A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis

New England Journal of Medicine, Journal Year: 2024, Volume and Issue: 390(6), P. 497 - 509

Published: Feb. 7, 2024

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom an oral, liver-directed, thyroid hormone receptor beta–selective agonist in development for the treatment of NASH fibrosis. Download PDF Research Summary. We are conducting ongoing phase 3 trial involving adults biopsy-confirmed and fibrosis stage F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned 1:1:1 ratio receive once-daily resmetirom at dose 80 mg 100 placebo. The two primary end points week 52 resolution (including reduction nonalcoholic fatty [NAFLD] activity score by ≥2 points; scores 0 8, higher indicating more severe disease) worsening fibrosis, improvement (reduction) least one NAFLD score. Overall, 966 patients formed analysis population (322 80-mg group, 323 100-mg 321 placebo group). was achieved 25.9% group 29.9% those as compared 9.7% (P<0.001 both comparisons placebo). Fibrosis 24.2% 14.2% change low-density lipoprotein cholesterol levels baseline 24 −13.6% −16.3% 0.1% Diarrhea nausea frequent than incidence serious adverse events similar across groups: 10.9% 12.7% 11.5% group. Both superior respect stage. (Funded Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.) QUICK TAKE VIDEO SUMMARYResmetirom Liver 02:17

Language: Английский

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EASL–EASD–EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD)

Journal of Hepatology, Journal Year: 2024, Volume and Issue: 81(3), P. 492 - 542

Published: June 7, 2024

Language: Английский

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Hepatocellular carcinoma surveillance — utilization, barriers and the impact of changing aetiology

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 20(12), P. 797 - 809

Published: Aug. 3, 2023

Language: Английский

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Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis

˜The œLancet. Gastroenterology & hepatology, Journal Year: 2023, Volume and Issue: 8(9), P. 829 - 836

Published: July 4, 2023

Summary

Background

Data are scarce regarding the development of hepatic decompensation in patients with non-alcoholic fatty liver disease (NAFLD) and without type 2 diabetes. We aimed to assess risk people NAFLD

Methods

did a meta-analysis individual participant-level data from six cohorts USA, Japan, Turkey. Included participants had magnetic resonance elastography between Feb 27, 2007, June 4, 2021. Eligible studies included those fibrosis characterisation by elastography, longitudinal assessment for death, adult (aged ≥18 years) NAFLD, whom were available presence diabetes at baseline. The primary outcome was decompensation, defined as ascites, encephalopathy, or variceal bleeding. secondary hepatocellular carcinoma. used competing regression using Fine Gray subdistribution hazard ratio (sHR) compare likelihood Death event.

Findings

2016 (736 diabetes; 1280 diabetes) this analysis. 1074 (53%) female mean age 57·8 years (SD 14·2) BMI 31·3 kg/m² 7·4). Among 1737 (602 1135 data, 105 developed over median follow-up time 2·8 (IQR 1·4–5·5). Participants significantly higher 1 year (3·37% [95% CI 2·10–5·11] vs 1·07% [0·57–1·86]), 3 (7·49% [5·36–10·08] 2·92% [1·92–4·25]), 5 (13·85% [10·43–17·75] 3·95% [2·67–5·60]) than (p<0·0001). After adjustment multiple confounders (age, BMI, race), (sHR 2·15 1·39–3·34]; p=0·0006) glycated haemoglobin (1·31 1·10–1·55]; p=0·0019) independent predictors decompensation. association remained consistent after baseline stiffness determined elastography. Over 2·9 1·4–5·7), 22 1802 analysed (18 639 four 1163 incident carcinoma (1·34% 0·64–2·54] 0·09% [0·01–0·50], (2·44% [1·36–4·05] 0·21% [0·04–0·73]), (3·68% [2·18–5·77] 0·44% [0·11–1·33]) Type an predictor 5·34 [1·67–17·09]; p=0·0048).

Interpretation

is associated

Funding

National Institute Diabetes Digestive Kidney Diseases.

Language: Английский

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EASL-EASD-EASO Clinical Practice Guidelines on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Obesity Facts, Journal Year: 2024, Volume and Issue: 17(4), P. 374 - 444

Published: Jan. 1, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty (NAFLD), is defined as (SLD) in the presence of one or more cardiometabolic risk factor(s) and absence harmful alcohol intake. The spectrum MASLD includes steatosis, metabolic steatohepatitis (MASH, NASH), fibrosis, cirrhosis MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis treatment for MASLD. Case-finding strategies with using non-invasive tests, should be applied individuals factors, abnormal enzymes, and/or radiological signs hepatic particularly type 2 diabetes (T2D) obesity additional factor(s). A stepwise approach blood-based scores (such FIB-4) and, sequentially, imaging techniques transient elastography) suitable to rule-out/in advanced which predictive liver-related outcomes. In adults MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise discouraging consumption well optimal management comorbidities use incretin-based therapies (e.g. semaglutide, tirzepatide) T2D obesity, if indicated advised. Bariatric surgery also option obesity. If locally approved dependent label, non-cirrhotic MASH significant fibrosis (stage ≥2) considered a MASH-targeted resmetirom, demonstrated histological effectiveness acceptable safety tolerability profile. No pharmacotherapy can currently recommended cirrhotic stage. Management adaptations drugs, nutritional counselling, surveillance portal hypertension HCC, transplantation decompensated cirrhosis.

Language: Английский

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Role of Insulin Resistance in the Development of Nonalcoholic Fatty Liver Disease in People With Type 2 Diabetes: From Bench to Patient Care

Diabetes Spectrum, Journal Year: 2024, Volume and Issue: 37(1), P. 20 - 28

Published: Feb. 1, 2024

Insulin resistance is implicated in both the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and its progression from steatosis to steatohepatitis, cirrhosis, even hepatocellular carcinoma, which known be more common people with type 2 diabetes. This article reviews role insulin metabolic dysfunction observed obesity, diabetes, atherogenic dyslipidemia, hypertension how it a driver natural history NAFLD by promoting glucotoxicity lipotoxicity. The authors also review genetic environmental factors that stimulate steatohepatitis fibrosis their relationship cardiovascular summarize guidelines supporting treatment diabetes medications reduce resistance, such as pioglitazone or glucagon-like peptide 1 receptor agonists.

Language: Английский

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Epidemiology, screening, and co-management of type 2 diabetes mellitus and metabolic dysfunction–associated steatotic liver disease

Hepatology, Journal Year: 2024, Volume and Issue: unknown

Published: May 8, 2024

Metabolic dysfunction–associated steatotic liver disease (MASLD), previously known as NAFLD, is increasingly recognized a prevalent global burden. Type 2 diabetes mellitus (T2DM), another important metabolic disease, considered major contributor to the development of MASLD. MASLD and T2DM have strong association with each other due shared pathogenic mechanisms. The co-existence diseases increases risk liver-related adverse outcomes imposes heavier burden on extrahepatic outcomes, representing substantial public health issue. Effective assessment management combined necessitate multidisciplinary approach. emergence numerous RCTs has shed light treatment This review uncovers epidemiology intertwined MASLD, offers insights into evaluation hepatic fibrosis in patients T2DM, glucose monitoring population, provides comprehensive co-management strategies for addressing both diseases.

Language: Английский

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The rationale for the aggressive progression of MASLD in patients with type 2 diabetes

Annals of Hepatology, Journal Year: 2025, Volume and Issue: unknown, P. 101778 - 101778

Published: Jan. 1, 2025

Language: Английский

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Identification of biomarkers for the diagnosis of type 2 diabetes mellitus with metabolic associated fatty liver disease by bioinformatics analysis and experimental validation

Frontiers in Endocrinology, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 28, 2025

Background Type 2 diabetes (T2DM) combined with fatty liver is a subtype of metabolic disease (MAFLD), and the relationship between T2DM MAFLD close mutually influential. However, connection mechanisms two are still unclear. Therefore, we aimed to identify potential biomarkers for diagnosing both conditions. Methods We performed differential expression analysis weighted gene correlation network (WGCNA) on publicly available data diseases in Gene Expression Omnibus database find genes related utilised protein–protein interactions (PPIs), Ontology, Kyoto Encyclopedia Genes Genomes T2DM-associated mechanisms. Candidate were screened using machine learning algorithms 12 cytoHubba algorithms, diagnostic model T2DM-related was constructed evaluated.The CIBERSORT method used investigate immune cell infiltration immunological significance central genes. Finally, collected whole blood from patients MAFLD, healthy individuals, high-fat, high-glucose high-fat models verify hub Results Differential WGCNA identified 354 dataset. The T2DM-peripheral mononuclear cells/liver dataset 91 secreted proteins. PPI revealed important modules pathogenic which contained 49 nodes, suggesting their involvement interaction, inflammation, other processes. TNFSF10, SERPINB2, TNFRSF1A only coexisting shared key proteins, enabling construction highly accurate disorders. Additionally, successfully produced. patterns SERPINB2 verified patient our cellular model. Immune dysregulation observed strongly linked regulation. Conclusion sensitivity accuracy predicting can be greatly improved TNFRSF1A. These may significantly influence development offering new options MAFLD.

Language: Английский

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Metabolic dysfunction-associated steatotic liver disease in adults

Nature Reviews Disease Primers, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 6, 2025

Language: Английский

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