Advances in the Management of Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD).

Metabolic dysfunction–associated steatotic liver disease (MASLD), previously known as NAFLD, affects up to 38% of the adult population worldwide, with even higher prevalence in individuals with type 2 diabetes (65%). Beyond hepatic complications such as cirrhosis and hepatocellular carcinoma, MASLD significantly increases the risk of cardiovascular disease, chronic kidney disease, type 2 diabetes, and certain extrahepatic cancers. Cardiovascular disease remains the leading cause of death among affected individuals.

Lifestyle modifications with clinically significant weight loss remain the cornerstone of management. However, pharmacological options are expanding rapidly. In March 2024, the FDA granted conditional approval to resmetirom, a liver-directed thyroid hormone receptor beta–selective agonist, for adults with noncirrhotic metabolic dysfunction–associated steatohepatitis (MASH) and moderate-to-advanced fibrosis. In the MAESTRO-NASH phase 3 trial, both 80 mg and 100 mg daily doses significantly increased rates of MASH resolution without fibrosis worsening and fibrosis regression by at least one stage compared with placebo.

Incretin-based therapies, particularly semaglutide (2.4 mg weekly), have shown substantial efficacy in achieving MASH resolution and improving metabolic parameters. Dual and triple receptor agonists, such as tirzepatide, survodutide, and retatrutide, demonstrated promising effects on liver histology, liver fat reduction, and weight loss in phase 2 studies. Other metabolism-targeted agents under investigation include pan-PPAR agonists (lanifibranor), FGF21 analogues (efruxifermin, pegozafermin, pegozafermin), and SGLT2 inhibitors (dapagliflozin), which have shown favorable hepatic and cardiometabolic profiles.

Despite these advances, long-term safety, cost-effectiveness, and treatment strategies for advanced disease and cirrhosis remain key challenges. The potential for combination therapies, integrating incretin receptor agonists with liver-directed agents, is a promising avenue for comprehensive MASLD management.

Editorial note: This content was developed with the support of artificial intelligence technologies to optimize the writing and structuring of the information. All material was carefully reviewed, validated, and supplemented by human experts prior to publication, ensuring scientific accuracy and adherence to good editorial practices.

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