MASH Treatment in 2026: Where GLP-1 RAs Now Sit Beside Resmetirom

MASH treatment shifted twice in 18 months — resmetirom in March 2024, then semaglutide in August 2025. The 2026 ADA Standards of Care now formally place GLP-1 RAs in the MASH algorithm.

April 25, 2026 · 4 min read

Why MASH Treatment Is Different in 2026

MASH treatment is moving faster than most clinicians realize. Until March 2024, no drug was approved for metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH). Eighteen months later, two are.

Resmetirom (Rezdiffra), an oral thyroid hormone receptor-β agonist, became the first FDA-approved MASH-specific therapy on March 14, 2024 for non-cirrhotic MASH with moderate to advanced fibrosis (F2–F3). On August 15, 2025, the FDA followed by approving once-weekly subcutaneous semaglutide 2.4 mg (Wegovy) for the same population, making it the first GLP-1 receptor agonist (GLP-1 RA) with a MASH indication.

The American Diabetes Association’s 2026 Standards of Care, published in January, codified the change: in patients with type 2 diabetes and MASH or high fibrosis risk, a GLP-1 RA with demonstrated MASH benefit is now preferred for glycemic management. That recommendation reshapes the decision tree for primary care.

The Background

MASLD — metabolic dysfunction-associated steatotic liver disease, the umbrella term that replaced NAFLD in 2023 — affects more than 70% of U.S. adults with type 2 diabetes. Roughly 1 in 20 American adults has MASH, the inflammatory progressive form, and untreated MASH carries meaningful risk of cirrhosis, hepatocellular carcinoma, and liver-related mortality.

For two decades, management was indirect: weight loss, glycemic control, statins, and treatment of comorbidities. The two new therapies attack the disease from different angles. Resmetirom acts directly on the liver via THR-β to reduce hepatic fat and inflammation; it is weight-neutral. Semaglutide acts upstream — on appetite, gut motility, and insulin signaling — producing weight loss of about 10% that drives both hepatic and cardiometabolic benefit.

The Evidence Behind GLP-1s in MASH Treatment

The semaglutide approval rests on the phase 3 ESSENCE trial (Sanyal et al., NEJM, April 30, 2025), enrolling 1,197 patients with biopsy-defined MASH and F2–F3 fibrosis. The published interim analysis at week 72 in the first 800 patients showed:

MASH resolution without fibrosis worsening: 62.9% with semaglutide vs 34.3% placebo (Δ 28.7 percentage points; 95% CI 21.1–36.2; P<0.001).
Fibrosis improvement without MASH worsening: 36.8% vs 22.4% (Δ 14.4 pp; 95% CI 7.5–21.3; P<0.001).
Combined endpoint (both MASH resolution and fibrosis improvement): 32.7% vs 16.1%.
Weight loss: -10.5% vs -2.0% at 72 weeks.
Liver enzymes: placebo-adjusted ALT -40%, AST -30%, GGT -40%.
Adverse events: consistent with prior semaglutide trials — predominantly gastrointestinal (nausea 36% vs 13% placebo), no drug-induced liver injury signal.

Tirzepatide’s phase 2 SYNERGY-NASH trial showed similar histologic benefit at 52 weeks but does not yet carry an FDA MASH indication. The 2026 ADA Standards reflect that distinction: GLP-1 RAs with demonstrated MASH benefit (Grade A); dual GIP/GLP-1 RAs with potential benefit (Grade B).

Where Experts Disagree on Sequencing

The debate is not whether GLP-1 RAs work in MASH — they clearly do — but how to position them against resmetirom in patients who could plausibly receive either.

“The ESSENCE Trial demonstrated, for the first time, improvement in fibrosis with semaglutide.” — Paul Y. Kwo, MD, FACG, Stanford University, in ACG Evidence-Based GI commentary, September 2025

Independent commentators broadly agree the ESSENCE results are practice-shifting, but with caveats. The 14-percentage-point fibrosis-improvement delta is meaningful but modest, and there are no head-to-head comparative trials with resmetirom. Resmetirom remains attractive for patients who cannot tolerate GLP-1 RA gastrointestinal side effects, who lack obesity or diabetes, or whose insurance restricts GLP-1 access. Combination therapy — resmetirom plus a GLP-1 RA — is biologically rational but unproven and expensive. The European EASL/EASD/EASO guidelines and U.S. AASLD positioning continue to evolve in parallel.

The Practical Question for Clinicians

For internists and primary care physicians, the ADA 2026 algorithm gives a workable starting framework:

Identify the population first. Use FIB-4 (fibrosis-4 index) on routine labs as the entry screen. FIB-4 ≥1.3 (or ≥2.0 in patients ≥65) warrants further workup with vibration-controlled transient elastography (FibroScan) or specialty referral.
Patient with type 2 diabetes + obesity + MASLD/MASH: a GLP-1 RA with demonstrated MASH benefit is preferred (semaglutide currently labeled). Pioglitazone or a dual GIP/GLP-1 RA (tirzepatide) are reasonable alternatives.
Patient without diabetes, with biopsy- or imaging-confirmed F2–F3 MASH: resmetirom remains the on-label choice; semaglutide 2.4 mg is now also approved.
Patient with decompensated cirrhosis: insulin is preferred for glycemic control; statins should be used cautiously.

Coverage is the practical bottleneck. Resmetirom and high-dose semaglutide both require prior authorization in most plans, and payer criteria for the MASH indication are still consolidating.

What to Watch For

Whether tirzepatide’s MASH dossier (SYNERGY-NASH phase 3) lands an FDA filing and how that would refine the GLP-1/GIP position in the MASH treatment algorithm
The full 240-week ESSENCE readout, which will clarify whether 72-week histologic gains translate into reductions in cirrhosis and liver-related events
Updated AASLD MASH practice guidance — expected to align primary care, hepatology, and endocrinology pathways
Payer prior-authorization criteria as both resmetirom and semaglutide compete for MASH-indication coverage
Trials of combination therapy (resmetirom + GLP-1 RA), which are biologically rational but not yet powered for histologic endpoints

Sources

American Diabetes Association. Standards of Care in Diabetes — 2026. Diabetes Care, January 2026. ADA Summary of Revisions — 2026 Standards of Care
American Diabetes Association. Section 9: Pharmacologic Approaches to Glycemic Treatment — Standards of Care 2026. ADA 2026 Section 9 — Pharmacologic Glycemic Treatment
Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med, April 30, 2025. Sanyal et al., NEJM — ESSENCE Phase 3 Trial
Novo Nordisk. ESSENCE Phase 3 Trial of Semaglutide Showed Significant Improvements at 72 Weeks in Adults with MASH. Press release, April 30, 2025. Novo Nordisk ESSENCE Topline Announcement
Kwo PY. Semaglutide for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis. ACG Evidence-Based GI, September 2025. Kwo, ACG Evidence-Based GI — Independent ESSENCE Commentary
Patient Care Online. ADA Publishes 2026 Standards of Care with Updates to Sections on Technology, Obesity, Cardiometabolic Disease Management. 2026. Patient Care Online — ADA 2026 Standards Coverage
U.S. Food and Drug Administration. FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease (Resmetirom). March 14, 2024. FDA Resmetirom Approval Announcement (March 2024)
Marabotto E, et al. Targeting Fibrosis and Steatohepatitis Through the Metabolism — Results from the ESSENCE Trial. JHEP Reports, August 2025. JHEP Reports — ESSENCE Editorial Commentary