MASLD Treatment Enters New Era With Two Approved Drugs and a Robust Pipeline

MASLD represents a global epidemic, affecting approximately one-third of adults worldwide and spanning a spectrum from simple hepatic steatosis to steatohepatitis (MASH), advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Fibrosis stage is the dominant predictor of liver-related outcomes, while cardiovascular disease accounts for roughly 40% of deaths in this population—underscoring the systemic metabolic nature of the disease. Lifestyle modification producing ≥10% weight loss can induce fibrosis regression in a meaningful proportion of patients, but sustained success occurs in fewer than 15% in real-world practice, creating an urgent gap that pharmacotherapy must fill.

The most consequential development is resmetirom, a liver-selective thyroid hormone receptor-β (THR-β) agonist approved by the FDA in March 2024. In the pivotal MAESTRO-NASH phase 3 trial (F1B–F3 MASH), resmetirom 100 mg daily achieved MASH resolution without fibrosis worsening in 29.9% versus 9.7% with placebo, and ≥1-stage fibrosis improvement in 25.9% versus 14.2%. The drug also reduced LDL-cholesterol by approximately 15–20 mg/dL, providing additive cardiovascular benefit. Secondary analyses showed markedly superior outcomes in patients achieving concurrent ≥5% weight loss, reinforcing the lifestyle-pharmacotherapy synergy principle.

Semaglutide 2.4 mg weekly (GLP-1 receptor agonist) gained approval in 2025 after the ESSENCE trial demonstrated MASH resolution in 62.9% versus 34.3% with placebo, and fibrosis improvement in 36.8% versus 22.4%, alongside 10.5% mean weight loss. Tirzepatide (GLP-1/GIP dual agonist) delivered even higher histologic response rates in phase 2b (MASH resolution: 44%–62% across doses vs. 10% placebo; fibrosis improvement: ~51%–55%), with up to 17% weight loss at the 15 mg dose; phase 3 is enrolling. Efruxifermin (FGF21 analogue) showed 49% fibrosis improvement at 96 weeks in F2–F3 MASH and a notable 29% improvement even in compensated cirrhosis (F4), a historically difficult population.

Among non-incretin agents, lanifibranor (pan-PPAR agonist) reduced intrahepatic triglycerides ~50% and improved multi-tissue insulin sensitivity; biomarker analyses identified predictive signatures that could enable precision prescribing. Denifanstat (FASN inhibitor) achieved ≥2-point NAS improvement in 38% versus 16% with placebo and ≥1-stage fibrosis improvement in 41% versus 18%, with an acceptable tolerability profile including mild dry eye and alopecia. Novel dual agonists pemvidutide (GLP-1/glucagon) and survodutide (GLP-1/glucagon) also showed strong early histologic signals. Updated AASLD and EASL guidelines now recommend pharmacotherapy for biopsy-confirmed or high-probability F2–F3 MASH, prioritizing comorbidity-guided agent selection and integration with lifestyle intervention.

Despite transformative progress, critical challenges remain. Most trials used 52-week histologic endpoints as surrogates; long-term outcome trials demonstrating reduction in cirrhosis, liver failure, and mortality are still needed. Non-invasive biomarkers (MRI-PDFF, liver stiffness, serum panels) must be validated to replace repeated liver biopsies. Combination regimens exploiting complementary mechanisms are under investigation but require careful safety evaluation. Access, cost, and health equity concerns—particularly for under-resourced populations—must be addressed as these therapies enter clinical practice.