Semaglutide Normalized Liver Fat in Most Adults With Obesity

Once-weekly semaglutide (Wegovy; Novo Nordisk) lowered liver fat below the 5% threshold considered normal in 23 of 26 adults with obesity and elevated baseline liver fat, according to a post hoc analysis of the STEP UP trial (NCT05646706) program presented at the European Association for the Study of Diabetes (EASD) Annual Meeting 2026 in Milan, Italy. The findings come from a small imaging subgroup, but they add liver data to a weight management regimen many pharmacists already dispense and counsel on.¹

Liver Fat Fell From 8.8% to 3.1%

The analysis measured liver fat directly in 55 participants using magnetic resonance imaging–proton density fat fraction (MRI-PDFF), the noninvasive gold-standard technique for quantifying hepatic steatosis. Among participants receiving semaglutide, with the 7.2-mg and 2.4-mg doses pooled, mean liver fat declined from 8.8% at baseline to 3.1% at week 72. Of the 26 participants who entered with liver fat above 5%, 23 (88.5%) fell below that threshold by week 72. The release did not report a placebo comparison for these liver fat outcomes.¹

A High-Risk Population With Little Advanced Disease

The broader exploratory analysis pooled 1919 adults from STEP UP and STEP UP T2D, including 1312 who received semaglutide 7.2 mg, 304 who received semaglutide 2.4 mg, and 303 who received placebo. At baseline, more than 94% of participants in all groups were classified as high risk for fatty liver by the Fatty Liver Index (FLI), a composite score built from BMI, waist circumference, triglycerides, and gamma-glutamyl transferase. Fewer than 1% met criteria for advanced fibrosis risk by the FIB-4 index. Liver outcomes were not prespecified primary or secondary end points of either parent trial.^1-3

Parent Trials and Tolerability

STEP UP randomly assigned 1407 adults with obesity and without diabetes 5:1:1 to semaglutide 7.2 mg, semaglutide 2.4 mg, or placebo with a lifestyle intervention for 72 weeks. Mean body weight changed by −18.7% with 7.2 mg, −15.6% with 2.4 mg, and −3.9% with placebo. Gastrointestinal adverse events occurred in 70.8%, 61.2%, and 42.8% of participants, respectively, and dysesthesia, or abnormal skin sensation, occurred in 22.9%, 6.0%, and 0.5%.²

STEP UP T2D enrolled 512 adults with obesity and type 2 diabetes, randomly assigned 3:1:1. Semaglutide 7.2 mg reduced body weight by 13.2% vs 3.9% with placebo. Dysesthesia was reported in 18.9% of participants receiving 7.2 mg, 4.9% receiving 2.4 mg, and none receiving placebo. Both trials were funded by Novo Nordisk.^2,3

For pharmacists, the higher rates of gastrointestinal effects and dysesthesia at the 7.2-mg dose are practical counseling points, particularly for patients stepping up from 2.4 mg.

MASH Indication Applies to the 2.4-mg Dose

According to Novo Nordisk, semaglutide 2.4 mg is approved under the Wegovy brand for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) in the US, Canada, the UK, China, and several other markets. The company stated that semaglutide 7.2 mg is not being investigated for MASH, a distinction pharmacists may need to keep in view when reviewing prescriptions or prior authorization requests that cite liver disease.¹

Investigators framed the STEP UP analysis as reinforcing results from the dedicated phase 3 ESSENCE trial (NCT04822181). That trial randomly assigned 1197 patients with MASH and moderate to advanced fibrosis (stage F2 or F3) 2:1 to semaglutide 2.4 mg or placebo on top of standard of care. In part 1, semaglutide improved fibrosis without worsening steatohepatitis and resolved steatohepatitis without worsening fibrosis compared with placebo at 72 weeks. Part 2 results are expected in 2029.¹

Metabolic dysfunction-associated steatotic liver disease, formerly called nonalcoholic fatty liver disease, can progress to MASH, fibrosis, and cirrhosis if left unaddressed.¹

REFERENCES

1. Novo's Wegovy (semaglutide) reduced liver fat to normal levels in 9 out of 10 adults with obesity and excess liver fat – EASD2026. News release. Novo Nordisk. October 1, 2026. Accessed October 5, 2026. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=917205

2. Wharton S, Freitas P, Hjelmesæth J, et al. Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial. Lancet Diabetes Endocrinol. 2025;13(11):949-963. doi:10.1016/S2213-8587(25)00226-8

3. Lingvay I, Bergenheim SJ, Buse JB, et al. Once-weekly semaglutide 7·2 mg in adults with obesity and type 2 diabetes (STEP UP T2D): a randomised, controlled, phase 3b trial. Lancet Diabetes Endocrinol. 2025;13(11):935-948. doi:10.1016/S2213-8587(25)00225-6