Ozempic for NASH: Off-Label Use, Evidence, and Monitoring Requirements

What is NASH called now?

NASH is now MASH. A 2023 multisociety Delphi process replaced nonalcoholic fatty liver disease with metabolic dysfunction-associated steatotic liver disease, and NASH with metabolic dysfunction-associated steatohepatitis [4]. A 2026 review estimates MASH affects roughly 3% to 5% of adults worldwide and up to 30% to 40% of people with type 2 diabetes or those attending diabetes and endocrine centers [5].

Is Ozempic approved for NASH?

No. The Ozempic label lists three uses, all in adults with type 2 diabetes: glycemic control, reduction of major adverse cardiovascular events in people with established cardiovascular disease, and reduction of sustained eGFR decline, end-stage kidney disease and cardiovascular death in people with chronic kidney disease [1]. NASH or MASH is not an Ozempic indication.

The semaglutide product that carries a MASH indication is Wegovy injection. It is approved for noncirrhotic MASH with moderate to advanced fibrosis, stage F2 or F3, under accelerated approval based on improvement in steatohepatitis and fibrosis; continued approval may be contingent on a confirmatory trial [3][11]. That indication does not extend to Ozempic, so using Ozempic for NASH would be off-label.

What the trials actually measured

NASH-1: once-daily semaglutide, phase 2

Newsome and colleagues ran a 72-week, double-blind trial in 320 adults with biopsy-confirmed NASH and fibrosis stage F1, F2 or F3. Of those, 230 had F2 or F3 fibrosis, and the two histologic endpoints were analysed only in that group. Patients received subcutaneous semaglutide 0.1, 0.2 or 0.4 mg once daily or placebo [2].

• NASH resolution without worsening fibrosis: 40% (0.1 mg), 36% (0.2 mg) and 59% (0.4 mg) versus 17% on placebo (P<0.001 for 0.4 mg versus placebo) [2]
• Fibrosis improvement of at least one stage: 43% on 0.4 mg versus 33% on placebo (P=0.48) [2]
• Mean weight change: -13% on 0.4 mg versus -1% on placebo [2]
• Nausea 42% versus 11%; constipation 22% versus 12%; vomiting 15% versus 2% [2]

That fibrosis result is the one to keep in view. The daily 0.4 mg dose resolved steatohepatitis more often than placebo but did not significantly improve fibrosis in this trial.

ESSENCE: once-weekly 2.4 mg, phase 3

ESSENCE randomised 1,197 adults with biopsy-defined MASH and fibrosis stage F2 or F3, in a 2:1 ratio, to semaglutide 2.4 mg weekly or placebo for a planned 240 weeks. The published results are a planned interim analysis at week 72 covering the first 800 patients [3].

• Steatohepatitis resolution without worsening fibrosis: 62.9% versus 34.3% (difference 28.7 percentage points, 95% CI 21.1 to 36.2; P<0.001) [3]
• Fibrosis reduction without worsening steatohepatitis: 36.8% versus 22.4% (difference 14.4 percentage points, 95% CI 7.5 to 21.3; P<0.001) [3]
• Mean weight change: -10.5% versus -2.0% [3]

These are the numbers behind the Wegovy MASH approval, and they came from 2.4 mg once weekly, not from an Ozempic dose.

Class-level data

A 2021 meta-analysis pooled 11 randomised phase 2 trials of GLP-1 receptor agonists in fatty liver disease, 936 participants in total: six of liraglutide, three of exenatide, one of dulaglutide and one of semaglutide. Liver fat on MRI-based techniques fell by a pooled weighted mean difference of 3.92 percentage points (95% CI -6.27 to -1.56), and NASH resolved more often (pooled odds ratio 4.06, 95% CI 2.52 to 6.55, for the liraglutide and semaglutide trials) [7].

What doses were studied, and how do they compare with Ozempic?

Ozempic's label titration is 0.25 mg once weekly for 4 weeks (not a maintenance dose), then 0.5 mg; 1 mg after at least 4 weeks on 0.5 mg; 2 mg after at least 4 weeks on 1 mg; maximum 2 mg weekly [1].

Neither studied regimen matches that schedule. NASH-1 used once-daily dosing, and ESSENCE used 2.4 mg once weekly, a Wegovy dose above Ozempic's 2 mg ceiling [2][3]. Because neither trial used 0.5, 1 or 2 mg once weekly, these results do not show what an Ozempic dose does to liver histology.

What the Ozempic label says to monitor

The Ozempic warnings list no liver-enzyme monitoring schedule. Its monitoring instructions point elsewhere [1]:

• Kidney function in patients reporting reactions that could lead to volume depletion, especially during dose escalation. Acute kidney injury has been reported, mostly after gastrointestinal fluid loss [1].
• Progression of diabetic retinopathy in patients with a history of it. In a 2-year cardiovascular trial, retinopathy complications occurred in 3.0% on semaglutide versus 1.8% on placebo, and in 8.2% versus 5.2% of those who had retinopathy at baseline [1].
• Hypoglycemia when Ozempic is combined with insulin or a sulfonylurea; the label says to consider a lower dose of the insulin or secretagogue when starting [1].

The label says to discontinue Ozempic if pancreatitis is suspected, and that gallbladder studies are indicated if cholelithiasis or cholecystitis is suspected [1]. It recommends no dose adjustment for renal or hepatic impairment [1], and says to discontinue at least 2 months before a planned pregnancy because of the long washout period [1]. The boxed warning describes thyroid C-cell tumors in rodents; whether Ozempic causes them in humans is unknown [1]. Contraindications are a personal or family history of medullary thyroid carcinoma or MEN 2, and a prior serious hypersensitivity reaction to semaglutide or an excipient [1].

In Ozempic's pooled placebo-controlled trials, with a mean exposure of 32.9 weeks, nausea was 20.3% on 1 mg versus 6.1% on placebo, any gastrointestinal reaction 36.4% versus 15.3%, and discontinuation for gastrointestinal reasons 3.8% versus 0.4% [1]. The label also says Ozempic is not recommended in patients with severe gastroparesis [1].

How liver response was assessed

The trials judged success on paired liver biopsies at 72 weeks [2][3]. Weight loss itself tracks with liver improvement: in a prospective study of 293 adults with NASH who followed lifestyle changes for 52 weeks, with paired biopsies available for 261, 90% of those who lost at least 10% of body weight had NASH resolution and 45% had regression of fibrosis [9].

Who the trials enrolled

NASH-1 enrolled fibrosis stages F1 to F3 and ESSENCE stages F2 to F3, so neither trial speaks to cirrhosis [2][3].

How semaglutide compares with resmetirom

Resmetirom (Rezdiffra), a thyroid hormone receptor beta agonist, is an FDA-approved MASH drug [5]. In MAESTRO-NASH, 966 adults with biopsy-confirmed NASH and fibrosis stage F1B to F3 took resmetirom 80 mg, 100 mg or placebo for 52 weeks. NASH resolution without worsening fibrosis occurred in 25.9% on 80 mg and 29.9% on 100 mg versus 9.7% on placebo, and fibrosis improvement of at least one stage without worsening the activity score in 24.2% and 25.9% versus 14.2% [10].

Those figures come from a separate trial with a shorter duration (52 versus 72 weeks) and different entry criteria than ESSENCE, so they cannot be used to rank the two drugs.