Rezdiffra (resmetirom) is the first and only FDA-approved medication to treat metabolic-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis (stages F2โF3) โ a condition closely linked to obesity, Type 2 diabetes, and metabolic syndrome. Its approval in March 2024 marked a landmark moment in liver disease treatment after decades with no approved options.
๐ซ Why Endocrinologists Manage MASH: MASH is driven by the same metabolic forces as obesity, Type 2 diabetes, and insulin resistance. Our endocrinologists are uniquely positioned to treat MASH by addressing its root metabolic causes โ including prescribing Rezdiffra when appropriate. Call 832-968-7003.
What Is MASH?
MASH (metabolic-associated steatohepatitis) โ previously called NASH (nonalcoholic steatohepatitis) โ is the progressive, inflammatory form of metabolic fatty liver disease. It progresses through stages:
- Steatosis (fatty liver, F0): Fat accumulates in liver cells โ often reversible
- MASH (F1โF2): Fat plus inflammation and early scarring (fibrosis)
- Advanced fibrosis (F3): Significant scarring โ higher risk of progression
- Cirrhosis (F4): End-stage scarring โ irreversible; risk of liver failure and liver cancer
MASH affects roughly 6โ8% of the US population. It is the fastest-growing cause of liver transplant need and liver cancer. Patients with Type 2 diabetes have a 2โ3x higher risk of MASH progression to cirrhosis.
How Rezdiffra Works
Rezdiffra is a thyroid hormone receptor beta (THR-ฮฒ) selective agonist. It works by activating thyroid hormone receptors specifically in the liver โ without significantly activating receptors in the heart, bone, or muscle (which would cause adverse effects).
In the liver, THR-ฮฒ activation:
- Increases fat metabolism and oxidation (burns fat from liver cells)
- Reduces fat synthesis (lipogenesis)
- Improves mitochondrial function in liver cells
- Reduces liver inflammation and fibrosis-driving signals
- Lowers LDL cholesterol and triglycerides (a beneficial metabolic side effect)
Clinical Evidence โ MAESTRO-NASH Trial
The pivotal Phase 3 MAESTRO-NASH trial enrolled 966 patients with biopsy-confirmed MASH and F2โF3 fibrosis:
- MASH resolution without worsening fibrosis: 25.9% with Rezdiffra 80 mg vs. 9.7% placebo; 29.9% with 100 mg vs. 9.7% placebo
- Fibrosis improvement by โฅ1 stage: 24.2% (80 mg) and 25.9% (100 mg) vs. 14.2% placebo
- LDL cholesterol reduced by 13โ16%
- Triglycerides reduced by 18โ23%
- ALT and AST (liver enzymes) significantly reduced
- Well tolerated overall โ most side effects were gastrointestinal and mild
Who Is Rezdiffra For?
Rezdiffra is FDA-approved for adults with:
- Non-cirrhotic MASH AND
- Moderate to advanced fibrosis (stage F2 or F3 on liver biopsy or validated non-invasive testing)
- Used alongside diet and exercise โ not a replacement for lifestyle intervention
It is not approved for cirrhotic liver disease (F4), or for simple steatosis without inflammation/fibrosis.
Diagnosing MASH โ What Tests Are Needed?
Historically, MASH diagnosis required a liver biopsy. Increasingly, validated non-invasive tests help stage fibrosis:
- FibroScan (transient elastography): Measures liver stiffness; available at our clinic. A CAP score measures fat content; kPa score measures fibrosis severity.
- FIB-4 score: Calculated from age, AST, ALT, and platelet count โ a simple, validated screening tool
- ELF test, PRO-C3: Blood-based fibrosis markers
- MRI-PDFF + MRE: Gold-standard non-invasive imaging for fat and fibrosis
- Liver biopsy: Still the definitive test when non-invasive results are indeterminate
Dosing
- Route: Oral tablet, taken once daily with food
- Doses available: 80 mg and 100 mg
- Starting dose: Determined based on patient profile; 80 mg is commonly used initially
- Dose adjustment required in patients with moderate hepatic impairment
Side Effects
- Nausea and diarrhea: Most common (~30%); usually mild, occurring early in treatment and improving over time. Taking with food helps.
- Pruritus (itching): Seen in some patients
- Gallstones: Increased risk of cholelithiasis โ monitor for symptoms
- LDL reduction: Generally beneficial, but monitor in patients on statins (additive LDL lowering)
- Cardiac effects: Designed to be THR-ฮฒ selective (liver) โ limited heart receptor activation; EKG changes not a primary concern in trials but monitoring continues post-approval
๐ Rezdiffra + GLP-1 Medications: Many MASH patients are also on GLP-1 agonists (Ozempic, Mounjaro) for diabetes or weight management โ which also benefit the liver. These can be used together. Our endocrinologists are experienced in managing both therapies simultaneously.
Rezdiffra vs. Other MASH Approaches
| Approach | Evidence | Role |
|---|---|---|
| Rezdiffra (resmetirom) | Phase 3 RCT โ FDA approved | First-line approved pharmacotherapy for F2โF3 MASH |
| GLP-1 agonists (semaglutide) | Strong Phase 2 data; Phase 3 ongoing | Improve steatosis and inflammation; pending MASH-specific approval |
| Lifestyle (diet + exercise) | Strong evidence | Foundation of all MASH treatment; โฅ7โ10% weight loss reduces fibrosis |
| Vitamin E | Modest evidence (non-diabetics) | Off-label option for select non-diabetic patients |
| Obeticholic acid (Ocaliva) | Filed; not approved for MASH | Not currently an option |
Key Takeaways
- Rezdiffra is the first FDA-approved medication for MASH with liver fibrosis (F2โF3) โ approved March 2024
- Works by selectively activating thyroid hormone receptors in the liver to reduce fat, inflammation, and fibrosis
- Also lowers LDL and triglycerides โ a metabolic bonus
- Used alongside diet and exercise, not as a replacement
- GI side effects (nausea, diarrhea) are most common but usually mild and short-lived
- Endocrinologists are uniquely suited to manage MASH alongside diabetes, obesity, and metabolic syndrome
Our Team Can Help with Your Medications
All five of our providers prescribe and manage endocrine medications. Book with any member of our team:
Book an Appointment โ or call 832-968-7003