Early observations and pilot data that first suggested a new direction
Nonalcoholic steatohepatitis (NASH, now termed MASH under the MASLD nomenclature) lacked any approved pharmacotherapy for years despite being the leading cause of chronic liver disease globally. The PIVENS trial in 2010 provided the first rigorous evidence, randomizing 247 non-diabetic NASH patients to pioglitazone, vitamin E, or placebo for 96 weeks. Vitamin E (800 IU/day) achieved histologic improvement in 43% versus 19% placebo (p<0.001). Pioglitazone showed a trend but did not reach the pre-specified significance threshold (34% vs 19%, p=0.04).
Landmark RCTs and pivotal trials that established the evidence base
The MAESTRO-NASH trial represented a landmark achievement: the first phase 3 trial to demonstrate both NASH resolution and fibrosis improvement, leading to the first FDA-approved therapy for MASH. Among 966 patients with biopsy-confirmed NASH and F1B-F3 fibrosis, resmetirom (a thyroid hormone receptor-beta selective agonist) at 100 mg daily achieved NASH resolution in 29.9% versus 9.7% placebo (p<0.001) and fibrosis improvement by at least one stage in 25.9% versus 14.2% placebo (p<0.001) at week 52. Resmetirom received accelerated FDA approval in March 2024.
Follow-up studies, subgroup analyses, and real-world validation
GLP-1 receptor agonists emerged as promising MASH therapies given their effects on weight, insulin resistance, and hepatic steatosis. Semaglutide demonstrated NASH resolution in 59% versus 17% placebo in a phase 2 trial (PMID 33185364). Multiple GLP-1 RA trials in MASH are ongoing. Additionally, the nomenclature change from NAFLD/NASH to MASLD/MASH in 2023 reflected a shift toward inclusive, non-stigmatizing terminology and a metabolic disease framework rather than an exclusionary diagnosis.
Integration into clinical practice guidelines and recommendations
AASLD and EASL guidelines incorporated lifestyle modification with 7-10% weight loss as the foundation. Vitamin E was conditionally recommended for non-diabetic NASH. Following MAESTRO-NASH, resmetirom became the first guideline-endorsed pharmacotherapy for MASH with significant fibrosis. The role of GLP-1 receptor agonists is increasingly recognized, particularly for patients with comorbid type 2 diabetes and obesity.
AASLD
Lifestyle modification as foundation; vitamin E for non-diabetic NASH; resmetirom for MASH with F2-F3 fibrosis (following FDA approval)
EASL
Resmetirom recommended for non-cirrhotic MASH with significant fibrosis; GLP-1 RAs for patients with comorbid T2D and obesity
Now
Current standard of care and ongoing research directions
MASLD/MASH pharmacotherapy has entered a new era with the first FDA-approved therapy (resmetirom) and a robust pipeline including GLP-1 RAs, FGF21 analogues, PPAR agonists, and combination approaches. The key challenges include identifying patients who will benefit most, non-invasive biomarkers to replace liver biopsy for treatment monitoring, and addressing the massive global disease burden where most patients remain undiagnosed. The convergence of liver-targeted and metabolic therapies represents a paradigm shift in hepatology.
Resmetirom (Rezdiffra) is a thyroid hormone receptor-beta selective agonist that targets hepatic lipid metabolism. In the MAESTRO-NASH trial (966 patients), the 100 mg dose achieved NASH resolution in 29.9% vs 9.7% placebo and fibrosis improvement in 25.9% vs 14.2% placebo at 52 weeks. It received accelerated FDA approval in March 2024 for non-cirrhotic MASH with moderate-to-advanced fibrosis.
What is the difference between NAFLD/NASH and MASLD/MASH?+
In 2023, an international consensus renamed NAFLD to metabolic dysfunction-associated steatotic liver disease (MASLD) and NASH to metabolic dysfunction-associated steatohepatitis (MASH). The new terminology uses inclusive metabolic criteria (obesity, diabetes, dyslipidemia, hypertension) rather than exclusionary criteria (absence of alcohol use), reducing stigma and better reflecting the metabolic disease pathophysiology.
