Treating MASLD and MASH
MASH is now a treatable disease. The foundation is weight loss and control of insulin resistance; on top of that, two medicines are FDA-approved for MASH with moderate-to-advanced fibrosis — and both work through hormone pathways. Here is how each option works, who it is for, and how we choose therapies that protect the liver, heart and kidneys at the same time.
Key takeaways
- The goals are to resolve MASH, stop or reverse fibrosis, and lower cardiovascular and kidney risk — one plan, several organs.
- Weight loss of 7–10% is the most effective single intervention; medication and metabolic surgery help people reach it.
- Semaglutide 2.4 mg (a GLP-1 receptor agonist) and resmetirom (a liver-targeted thyroid-hormone receptor-β agonist) are FDA-approved for noncirrhotic MASH with F2–F3 fibrosis.
- Pioglitazone improves MASH in people with prediabetes or diabetes; statins are safe and indicated for heart protection.
What this means for you
If you have fatty liver without significant scarring, treatment means getting your weight, blood sugar, blood pressure and cholesterol where they should be — often with a medication that also helps the liver. If you have MASH with moderate or advanced fibrosis, you are a candidate for an approved liver-directed medicine, and we will re-measure to make sure it is working.
Treatment goals
- All patients with MASLD: treat the metabolic drivers — weight, insulin resistance, diabetes, hypertension, lipids — and remove added liver insults such as alcohol.
- MASH with F2–F3 fibrosis: add a therapy with proven histologic benefit (semaglutide or resmetirom), in addition to metabolic care.
- Cirrhosis: hepatology-led care; we continue diabetes, weight and cardiovascular treatment with drugs that are safe in cirrhosis (see When we refer).
Semaglutide and incretin therapies
GLP-1 receptor agonists are gut-hormone analogs. They reduce appetite and body weight, improve insulin secretion and sensitivity, and lower liver fat and inflammation. Newer dual agonists add GIP (tirzepatide) or glucagon signaling.
Semaglutide 2.4 mg weekly (Wegovy)
Grade A · FDA-approved for MASH F2–F3Tirzepatide (GIP/GLP-1 dual agonist)
Grade B · Strong phase 2 dataResmetirom — a thyroid-hormone pathway drug for the liver
Resmetirom is the clearest illustration that MASH is an endocrine disease. Thyroid hormone, acting on the thyroid hormone receptor-β (THR-β) that dominates in the liver, drives fat burning, mitochondrial function and cholesterol clearance; in MASH this signaling is impaired. Resmetirom is an oral, once-daily, liver-targeted partial THR-β agonist designed to restore that signal in the liver without the heart and bone effects of thyroid hormone, which act mainly through THR-α.
Resmetirom (Rezdiffra) 80–100 mg daily
Grade A · FDA-approved for MASH F2–F3For cliniciansChoosing between semaglutide and resmetirom
There are no head-to-head trials. In practice the choice follows the rest of the phenotype: semaglutide when obesity, type 2 diabetes or established ASCVD make weight loss and cardiovascular risk reduction a priority; resmetirom when weight is not the dominant driver, when GLP-1 therapy is not tolerated or already maximized without adequate liver response, or when atherogenic dyslipidemia is prominent. The two act on different pathways, and patients were on stable GLP-1 therapy in MAESTRO-NASH (about 15%); combination is used in practice though outcome data are limited. We document baseline LSM, CAP and FIB-4 and reassess at 12 months — AASLD guidance suggests considering discontinuation if noninvasive tests show no improvement or worsening. Payers generally require documentation of F2–F3 disease and exclusion of cirrhosis.
Pioglitazone and other diabetes drugs
Pioglitazone
Grade B · Recommended in type 2 diabetesSGLT2 inhibitors (empagliflozin, dapagliflozin and others)
Grade C · Liver data limitedVitamin E (800 IU/day)
Grade B · Selected patientsMetformin remains a good diabetes drug and is safe in MASLD, but trials show no meaningful improvement in liver histology, so it is not a MASH treatment. Insulin is safe in MASLD when needed for glucose control.
Protecting the heart and kidneys
Because cardiovascular disease is the leading cause of death in MASLD, cardiorenal protection is built into every plan:
- Statins for LDL lowering whenever cardiovascular risk calls for them. They are safe in MASLD and compensated cirrhosis. Elevated liver enzymes are not a reason to withhold them.
- Blood pressure to guideline targets, with ACE inhibitors or ARBs when albuminuria is present.
- Diabetes drugs with proven heart and kidney benefit — GLP-1 receptor agonists and SGLT2 inhibitors — preferred when diabetes is present.
- Smoking cessation.
Established coronary artery disease, and severe or complex lipid disorders, are managed together with cardiology (see When we refer).
Bariatric (metabolic) surgery
Grade B · Strong for severe obesityWho treats what
| Part of the disease | Who leads |
|---|---|
| Insulin resistance, diabetes, obesity, thyroid and sex-hormone drivers | Endocrinology (our practice) |
| MASLD and MASH with F0–F2 fibrosis, including liver-directed medication | Endocrinology |
| Advanced fibrosis (F3) | Hepatology co-management |
| Cirrhosis, liver cancer surveillance, transplant | Hepatology |
| Coronary artery disease; complex or severe lipid disorders | Cardiology |
What we know
- Weight loss of 7–10% resolves MASH in most patients who achieve it.
- Semaglutide and resmetirom improve MASH and fibrosis on biopsy.
- Statins, GLP-1 receptor agonists and SGLT2 inhibitors protect the heart and kidneys in people who share MASLD's risk profile.
What we don't know
- Whether the approved drugs reduce cirrhosis, transplant and death (confirmatory trials ongoing).
- Which drug is best for which patient — there are no head-to-head trials.
- How long treatment should continue, and what happens when it stops.
When to call your doctor
- Severe or persistent vomiting, or abdominal pain radiating to the back, on a GLP-1 or tirzepatide.
- Persistent diarrhea on resmetirom.
- Swelling of the legs or shortness of breath on pioglitazone.
- Any yellowing of the eyes, dark urine, or confusion.
Questions to ask your doctor
- Is my fibrosis stage one where a liver-directed medication is indicated?
- Would semaglutide or resmetirom fit my situation better — and why?
- Are my diabetes and cholesterol medicines also helping my liver, heart and kidneys?
- How and when will we check whether treatment is working?
How we grade evidence. Every intervention carries a plain label — from established, guideline-supported care (A) through moderate (B) and mixed or limited (C) to experimental (D) and insufficient (E). An improvement on a liver biopsy or scan is not the same as fewer cirrhosis cases, heart attacks, or deaths, and we say which we mean.
Real questions we hear about MASH treatment.
Should I take semaglutide or resmetirom? Grade B
What the evidence shows
Both improved MASH and fibrosis in phase 3 trials; they have never been compared directly.
In our practice
We match the drug to your metabolic profile, check insurance requirements, and re-stage at about a year.
I take levothyroxine. Can I take resmetirom? Grade A
What the evidence shows
About 14% of MAESTRO-NASH participants were on thyroxine; the label does not require routine thyroid monitoring.
In our practice
We keep thyroid replacement at the usual target and monitor as we normally would — see HashiExperts.
Is it safe to take a statin with a fatty liver? Grade A
What the evidence shows
Guidelines (AASLD, AACE, EASL) endorse statins in MASLD and MASH, including compensated cirrhosis.
In our practice
We check your cardiovascular risk and start or continue a statin when indicated, adjusting the dose if you start resmetirom.
References
- Sanyal AJ, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089–2099.
- Harrison SA, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497–509.
- Loomba R, et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391(4):299–310.
- Chen VL, et al. Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease: October 2024 updates to AASLD Practice Guidance. Hepatology. 2025;81(1):312–320.
- Cusi K, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus. Ann Intern Med. 2016;165(5):305–315.
- Sanyal AJ, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675–1685.
- Verrastro O, et al. Bariatric–metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES). Lancet. 2023;401(10390):1786–1797.
- Lincoff AM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med. 2023;389(24):2221–2232.
- Perkovic V, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes (FLOW). N Engl J Med. 2024;391(2):109–121.
- Cusi K, et al. AACE clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings. Endocr Pract. 2022;28(5):528–562.
- Rinella ME, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797–1835.
- EASL–EASD–EASO Clinical Practice Guidelines on the management of MASLD. J Hepatol. 2024;81(3):492–542.
Considering MASH treatment — or unsure which option fits?
We match the therapy to your metabolism, protect your heart and kidneys, and re-measure to prove it's working.