NASH Medication: Approved and Emerging Treatments

For decades, the only medical advice for nonalcoholic steatohepatitis (NASH, now increasingly called MASH) was to lose weight and exercise. That changed in March 2024, when the FDA approved resmetirom as the first drug specifically for non-cirrhotic NASH with moderate-to-severe liver fibrosis, followed by semaglutide’s approval for the same indication in 2025. Several other drugs are now in late-stage trials, and the pipeline is evolving fast enough that the treatment landscape a few years from now will look very different from today.

Resmetirom, the First Drug Across the Finish Line

Resmetirom (brand name Rezdiffra) works by activating a specific thyroid hormone receptor in the liver called TRβ. That receptor normally helps the liver burn fat, and in NASH it is underactive. By restoring TRβ signaling, resmetirom reduces the toxic fat buildup that drives inflammation and scarring.¹

The pivotal phase 3 trial enrolled adults with NASH and stage F2 or F3 fibrosis. After 52 weeks, about 26% of patients on the 80 mg dose and 30% on the 100 mg dose achieved resolution of NASH without worsening fibrosis, compared with roughly 10% on placebo. For the fibrosis-specific endpoint, about 24–26% of treated patients improved by at least one fibrosis stage without worsening of their overall liver inflammation score, versus about 14% on placebo. Resmetirom also lowered LDL cholesterol by 14–16% from baseline, a useful bonus in a population already at high cardiovascular risk. The most common side effects were diarrhea and nausea, but rates of serious adverse events were similar to placebo.¹

Those response rates are real but modest. Roughly seven out of ten patients who took resmetirom for a year did not meet the primary endpoints. The approval was granted under an accelerated pathway, meaning the FDA still requires longer-term data confirming that the liver improvements translate into fewer cases of cirrhosis, liver failure, and death. That confirmatory evidence is being gathered now.

Semaglutide Steps In

Semaglutide, the GLP-1 receptor agonist already well known for diabetes and weight loss, earned FDA approval for MASH with liver fibrosis in 2025. Its path to that approval was bumpy in ways that reveal how complicated NASH treatment really is.

In a phase 2 trial, semaglutide at the highest dose tested (0.4 mg daily, subcutaneous) led to NASH resolution without fibrosis worsening in 59% of patients, compared with 17% on placebo. That was one of the most impressive NASH-resolution numbers any drug had produced. But fibrosis improvement was less clear-cut: 43% of the treatment group improved at least one fibrosis stage, versus 33% on placebo, a difference that was not statistically significant.²

The picture got more complicated in patients who already had cirrhosis. A separate phase 2 trial tested weekly semaglutide 2.4 mg in people with NASH-related compensated cirrhosis. After 48 weeks, fibrosis improvement was actually numerically lower in the semaglutide group than in the placebo group, and NASH resolution rates were not significantly different between the two groups.³ That means semaglutide’s benefits in NASH may not extend to the most advanced stage of the disease, at least not as a standalone treatment. The broader phase 3 program in non-cirrhotic patients produced stronger results, leading to the eventual approval.

Tirzepatide and the Multi-Agonist Approach

If one gut hormone receptor is good, the thinking goes, two might be better. Tirzepatide activates both the GLP-1 receptor and the GIP receptor, and it has produced some of the most striking NASH data in any trial so far. In a phase 2 trial of patients with MASH and moderate-to-severe fibrosis, treatment for 52 weeks led to MASH resolution without worsening fibrosis in 44%, 56%, and 62% of patients on the 5 mg, 10 mg, and 15 mg doses, compared with 10% on placebo. Fibrosis improvement of at least one stage without worsening of MASH occurred in about half of treated patients across all three dose groups, compared with 30% on placebo.⁴

The MASH resolution numbers are eye-catching, but the fibrosis results tell a slightly more cautious story. The difference over placebo for fibrosis improvement was roughly 20–25 percentage points, which is meaningful but narrower than the gap for NASH resolution. And this was a phase 2 study, meaning the patient numbers were relatively small. Phase 3 trials are underway to determine whether tirzepatide will join resmetirom and semaglutide as an approved NASH therapy.

Efruxifermin and the FGF21 Pathway

Fibroblast growth factor 21 (FGF21) is a hormone that regulates fat and sugar metabolism. Efruxifermin is an engineered analog of FGF21 designed to last longer in the body, and it has become one of the more closely watched compounds in the NASH pipeline, particularly for advanced disease.

In the HARMONY trial, which enrolled patients with moderate-to-severe fibrosis (F2–F3), about 39–41% of patients on efruxifermin (28 mg or 50 mg) achieved fibrosis improvement of at least one stage without worsening NASH after 24 weeks, compared with 20% on placebo.⁵ A meta-analysis pooling data across efruxifermin trials found that treated patients were roughly twice as likely to achieve that fibrosis improvement endpoint compared with placebo, and the drug also improved blood-based markers of fibrosis severity.⁶

What sets efruxifermin apart is its potential in cirrhosis. Many NASH drugs have shown limited or no benefit once the liver has progressed to stage F4 fibrosis. FGF21 analogs have shown the most encouraging early signals in that population, and a phase 2b trial testing efruxifermin specifically in patients with compensated cirrhosis due to MASH has been conducted, with results that could shape whether this drug enters late-stage development for the hardest-to-treat patients.⁷⁸

Lanifibranor and the PPAR Family

Lanifibranor takes yet another approach: it activates all three types of PPAR receptors, a family of proteins that regulate fat storage, inflammation, and the formation of scar tissue. In a phase 2 trial, the higher dose (1200 mg) led to NASH resolution without worsening fibrosis in 49% of patients versus 22% on placebo, and fibrosis improvement of at least one stage in 48% versus 29% on placebo. The combined endpoint of resolving NASH and improving fibrosis was met by 35% of patients on the higher dose versus 9% on placebo.⁹

Beyond the liver biopsy endpoints, lanifibranor showed meaningful metabolic benefits in a separate trial of patients with type 2 diabetes and liver fat. Liver fat content dropped by roughly 44% with lanifibranor versus 12% with placebo, and the drug improved both liver and whole-body insulin sensitivity. Blood sugar control also improved across several markers.¹⁰ Phase 3 trials are now in progress.

What Happened to Obeticholic Acid

Not every promising candidate makes it. Obeticholic acid (OCA), which activates the farnesoid X receptor (FXR) in the gut and liver, was for years the frontrunner in the NASH race. In its large REGENERATE trial, the 25 mg dose achieved fibrosis improvement in about 22% of patients versus 10% on placebo, a statistically significant result. But NASH resolution rates were low, reaching only about 7% versus 4% on placebo, a difference that did not reach significance.¹¹

The FDA ultimately declined to approve OCA, concluding that its moderate liver benefits did not outweigh a troublesome side-effect profile that included intense itching, worsened cholesterol levels, gallstones, and a signal of liver toxicity at higher doses.¹² OCA’s failure did not kill interest in the FXR pathway entirely. Newer FXR agonists with cleaner safety profiles are in development, and the FXR mechanism appears in several combination strategies.

Why Combination Therapy Is Probably the Future

NASH is driven by a tangle of overlapping problems: excess fat in the liver, chronic inflammation, insulin resistance, and progressive scarring. No single drug addresses all of these at once. The best monotherapy response rates top out around 30–60% for NASH resolution and lower for fibrosis improvement. The logic of combining drugs that hit different parts of the disease process is straightforward: if one drug reduces fat while another fights fibrosis, the pair could push response rates substantially higher than either alone.¹³

Early combination trials have already been run. One studied pairings of cilofexor (an FXR agonist), firsocostat (a fat-synthesis inhibitor), and selonsertib (an anti-inflammatory/antifibrotic agent) in patients with advanced fibrosis and cirrhosis. The cilofexor-firsocostat pair showed the most promise, producing improvements in NASH activity scores and several blood-based markers of fibrosis, although the primary biopsy endpoint did not reach statistical significance over placebo in this relatively small study.¹⁴

Designing combination trials is harder than it sounds. You need evidence that each drug in the pair adds something the other does not, and early-phase trials rarely generate enough data to predict how two mechanisms will interact. Safety monitoring becomes more complicated, regulatory pathways are less well-defined, and costs balloon.¹⁵ Still, the field widely expects that the most effective long-term treatment for NASH will involve two or more drugs used together, much like how hypertension and HIV are managed today.

The Biopsy Problem

One of the most frustrating aspects of NASH drug development is how researchers measure whether a drug is working. The gold standard is a liver biopsy: a needle punched through the skin to remove a small core of liver tissue, which a pathologist then scores under a microscope. The procedure is invasive, carries a small risk of serious bleeding, and can be painful enough that many patients refuse to repeat it.

Worse, biopsies are not as reliable as people assume. An analysis of how pathologists score the two main trial endpoints found poor agreement between readers. The weighted kappa scores, a measure of how consistently two experts rate the same slide, were just 0.40 for “NASH resolution without worsening fibrosis” and 0.37 for “fibrosis improvement without worsening NASH.”¹⁶ In practical terms, that means if two expert pathologists read the same biopsy slide, they would disagree about whether the patient met the treatment target a substantial fraction of the time. That level of disagreement adds noise to every trial result and may explain why some drugs show inconsistent benefits across studies.

Non-invasive alternatives are gaining ground. Blood-based markers of fibrosis, imaging techniques that measure liver stiffness, and composite scoring systems are all being tested as ways to select patients for treatment and monitor their response without repeated biopsies.¹⁷ Data from the obeticholic acid REGENERATE trial showed that certain non-invasive tests tracked well with biopsy-proven responses, meaning patients who improved on biopsy also improved on blood tests, and vice versa.¹⁸ If regulators eventually accept these surrogate markers, trials could become faster, cheaper, and far more patient-friendly.

What These Drugs Cost and Who Can Get Them

Resmetirom carries an annual price tag of roughly $19,000. A cost-effectiveness analysis found that at that price, it exceeded the commonly used willingness-to-pay threshold of $100,000 per quality-adjusted life-year, landing at about $140,000 per QALY. The researchers estimated the drug would need to be priced closer to $15,400 per year to meet that threshold.¹⁹

A broader comparison of pharmacologic options found that tirzepatide, if approved for NASH, would likely offer the best value, with a projected cost-effectiveness ratio of about $43,000 per QALY relative to standard care. Semaglutide was also cost-effective at roughly $80,000 per QALY. Resmetirom, by contrast, came in well above the threshold at around $273,000 per QALY in this model. Drug price was the single most influential variable in all of these estimates.²⁰ One reason for the different estimates across models is how researchers handle patient adherence and discontinuation rates; small shifts in those assumptions can swing the cost-effectiveness ratio dramatically.

Insurance coverage remains inconsistent. Many plans impose prior authorization requirements, and some deny coverage outright, particularly for resmetirom. The GLP-1 drugs face their own access challenges: supply constraints, high demand for their weight-loss indication, and insurer pushback on price have all limited availability. For the millions of Americans living with NASH, having approved drugs on the market does not automatically mean those drugs are affordable or obtainable.

Children and Adolescents With NASH

NASH is not just an adult disease. As childhood obesity rates have risen, so has pediatric fatty liver disease, and adolescents with severe MASLD tend to develop fibrosis more readily than adults with the same body weight. The condition is now the fastest-growing reason for liver transplants in young adults.²¹

Yet there is no FDA-approved drug for pediatric NASH. The obstacles are practical as much as scientific: diagnosis still requires liver biopsy, which raises ethical issues in children; non-invasive markers are less validated in younger patients; and recruiting children for long trials is difficult due to consent requirements, travel to specialized centers, and caregiver burden. The result is a much smaller and weaker evidence base than exists for adults.²² Some off-label use of vitamin E and metformin occurs in pediatric practice, but neither has strong evidence for reversing fibrosis in children. Whether and when the newer approved agents will be tested in pediatric populations remains an open question.

Cardiovascular Spillover Effects

NASH does not kill most patients through liver failure. The leading cause of death in people with NASH is cardiovascular disease. That makes the heart-related effects of NASH drugs more than a side benefit; they are arguably central to whether these treatments save lives.

Both resmetirom and semaglutide have shown reductions in the risk of major cardiovascular events, cardiovascular death, and all-cause mortality in patients with MASH.²³ Semaglutide’s cardiovascular benefits were already established in diabetes trials before it was tested in NASH, and resmetirom’s cholesterol-lowering effects likely contribute to its cardiovascular profile. Other drugs in the pipeline, including PPAR agonists, FXR agonists, and FGF21 analogs, have improved lipid and blood sugar profiles in trials, but their effects on hard cardiovascular outcomes like heart attacks and strokes have not yet been tested in large dedicated trials.²³ As more data accumulate, the cardiovascular profile of a NASH drug may become just as important as its liver biopsy results in determining which treatments doctors reach for first.

The Gut Microbiome Angle

A less conventional area of research involves the bacteria living in the gut. The gut and the liver are directly connected by the portal vein, and substances produced by intestinal bacteria, including toxins, metabolites, and inflammatory signals, drain straight into the liver. Disruptions in the gut microbial community have been consistently linked to NASH, and modifying those communities through probiotics, prebiotics, or other approaches has been proposed as a potential therapeutic strategy.²⁴

Small randomized trials of probiotic supplements in people with fatty liver disease have shown some improvements in liver enzymes and metabolic markers, but the evidence remains preliminary. No gut-focused therapy has come close to approval for NASH, and it is unclear whether microbiome interventions could ever match the effect sizes seen with drugs like semaglutide or efruxifermin.²⁵ Still, microbiome-based treatments could eventually find a role as adjuncts, particularly for patients who cannot tolerate or access conventional drug therapies.