimensions of the pharmaceutical treatment of MASLD in the continuous effort of the medical society to improve patient outcomes., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2025, Koullias et al.)

IntroductionThyroid hormone receptor β (THR-β) plays a critical role in metabolism regulation and has become an attractive target for treating lipid metabolism disorders in recent years. Thus, in this study, we discovered CS271011, a novel THR-β agonist, and assessed the safety and efficiency of CS271011 compared to MGL-3196 in vitro and in vivo. MethodsWe conducted luciferase reporter gene assays to assess the activation of THR-β and α in vitro. C57BL/6J mice were fed a high-fat diet for 12 weeks, CS271011 was administered by gavage at the dose of 1 mg/kg and 3 mg/kg, and MGL-3196 was administered at the dose of 3 mg/kg for 10 weeks. Body weight, food intake, serum and hepatic parameters, histological analysis, pharmacokinetic studies, RNA sequencing of the liver and heart, and expression of hepatic lipid-metabolic genes were determined to evaluate the safety and efficiency of CS271011. ResultsCompared with MGL-3196, CS271011 showed higher THR-β activation in vitro. In the diet-induced obesity mice model, CS271011 demonstrated favourable pharmacokinetic properties in mice and was enriched in the liver. Finally, CS271011 improved dyslipidaemia and reduced liver steatosis in the diet-induced obesity murine model. Mechanistically, CS271011 and MGL-3196 showed potent regulation of lipid metabolism-related genes. ConclusionsCS271011 is a potent and liver-targeted THR-β agonist for treating lipid metabolism disorders.

Thyroid hormones (THs) and TH receptor-beta (TRβ) reduce hepatic triglycerides, indicating a therapeutic potential for TH analogs in liver steatosis. To avoid adverse extrahepatic, especially TRα-mediated effects such as tachycardia and bone loss, TH analogs with combined TRβ and hepatocyte specificity are desired. MGL-3196 is a new TH analog that supposedly meets these criteria. Here, we characterize the thyromimetic potential of MGL-3196 in cell-based assays and address its cellular uptake requirements. We studied the contribution of liver-specific organic anion transporters (OATP)1B1 and 1B3 to MGL-3196 action. The TR isoform-specific efficacy of MGL-3196 compared with 3,5,3′-triiodothyronine (T3) was determined with luciferase assays and gene expression analysis in OATP1B1 and OATP1B3 and TRα- or TRβ-expressing cells and in primary murine hepatocytes (PMHs) from wild-type and TRβ knockout mice. We measured the oxygen consumption rate to compare the effects of MGL-3196 and T3 on mitochondrial respiration. We identified OATP1B1 as the primary transporter for MGL-3196. MGL-3196 had a high efficacy (90% that of T3) in activating TRβ, while the activation of TRα was only 25%. The treatment of PMHs with T3 and MGL-3196 at EC50 resulted in a similar induction of Dio1 and repression of Serpina7. In HEK293 cells stably expressing OATP1B1, MGL-3196 had comparable effects on mitochondrial respiration as T3. These data indicate that MGL-3196's hepatic thyromimetic action, the basis for its therapeutic use, results from a combination of hepatocyte-specific transport by OATP1B1 and the selective activation of TRβ over TRα. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a worldwide rising challenge because of hepatic, but also extrahepatic, complications. Thyroid hormones are master regulators of energy and lipid homeostasis, and the presence of abnormal thyroid function in NAFLD suggests pathogenic relationships. Specifically, persons with hypothyroidism feature dyslipidemia and lower hepatic β-oxidation, which favors accumulation of triglycerides and lipotoxins, insulin resistance, and subsequently de novo lipogenesis. Recent studies indicate that liver-specific thyroid hormone receptor β agonists are effective for the treatment of NAFLD, likely due to improved lipid homeostasis and mitochondrial respiration, which, in turn, may contribute to a reduced risk of NAFLD progression. Taken together, the possible coexistence of thyroid disease and NAFLD calls for increased awareness and optimized strategies for mutual screening and management. Hypothyroidism is present in a significant proportion of people with nonalcoholic fatty liver disease (NAFLD) and may contribute to their higher all-cause as well as cardiovascular mortality. Accelerated hepatic de novo lipogenesis and adipose tissue-derived fatty acid flux to the liver with subsequent insulin resistance may contribute to this association. International guidelines recommend screening for liver disease in all adults with hypo- or hyperthyroidism and for thyroid disease in those with NAFLD. Novel selective thyroid hormone receptor β agonists have been developed to combat NAFLD, but possible extrahepatic effects need close monitoring. [ABSTRACT FROM AUTHOR]

Resmetirom is a thyroid hormone receptor agonist that has been recently approved by the FDA for the management of metabolic dysfunction-associated steatohepatitis (MASH). MASH is a severe form of metabolic dysfunction-associated fatty liver disease (MASLD), which is marked by hepatic inflammation and potential progression to cirrhosis and liver cancer. This review analyzes and demonstrates the efficacy of resmetirom in reducing intra-hepatic lipids, improving liver histology, and improving metabolic parameters. Key outcomes of this study indicate that resmetirom leads to non-alcoholic steatohepatitis (NASH) resolution and fibrosis improvement in a substantial percentage of patients. Although this drug has common gastrointestinal side effects, it maintains a favorable safety profile. With the increase in demand for treatments of MASH, the ongoing phase 3 trials will provide critical insights into the long-term efficacy and safety profile of resmetirom and further solidify its potential as a groundbreaking therapeutic option for the management of MASH., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Patel et al.)

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) associated with metabolic syndrome and increased cardiovascular risk. Resmetirom, a novel liver-directed selective thyroid hormone receptor-β (THR-β) agonist, has shown promise in addressing both hepatic and systemic lipid metabolism. This systematic review and meta-analysis aimed to evaluate the efficacy of resmetirom in improving cholesterol levels in NASH patients. A systematic literature search was conducted across multiple databases including PubMed, Embase, Cochrane Library, and ClinicalTrials.gov, identifying three randomized controlled trials for inclusion. The meta-analysis revealed that resmetirom significantly reduced low-density lipoprotein cholesterol (LDL-C) levels compared to placebo (MD: -23.62; 95% CI: -37.32 to -9.93; p < 0.001). Similarly, triglyceride (TG) levels showed a significant reduction in the resmetirom group (MD: -33.86; 95% CI: -47.79 to -19.92; p < 0.001). Importantly, there was no significant difference in the risk of serious adverse events between resmetirom and placebo groups (RR: 1.09; 95% CI: 0.73 to 1.63; p = 0.67). These findings suggest that resmetirom effectively improves lipid profiles in NASH patients without compromising safety. However, the analysis was limited by the small number of studies, all from the same research group, and high heterogeneity in results. Future research should include more diverse studies, longer follow-up periods, and cost-effectiveness evaluations. Despite these limitations, resmetirom shows promise as a potential treatment for managing dyslipidemia and cardiovascular risk in NASH patients, potentially influencing future treatment guidelines for both liver and cardiovascular health in this population., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Bejitual et al.)

Background and Purpose: Activation of hepatic thyroid hormone receptor β (THR-β) is associated with systemic lipid lowering, increased bile acid synthesis, and fat oxidation. In patients with non-alcoholic steatohepatitis (NASH), treatment with THR-β agonists decreased hepatic steatosis and circulating lipids, and induced resolution of NASH. We chose resmetirom (MGL-3196), a liver-directed, selective THR-β agonist, as a prototype to investigate the effects of THR-β activation in mice with diet-induced obesity (DIO) and biopsy-confirmed advanced NASH with fibrosis.Experimental Approach: C57Bl/6J mice were fed a diet high in fat, fructose, and cholesterol for 34 weeks, and only biopsy-confirmed DIO-NASH mice with fibrosis were included. Resmetirom was administered at a daily dose of 3 mg·kg-1 p.o., for 8 weeks. Systemic and hepatic metabolic parameters, histological non-alcoholic fatty liver disease (NAFLD) activity and fibrosis scores, and liver RNA expression profiles were determined to assess the effect of THR-β activation.Key Results: Treatment with resmetirom did not influence body weight but led to significant reduction in liver weight, hepatic steatosis, plasma alanine aminotransferase activity, liver and plasma cholesterol, and blood glucose. These metabolic effects translated into significant improvement in NAFLD activity score. Moreover, a lower content of α-smooth muscle actin and down-regulation of genes involved in fibrogenesis indicated a decrease in hepatic fibrosis.Conclusion and Implications: Our model robustly reflected clinical observations of body weight-independent improvements in systemic and hepatic metabolism including anti-steatotic activity. [ABSTRACT FROM AUTHOR]

There has been a rise in the prevalence of non-alcoholic steatohepatitis (NASH), a subset of non-alcoholic fatty liver disease (NAFLD) with an ongoing increase in the prevalence of linked conditions such as obesity, type II diabetes mellitus, and metabolic syndrome. To date, there are no specific drugs that are approved for the treatment of NAFLD/NASH. With the recent discovery of association between subclinical hypothyroidism and NASH, various trials exploring treatment options for NASH using thyroid hormone derivatives led to the discovery of resmetirom (MGL-316) with high affinity to thyroid hormone receptors (THRs) targeting the liver. Following standardized guidelines, a systematic review was performed on the safety, efficacy, and other practical aspects of resmetirom in the treatment of NASH. Advanced search was carried out using the MeSH search strategy and appropriate keywords in major databases using various inclusion and exclusion criteria. The search was narrowed down to seven high-quality articles: four randomized control trials (RCTs), and three reviews to be included in the current study. The online database search yielded 62 articles, out of which six high-quality articles were selected to be included in the current systematic review after deleting duplicates and screening for irrelevant titles, and articles. Out of the three RCTs, two of them assessed the safety and efficacy of resmetirom, while the remaining RCT assessed the impact on health-related quality of life with resmetirom on patients with NASH. resmetirom (MGL-316) is a thyroid hormone derivative with high affinity to THRs targeting the liver and acts by improving mitochondrial oxidation, and lipophagy in the hepatic cell line. All the trials suggested in favor of resmetirom with a decrease in NASH fibrosis score by at least two points, along with reduction in hepatic fat content (minimum relative reduction of 20%), liver volume by 61%, improving secondary outcomes such as low-density lipoprotein-C, apolipoprotein-B, triglycerides, and hepatic enzymes with greater reduction in the study groups treated with higher doses of resmetirom with no significant increase in adverse events. Resmetirom was found to improve patient-reported outcomes, and thereby quality-adjusted life years (QALYs) in 12 weeks while being cost-effective compared to placebo at a willingness-to-pay threshold of US$100,000 up to a daily threshold of US$72.00, and an effective incremental cost-effectiveness ratio of US$53,925 per QALY gained. After carefully analyzing the available data by our team members, it could be concluded that resmetirom holds a strong potential to be implemented as a drug of choice in treating NAFLD/NASH in the coming years with proven efficacy, safety while being cost-effective, and also reducing secondary co-morbidities by improving cardiovascular risk factors. The results can be best achieved when combined with conventional approaches such as weight loss and dietary modifications. Long-term safety and sustainability of the achieved results are yet to be confirmed with large-scale clinical trials. However, resmetirom is still an investigational drug and could be expected to be available for clinical practice in the near future., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Bittla et al.)