Resmetirom, the first approved drug for the management of metabolic dysfunction-associated steatohepatitis: Trials, opportunities, and challenges

Over the past decade, there have been several guideline updates for the diagnosis and management of non-alcoholic fatty liver disease (NAFLD), which is the most common chronic liver disease affecting approximately one-third of the world's population [1Katsiki N. Gastaldelli A. Mikhailidis D.P. Predictive models with the use of omics and supervised machine learning to diagnose non-alcoholic fatty liver disease: a "non-invasive alternative" to liver biopsy?.Metabolism. 2019; : 101https://doi.org/10.1016/J.METABOL.2019.154010Abstract Full Text Full Text PDF PubMed Google Scholar, 2Polyzos S.A. Mantzoros C.S. Necessity for timely noninvasive diagnosis of nonalcoholic fatty liver disease.Metabolism. 2014; 63: 161-167https://doi.org/10.1016/J.METABOL.2013.10.010Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 3Kokkorakis M. Muzurović E. Volčanšek Š. Chakhtoura M. Hill M.A. Mikhailidis D.P. et al.Steatotic liver disease: pathophysiology and emerging pharmacotherapies.Pharmacol Rev. 2024; ([PHARMREV-AR-2023-001087])https://doi.org/10.1124/PHARMREV.123.001087Crossref Google Scholar]. These changes were necessitated by our evolving understanding of the disease, the name of which has also recently been changed from "NAFLD", resulting from a lack of mechanistic understanding, to metabolic dysfunction-associated steatotic liver disease (MASLD), and from non-alcoholic steatohepatitis (NASH) to metabolic dysfunction-associated steatohepatitis (MASH) [4Kokkorakis M. Boutari C. Katsiki N. Mantzoros C.S. From non-alcoholic fatty liver disease (NAFLD) to steatotic liver disease (SLD): an ongoing journey towards refining the terminology for this prevalent metabolic condition and unmet clinical need.Metabolism. 2023; 147155664https://doi.org/10.1016/J.METABOL.2023.155664Abstract Full Text Full Text PDF Google Scholar, 5Rinella M.E. Lazarus J.V. Ratziu V. Francque S.M. Sanyal A.J. Kanwal F. et al.A multisociety Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol. 2023; 79: 1542-1556https://doi.org/10.1016/j.jhep.2023.06.003Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 6Valenzuela-Vallejo L. Mantzoros C.S. Time to transition from a negative nomenclature describing what NAFLD is not, to a novel, pathophysiology-based, umbrella classification of fatty liver disease (FLD).Metabolism. 2022; : 134https://doi.org/10.1016/J.METABOL.2022.155246Abstract Full Text Full Text PDF Google Scholar]. To date, MASLD and MASH remain unmet clinical needs. Individuals who also have obesity and type 2 diabetes (T2D) are managed by promoting lifestyle modification, including interventions for weight loss, and by targeting any coexisting cardiometabolic conditions, i.e., obesity or T2D, and using incretin mimetics such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) or by treating T2D with an insulin sensitizer such as pioglitazone (Table 1) [[3]Kokkorakis M. Muzurović E. Volčanšek Š. Chakhtoura M. Hill M.A. Mikhailidis D.P. et al.Steatotic liver disease: pathophysiology and emerging pharmacotherapies.Pharmacol Rev. 2024; ([PHARMREV-AR-2023-001087])https://doi.org/10.1124/PHARMREV.123.001087Crossref Google Scholar]. With regard to GLP-1RAs, emerging evidence shows that this class of medications, which is available to treat both obesity and T2D, reverses steatohepatitis, reduces cardiovascular risk, and is safe to use across the spectrum of MASLD with or without fibrosis but, as it appears to date, GLP-1RAs are not associated with significant improvement or worsening of fibrosis (Table 1) [[7]Mantovani A. Petracca G. Beatrice G. Csermely A. Lonardo A. Targher G. Glucagon-like peptide-1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an updated meta-analysis of randomized controlled trials.Metabolites. 2021; 11: 73https://doi.org/10.3390/METABO11020073Crossref PubMed Scopus (0) Google Scholar]. For example, liraglutide, Food and Drug Administration (FDA)-approved for the treatment of obesity, led to the resolution of MASH in 39 % of patients compared to 9 % in controls [[8]Armstrong M.J. Gaunt P. Aithal G.P. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.Lancet. 2016; 387: 679-690https://doi.org/10.1016/S0140-6736(15)00803-XAbstract Full Text Full Text PDF PubMed Scopus (1323) Google Scholar]. The study was not sufficiently powered, however, to conclusively show whether the beneficial effect on the liver was independent of the effect on weight loss. Subsequently, other GLP-1RAs, including semaglutide, tirzepatide (a dual GLP-1/glucose-dependent insulinotropic polypeptide receptor co-agonist), and survodutide (a glucagon/GLP-1 receptor dual receptor agonist) were investigated [9Aggarwal S. Bansal S. Aggarwal G. Effects of semaglutide on metabolic syndrome parameters in non-diabetics: a meta-analysis of randomized controlled trials.Metabolism. 2023; 142155462https://doi.org/10.1016/j.metabol.2023.155462Abstract Full Text Full Text PDF Google Scholar, 10Alabduljabbar K. le Roux C.W. Pharmacotherapy before and after bariatric surgery.Metabolism. 2023; : 148https://doi.org/10.1016/j.metabol.2023.155692Abstract Full Text Full Text PDF Scopus (4) Google Scholar, 11Tsilingiris D. Kokkinos A. Advances in obesity pharmacotherapy; learning from metabolic surgery and beyond.Metab - Clin Exp. 2024; 151155741https://doi.org/10.1016/J.METABOL.2023.155741Abstract Full Text Full Text PDF PubMed Google Scholar, 12Chakhtoura M. Mantzoros C.S. Advances in physiology, design and development of novel medications changing the landscape of obesity pharmacotherapy.Metabolism. 2023; : 142https://doi.org/10.1016/J.METABOL.2023.155531Abstract Full Text Full Text PDF Google Scholar]. In particular, treatment with semaglutide resulted in MASH resolution without worsening of fibrosis (59 % vs 17 % on placebo, p < 0.0001). No significant impact was observed on the regression of fibrosis, as compared to the placebo arm [[13]Newsome P.N. Buchholtz K. Cusi K. Linder M. Okanoue T. Ratziu V. et al.A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.N Engl J Med. 2021; 384: 1113-1124https://doi.org/10.1056/NEJMOA2028395/SUPPL_FILE/NEJMOA2028395_DATA-SHARING.PDFCrossref PubMed Scopus (0) Google Scholar]. A large registrational phase 3 randomized controlled trial (RCT) with semaglutide is currently enrolling [NCT04822181]. Moreover, according to a recent release from Boehringer Ingelheim at the end of February 2024, survodutide was associated with MASH resolution without worsening fibrosis among 83 % of participants in a phase 2 RCT while also demonstrating improvements in fibrosis by at least one stage [NCT04771273]. Survodutide is also being evaluated in five phase 3 studies, with two studies exploring the relative change in liver fat from baseline to week 76 when treated with survodutide versus placebo as a key secondary endpoint [NCT06176365, NCT06214741]. Nevertheless, these agents do not appear to significantly impact plasma lipid parameters; for example, reduction in low-density lipoprotein (LDL) levels has been estimated to be limited to approximately −3.7 mg/dL [[14]Song X. Jia H. Jiang Y. Wang L. Zhang Y. Mu Y. et al.Anti-atherosclerotic effects of the glucagon-like peptide-1 (GLP-1) based therapies in patients with type 2 Diabetes Mellitus: a meta-analysis OPEN.2015https://doi.org/10.1038/srep10202Crossref Google Scholar].Table 1Management of steatotic liver disease as proposed by the authors based on the latest terminology and pharmacological updates.General advice for steatotic liver disease•Healthy lifestyle and >8–10 % weight loss, proceed with pharmacological or surgical intervention if desired body weight is not reached•Mediterranean diet and DASH•Control lipids, blood pressure, and other cardiometabolic risks•Monitor eGFR and albuminuria and manage chronic kidney disease as necessary F0-F1•Lifestyle modification F2-F3•Lifestyle modification•Consider therapy as shown in the table below•Refer to hepatologist•Consider resmetirom (conditional FDA approval)•Monitor annually for hepatic events and secondary cardiometabolic outcomes F4•Lifestyle modification•Cirrhosis-based management•Refer to hepatologistOff label therapiesType 2 diabetes mellitusNoYesObesityNoVitamin E 800 U/day•Control hyperglycemia•Pioglitazone 30–45 mg orally daily•GLP1-RA or GIP/GLP1-RA•SGLT2isYes•Vitamin E 800 U/day•GLP1-RA for obesity•SGLT2is•Bariatric surgery•Control hyperglycemia•Pioglitazone 30–45 mg orally daily•GLP1-RA or GIP/GLP1-RA•SGLT2isAbbreviations: DASH, Dietary Approaches to Stop Hypertension; eGFR, estimated glomerular filtration rate; F, fibrosis (stage); FDA, Food and Drug Administration; GIP, glucose-dependent insulinotropic polypeptide; GLP1-RA, glucagon-like peptide-1 receptor agonist; SGLT2is, sodium-glucose cotransporter 2 inhibitors. Open table in a new tab Abbreviations: DASH, Dietary Approaches to Stop Hypertension; eGFR, estimated glomerular filtration rate; F, fibrosis (stage); FDA, Food and Drug Administration; GIP, glucose-dependent insulinotropic polypeptide; GLP1-RA, glucagon-like peptide-1 receptor agonist; SGLT2is, sodium-glucose cotransporter 2 inhibitors. In parallel, there is growing interest in the efficacy of thyroid hormone-related treatment strategies on MASLD, given the association between thyroid dysregulation and the development of MASLD [15Labenz C. Kostev K. Armandi A. Galle P.R. Schattenberg J.M. Impact of thyroid disorders on the incidence of non-alcoholic fatty liver disease in Germany.United Eur Gastroenterol J. 2021; 9: 829-836https://doi.org/10.1002/UEG2.12124Crossref PubMed Scopus (0) Google Scholar, 16Negi C.K. Babica P. Bajard L. Bienertova-Vasku J. Tarantino G. Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease.Metab - Clin Exp. 2022; 126154925https://doi.org/10.1016/J.METABOL.2021.154925Abstract Full Text Full Text PDF PubMed Google Scholar, 17Kouvari M. Valenzuela-Vallejo L. Axarloglou E. Verrastro O. Papatheodoridis G. Mingrone G. et al.Thyroid function, adipokines and mitokines in metabolic dysfunction-associated steatohepatitis: a multi-centre biopsy-based observational study.Liver Int. 2024; : 44https://doi.org/10.1111/LIV.15847Crossref Google Scholar, 18Yan M. Man S. Ma L. Gao W. Comprehensive molecular mechanisms and clinical therapy in nonalcoholic steatohepatitis: an overview and current perspectives.Metabolism. 2022; : 134https://doi.org/10.1016/J.METABOL.2022.155264Abstract Full Text Full Text PDF Google Scholar]. Thyroid stimulating hormone (TSH) levels display a positive linear relationship with the risk of MASLD even in euthyroid subjects [[19]Bano A. Chaker L. Plompen E.P.C. Hofman A. Dehghan A. Franco O.H. et al.Thyroid function and the risk of nonalcoholic fatty liver disease: the Rotterdam Study.J Clin Endocrinol Metab. 2016; 101: 3204-3211https://doi.org/10.1210/JC.2016-1300Crossref PubMed Scopus (0) Google Scholar] and T3 and T4 levels have been associated with an increased incidence of advanced liver fibrosis in patients with biopsy-proven euthyroid MASLD [[20]Li R. Zhou L. Chen C. Han X. Gao M. Cheng X. Li J. Sensitivity to thyroid hormones is associated with advanced fibrosis in euthyroid patients with non-alcoholic fatty liver disease: a cross-sectional study.Dig Liver Dis. 2023; 55 (PMID: 35853822): 254-261https://doi.org/10.1016/j.dld.2022.06.021Abstract Full Text Full Text PDF Scopus (4) Google Scholar]. Thyroid hormones principally mediate their effects through two receptors, thyroid hormone receptor alpha (THR-α) and beta (THR-β). THR-β is the dominant receptor isoform in hepatocytes, which plays a critical role in lowering cholesterol and triglyceride levels, increasing bile acid synthesis, and fat oxidation (Fig. 1) [[21]Sinha R.A. Bruinstroop E. Singh B.K. Yen P.M. Nonalcoholic fatty liver disease and hypercholesterolemia: roles of thyroid hormones, metabolites, and agonists.Thyroid. 2019; 29: 1173-1191https://doi.org/10.1089/THY.2018.0664Crossref PubMed Scopus (0) Google Scholar]. Moreover, thyromimetics inhibit TSH secretion, causing a decreased production of the natural thyroid hormones [[22]Coppola M. Glinni D. Moreno M. Cioffi F. Silvestri E. Goglia F. Thyroid hormone analogues and derivatives: actions in fatty liver.World J Hepatol. 2014; 6: 114-129https://doi.org/10.4254/wjh.v6.i3.114Crossref PubMed Scopus (38) Google Scholar,[23]Angelin B. Rudling M. Lipid lowering with thyroid hormone and thyromimetics.Curr Opin Lipidol. 2010; 21: 499-506https://doi.org/10.1097/MOL.0b013e3283402e9cCrossref PubMed Scopus (60) Google Scholar]. For instance, treatment with resmetirom (MGL-3196), an orally active, liver-targeted compound, selectively activating THR-β decreased free T4 levels by almost 16–19 % without affecting thyrotropin levels or the active thyroid hormone, free triiodothyronine [[24]Harrison S.A. Bedossa P. Guy C.D. Schattenberg J.M. Loomba R. Taub R. et al.A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis.N Engl J Med. 2024; 390: 497-509https://doi.org/10.1056/NEJMOA2309000Crossref PubMed Scopus (0) Google Scholar]. As a result, thyromimetics downregulate thyroid hormone levels, but by acting in specific peripheral tissues, improve liver lipid metabolism and outcomes [[23]Angelin B. Rudling M. Lipid lowering with thyroid hormone and thyromimetics.Curr Opin Lipidol. 2010; 21: 499-506https://doi.org/10.1097/MOL.0b013e3283402e9cCrossref PubMed Scopus (60) Google Scholar]. Thus, THR-β agonists, whose mechanisms of action include stimulation of β-oxidation in liver mitochondria, reduced production and secretion of very low-density lipoprotein, free fatty acid (FFA) uptake and synthesis, as well as enhancing expression of the LDL receptor in the liver, have been a principal approach for drug development for the treatment of dyslipidemia, obesity, and hepatic steatosis (Fig. 1). Importantly, THR-β agonists show minimal effects on other tissues, that are observed with THR-α agonists [[23]Angelin B. Rudling M. Lipid lowering with thyroid hormone and thyromimetics.Curr Opin Lipidol. 2010; 21: 499-506https://doi.org/10.1097/MOL.0b013e3283402e9cCrossref PubMed Scopus (60) Google Scholar,[25]Freitas F.R.S. Moriscot A.S. Jorgetti V. Soares A.G. Passarelli M. Scanlan T.S. et al.Spared bone mass in rats treated with thyroid hormone receptor TRβ-selective compound GC-1.Am J Physiol Endocrinol Metab. 2003; 285: 1135-1141https://doi.org/10.1152/AJPENDO.00506.2002/ASSET/IMAGES/LARGE/H11131490103.JPEGCrossref PubMed Google Scholar,[26]Ladenson P.W. Kristensen J.D. Ridgway E.C. Olsson A.G. Carlsson B. Klein I. et al.Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia.N Engl J Med. 2010; 362 (PMID: 20220185): 906-916https://doi.org/10.1056/NEJMoa0905633Crossref PubMed Scopus (276) Google Scholar]. Currently, the unmet clinical need of MASH-specific pharmacotherapies appears to be met by the landmark FDA conditional approval of resmetirom, based on a surrogate or intermediate clinical endpoint that is reasonably likely to predict clinical benefit (Fig. 1) [[27]FDA approves first treatment for patients with liver scarring due to fatty liver disease.Publisher Name: FDAhttps://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-diseaseDate accessed: March 15, 2024Google Scholar]. This accelerated approval for individuals with MASH (stages F2-F3) followed previous Breakthrough Therapy, Fast Track, and Priority Review designations for Madrigal Pharmaceuticals, which had initiated a submission process for a new drug application aiming for expedited approval from the FDA for resmetirom. Resmetirom improves MASH by increasing hepatic fat metabolism and reducing lipotoxicity (Fig. 1) [[28]Harrison S.A. Bashir M.R. Guy C.D. Zhou R. Moylan C.A. Frias J.P. et al.Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.Lancet (London, England). 2019; 394: 2012-2024https://doi.org/10.1016/S0140-6736(19)32517-6Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar,[29]Harrison S.A. Bashir M. Moussa S.E. McCarty K. Pablo Frias J. Taub R. Alkhouri N. Effects of resmetirom on noninvasive endpoints in a 36-week phase 2 active treatment extension study in patients with NASH.Hepatol Commun. 2021; 5: 573-588Crossref PubMed Scopus (70) Google Scholar]. The relative liver-specific expression of THR-β is crucial for lowering cholesterol and triglyceride levels, increasing bile acid synthesis, and fat oxidation (Fig. 1) [[21]Sinha R.A. Bruinstroop E. Singh B.K. Yen P.M. Nonalcoholic fatty liver disease and hypercholesterolemia: roles of thyroid hormones, metabolites, and agonists.Thyroid. 2019; 29: 1173-1191https://doi.org/10.1089/THY.2018.0664Crossref PubMed Scopus (0) Google Scholar]. Further, resmetirom is liver-directed due to its uptake being mediated by liver-specific organic anion transporting polypeptides 1B1 [[30]Hönes G.S. Sivakumar R.G. Hoppe C. König J. Führer D. Moeller L.C. Cell-specific transport and thyroid hormone receptor isoform selectivity account for hepatocyte-targeted thyromimetic action of MGL-3196.Int J Mol Sci. 2022; : 23https://doi.org/10.3390/IJMS232213714Crossref PubMed Google Scholar]. Resmetirom shows a 28-fold selectivity for THR-β over THR-α, thus potentially avoiding undesirable systemic effects associated with thyroid hormone excess in bone and heart, which are primarily mediated through THR-α (Fig. 1) [[31]Kelly M.J. Pietranico-Cole S. Larigan J.D. Haynes N.E. Reynolds C.H. Scott N. et al.Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3- yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a highly selective thyroid hormone receptor β agonist in clinical trials for the treatment of dyslipidemia.J Med Chem. 2014; 57: 3912-3923https://doi.org/10.1021/JM4019299/SUPPL_FILE/JM4019299_SI_001.PDFCrossref PubMed Scopus (0) Google Scholar]. Evidence from the phase 3 RCT "A Phase 3 Study to Evaluate Safety and Biomarkers of Resmetirom (MGL-3196) in Non-Alcoholic Fatty Liver Disease Patients (MAESTRO-NAFLD1)", completed in January 2023, displayed no significant differences between treatment arms (80 or 100 mg of resmetirom) over 52 weeks and four weeks of follow-up in treatment-emergent adverse events (primary outcome), including 1143 patients (NCT04197479) [[32]Harrison S.A. Taub R. Neff G.W. Lucas K.J. Labriola D. Moussa S.E. et al.Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial.Nat Med. 2023; 29: 2919-2928https://doi.org/10.1038/S41591-023-02603-1Crossref PubMed Scopus (0) Google Scholar]. Common treatment-emergent adverse events included diarrhea and nausea at treatment initiation compared to placebo (NCT04197479) [[32]Harrison S.A. Taub R. Neff G.W. Lucas K.J. Labriola D. Moussa S.E. et al.Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial.Nat Med. 2023; 29: 2919-2928https://doi.org/10.1038/S41591-023-02603-1Crossref PubMed Scopus (0) Google Scholar]. Significant improvements in LDL cholesterol, apolipoprotein B, triglycerides, 16-week hepatic fat, liver stiffness, and 52-week hepatic fat were observed as secondary outcomes (NCT04197479) [[32]Harrison S.A. Taub R. Neff G.W. Lucas K.J. Labriola D. Moussa S.E. et al.Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial.Nat Med. 2023; 29: 2919-2928https://doi.org/10.1038/S41591-023-02603-1Crossref PubMed Scopus (0) Google Scholar]. It is also important to be mentioned that resmetirom seems to improve the impaired health-related quality of life (HRQL) of patients with MASH. This was shown in a secondary analysis of a phase 2 clinical trial [NCT02912260], in which patients with biopsy-proven MASH experienced, beyond the improvement in hepatic fat fraction and/or NAFLD Activity Score, a significant improvement of HRQL after receiving resmetirom 80 mg daily for 36 weeks [[33]Younossi Z.M. Stepanova M. Taub R.A. Barbone J.M. Harrison S.A. Hepatic fat reduction due to resmetirom in patients with nonalcoholic steatohepatitis is associated with improvement of quality of life.Clin Gastroenterol Hepatol. 2022; 20: 1354-1361.e7https://doi.org/10.1016/J.CGH.2021.07.039Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Notably, there are three ongoing phase 3 RCTs investigating the safety and efficacy of resmetirom in MASLD, MASH and fibrosis, and well-compensated MASH cirrhosis: MAESTRO-NAFLD-OLE (NCT04951219), MAESTRO-NASH (NCT03900429), and MAESTRO-NASH-OUTCOMES (NCT05500222), respectively. The ongoing phase 3 MAESTRO-NASH (NCT03900429) RCT recently published results from the primary analysis, demonstrating resolution of MASH without worsening of fibrosis in 25.9 and 29.9 % for patients receiving 80 mg and 100 mg of resmetirom, respectively vs 9.7 % in the placebo arm, and a reduction in fibrosis by at least one stage without worsening of the NAFLD activity score in 24.2 and 25.9 % for patients receiving 80 mg and 100 mg of resmetirom, respectively vs 14.2 % of the placebo arm [[24]Harrison S.A. Bedossa P. Guy C.D. Schattenberg J.M. Loomba R. Taub R. et al.A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis.N Engl J Med. 2024; 390: 497-509https://doi.org/10.1056/NEJMOA2309000Crossref PubMed Scopus (0) Google Scholar]. Additionally, LDL cholesterol levels from baseline to week 24 were reduced by 13.6 % in the 80-mg resmetirom group and by 16.3 % in the 100-mg resmetirom group, as compared with a 0.1 % increase in the placebo group (p < 0.001 for both comparisons with placebo) [[24]Harrison S.A. Bedossa P. Guy C.D. Schattenberg J.M. Loomba R. Taub R. et al.A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis.N Engl J Med. 2024; 390: 497-509https://doi.org/10.1056/NEJMOA2309000Crossref PubMed Scopus (0) Google Scholar]. Regarding adverse events, diarrhea and nausea again occurred more frequently in the treatment groups than with placebo, while the incidence of serious adverse events remained similar between all trial groups [[24]Harrison S.A. Bedossa P. Guy C.D. Schattenberg J.M. Loomba R. Taub R. et al.A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis.N Engl J Med. 2024; 390: 497-509https://doi.org/10.1056/NEJMOA2309000Crossref PubMed Scopus (0) Google Scholar]. Recently, in a large observational study, our group demonstrated that elevated TSH levels (indicating decreased thyroid function) in individuals having normal levels of circulating thyroid hormone are associated with MASH and at-risk MASH [[17]Kouvari M. Valenzuela-Vallejo L. Axarloglou E. Verrastro O. Papatheodoridis G. Mingrone G. et al.Thyroid function, adipokines and mitokines in metabolic dysfunction-associated steatohepatitis: a multi-centre biopsy-based observational study.Liver Int. 2024; : 44https://doi.org/10.1111/LIV.15847Crossref Google Scholar]. These findings support research initiatives on administering thyroid hormone in treating MASLD for subclinical hypothyroidism and employing liver-specific thyroid receptor agonists for individuals regardless of TSH status [[17]Kouvari M. Valenzuela-Vallejo L. Axarloglou E. Verrastro O. Papatheodoridis G. Mingrone G. et al.Thyroid function, adipokines and mitokines in metabolic dysfunction-associated steatohepatitis: a multi-centre biopsy-based observational study.Liver Int. 2024; : 44https://doi.org/10.1111/LIV.15847Crossref Google Scholar]. It is worth specifically noting the apparent sustained benefits of resmetirom on cardiovascular risk factors observed as secondary endpoints of MAESTRO-NASH (NCT03900429). Improvements in accepted atherogenic risk factors (LDL cholesterol, triglyceride, apolipoprotein B, apolipoprotein C-III, and lipoprotein a) were reported, relative to placebo, at 24 weeks and maintained at 52 weeks. The improved lipid profile occurred despite no differences in effects on body weight and comparable use of antidiabetic agents, such as GLP-1RAs. Blood pressure was only slightly decreased in resmetirom treated groups compared to placebo. The beneficial impact on markers for increased atherogenic risk in MAESTRO-NASH is consistent with observations in pre-clinical studies and earlier-stage clinical trials. The importance of these observations relates to cardiovascular disease being the major cause of death in individuals with MASH [[34]Younossi Z. Henry L. Contribution of alcoholic and nonalcoholic fatty liver disease to the burden of liver-related morbidity and mortality.Gastroenterology. 2016; 150: 1778-1785https://doi.org/10.1053/J.GASTRO.2016.03.005Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Given the mechanism of action for resmetirom is mediated through THR-β and its uptake is liver-directed, it does not appear to exert direct effects on vascular smooth muscle or endothelial cells; however, it is considered to improve mitochondrial biogenesis, mitophagy, liver–mitochondrial respiration rate, and mitochondrial oxidation (Fig. 1) [[35]Karim G. Bansal M.B. Resmetirom: an orally administered, smallmolecule, liver-directed, β-selective THR agonist for the treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.TouchREVIEWS Endocrinol. 2023; 19: 60-70https://doi.org/10.17925/EE.2023.19.1.60Crossref PubMed Scopus (5) Google Scholar], and thus mitigate the cardiovascular risk [[36]Ballinger S.W. Patterson C. Knight-Lozano C.A. Burow D.L. Conklin C.A. Hu Z. et al.Mitochondrial integrity and function in atherogenesis.Circulation. 2002; 106: 544-549https://doi.org/10.1161/01.CIR.0000023921.93743.89Crossref PubMed Scopus (410) Google Scholar,[37]Jakobsson T. Vedin L.L. Parini P. Potential role of thyroid receptor β agonists in the treatment of hyperlipidemia.Drugs. 2017; 77: 1613-1621https://doi.org/10.1007/s40265-017-0791-4Crossref PubMed Scopus (16) Google Scholar]. A caveat on this is that long-term and off-target effects will require further studies. Regarding cost-effectiveness, analyses conducted by the Institute for Clinical and Economic Review (ICER) projected that resmetirom may meet commonly accepted cost-effectiveness thresholds if priced between $39,600 and $50,100 annually [[38]Non-alcoholic steatohepatitis.Publisher Name: ICERhttps://icer.org/assessment/non-alcoholic-steatohepatitis-2023/Date accessed: March 2, 2024Google Scholar]; with the underlying premise for this pricing assumption resting on the notion that short-term enhancements in liver fibrosis will result in long-term reductions in cirrhosis and its economic burden, which remains to be shown by ongoing studies. However, a previous cost-effectiveness simulation analysis concluded that a pharmaceutical intervention targeting the at-risk MASH population (≥F2) would be considered cost-effective if yearly drug costs are below $12,000, an amount more than three times less than the prices estimated by ICER [[39]Rustgi V.K. Duff S.B. Elsaid M.I. Cost-effectiveness and potential value of pharmaceutical treatment of nonalcoholic fatty liver disease.J Med Econ. 2022; 25: 347-355https://doi.org/10.1080/13696998.2022.2026702Crossref PubMed Scopus (9) Google Scholar]. Therefore, more pharmacoeconomic analyses are needed to calculate the justifiable yearly drug prices in relation to clinical efficacy, and ideally, the cost-effectiveness of the drug should be accompanied by safety and tolerability, given the need for long-term treatment [[40]The Lancet Gastroenterology & Hepatology Resmetirom for NASH: balancing promise and prudence.Lancet Gastroenterol Hepatol. 2024; 9: 273https://doi.org/10.1016/S2468-1253(24)00049-9Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Interestingly, despite the trial for which the primary analysis was recently published [[24]Harrison S.A. Bedossa P. Guy C.D. Schattenberg J.M. Loomba R. Taub R. et al.A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis.N Engl J Med. 2024; 390: 497-509https://doi.org/10.1056/NEJMOA2309000Crossref PubMed Scopus (0) Google Scholar] and drove the FDA accelerated approval [[27]FDA approves first treatment for patients with liver scarring due to fatty liver disease.Publisher Name: FDAhttps://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-diseaseDate accessed: March 15, 2024Google Scholar], including only patients with biopsy-proven MASH with moderate or advanced liver scarring, the drug's prescribing information does not include a biopsy requirement for diagnosis [[41]Madrigal Pharmaceuticals announces FDA approval of Rezdiffra™ (resmetirom) for the treatment of patients with noncirrhotic nonalcoholic steatohepatitis (NASH) with Moderate to advanced liver fibrosis.Publisher Name: Madrigal Pharmaceuticalshttps://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-fda-approval-rezdiffratmDate accessed: March 15, 2024Google Scholar]. Thus, the current diagnostic criteria would apply (Fig. 2). If a diagnosis of MASH and fibrosis for subsequent treatment can rely upon non-invasive testing, this is projected to lead to misclassifications due to the low accuracy of existing diagnostics and, thus, potential over- or under-treatment, even when currently recommended diagnostics are combined with FibroScan measurements [[42]Yki-Järvinen H. Diagnosis of non-alcoholic fatty liver disease (NAFLD).Diabetologia. 2016; 59: