MASLD (formerly NAFLD) and its inflammatory subset MASH (formerly NASH) affect ~38% and ~5% of U.S. adults respectively. Until recently, there were no FDA-approved drugs for either. In March 2024 resmetirom (Rezdiffra) was approved for MASH. GLP-1 receptor agonists are now showing strong phase 2 and phase 3 results that may add a second class to the MASH pharmacotherapy landscape.

What MASLD and MASH are

MASLD (metabolic dysfunction-associated steatotic liver disease): liver steatosis (≥5% liver fat) in the setting of cardiometabolic risk factors, without significant alcohol intake.
MASH: the inflammatory subset of MASLD, characterized by hepatocyte injury and inflammation. Progresses to fibrosis (F1–F4) and eventually cirrhosis.
The 2023 nomenclature change from NAFLD/NASH to MASLD/MASH reflected the understanding that the disease is fundamentally metabolic, not "non-alcoholic."

SYNERGY-NASH — tirzepatide phase 2 trial

Loomba et al. (NEJM 2024) randomized 190 adults with biopsy-confirmed MASH and stage F2–F3 fibrosis to tirzepatide 5/10/15 mg vs placebo for 52 weeks.

Endpoint at 52 weeks	5 mg	10 mg	15 mg	Placebo
MASH resolution	44%	56%	62%	10%
Fibrosis improvement ≥1 stage	55%	51%	51%	30%
Body weight change	−10.7%	−13.3%	−15.6%	−0.8%

This is the strongest MASH resolution effect ever reported in a randomized trial. Phase 3 program is enrolling.

ESSENCE — semaglutide phase 3 trial

Semaglutide 2.4 mg in MASH with stage F2–F3 fibrosis. Interim phase 3 data show MASH resolution in ~62% (semaglutide) vs ~34% (placebo) at 72 weeks; fibrosis improvement in ~37% vs ~22%. Full readout 2026.

Why GLP-1 may work in MASH

Multiple mechanisms beyond weight loss alone: improved insulin sensitivity (reduces hepatic lipogenesis), reduced systemic and hepatic inflammation, possible direct GLP-1 receptor effects in liver. The hepatic effect appears larger than would be predicted from weight loss alone, consistent with direct mechanism.

How to assess if you might have MASH

Elevated ALT and AST with cardiometabolic risk factors (T2D, obesity, hypertension, dyslipidemia).
FIB-4 score ≥1.3 (non-invasive risk stratification using age, AST, ALT, platelets).
Elastography (FibroScan) for non-invasive fibrosis staging.
Liver biopsy remains the gold standard for definitive MASH diagnosis and fibrosis staging.

What this means for compounded GLP-1 use

Use of compounded GLP-1 for off-label MASH-directed treatment is becoming more common in clinical practice, especially in patients with concurrent obesity and high FIB-4 scores. Considerations:

Coordination with hepatology is reasonable for patients with confirmed F2–F3 fibrosis.
Liver enzymes should be monitored at baseline and during therapy.
Compounded GLP-1 has the same active ingredient effect, but does not have FDA-approved MASH labeling. As of 2026, no GLP-1 product (compounded or branded) has FDA approval for MASH.
Patients with confirmed MASH and F3 fibrosis may benefit from coordinated care that includes the option of resmetirom (the FDA-approved MASH drug) alongside GLP-1, depending on phase 3 GLP-1 readouts and label changes.

What to expect over the next 2 years

Both semaglutide and tirzepatide are expected to file for MASH indications based on phase 3 readouts in 2026–2027. The MASH drug landscape will shift from "one approved drug (resmetirom)" to "multiple classes with strong evidence." Patients currently being treated for MASLD/MASH should expect treatment options to expand.