Once-Daily Semaglutide Promising for Treating Severe Nonalcoholic Fatty Liver Disease

In this featured study from the New England Journal of Medicine, British researchers share the results of a phase 2 trial for semaglutide in 230 patients with NASH.

British researchers writing in the New England Journal of Medicine report that once-daily subcutaneous semaglutide was effective in treating some patients with nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease characterized by excess fat, inflammation and liver damage.

Despite its prevalence and high rate of morbidity and mortality, there are few treatments options for patients with nonalcoholic steatohepatitis, which disproportionately affects patients with diabetes.

Led by Philip N. Newsome, MBChB, PhD, of the University of Birmingham, United Kingdom, researchers conducted a 72-week randomized double-blind placebo-controlled phase 2 clinical trial of 302 patients with biopsy confirmed nonalcoholic steatohepatitis and liver fibrosis of stage F1, F2, or F3.

Patients were recruited from 143 sites in 16 countries between 2017 and 2018. Patient characteristics included:  mean age 55 years, , 61% were women, 78% White, mean BMI was 35.8 kg/m2, 62% had type 2 diabetes, 28% had F1 fibrosis, 22% F2 fibrosis, and 49% had F3 fibrosis. They were randomized to receive once-daily subcutaneous semaglutide at a dose of 0.1 mg (80 patients), 0.2 (78 patients), or 0.4 mg (82 patients) or placebo (80 patients). s were collected at baseline and week 72.

The proportion of patients who improved by ³2 fibrosis stages was 25%, 19%, 20%, and 17% for the 0.1, 0.2, 0.4, mg semaglutide and placebo cohorts, respectively. Of patients who received low dose semaglutide, 10% experienced worsening fibrosis as compared to 8% of the intermediate group, 5% percent of the high dose group, and 19% of the placebo group. Few patients in the treatment group (3%, 3%, 0%) and placebo (4%) progressed to fibrosis stage F4.

At 72 weeks, a similar proportion of patients in the 0.4 mg treatment and placebo groups improved ³1 fibrosis stage (43% vs 33%; odds ratio [OR], 1.42; 95% CI, 0.62-3.28; P =.48). A total of 37% of the 0.4 mg semaglutide recipients and 15% of the placebo cohort had both nonalcoholic steatohepatitis resolution and an improvement of ³1 fibrosis stage.

Compared with placebo, treatment recipients were more likely to have resolution of nonalcoholic steatohepatitis without worsening of fibrosis with an OR of 3.36 (95% CI, 1.29-8.86) for low dose, 2.71 (95% CI, 1.06-7.56) for intermediate dose, and 6.87 (95% CI, 2.60-17.63; P <.001) for high dose treatment groups.

In addition, the placebo cohort lost 0.61% of their body weight during the trial compared with 4.84%, 8.91%, and 12.51% among the 0.1, 0.2, 0.4, mg semaglutide recipients, respectively.

Trial discontinuation due to adverse events occurred among 7% of the treatment and 5% of the placebo recipients. The motivation for discontinuation was most commonly gastrointestinal symptoms among the treatment group. Hepatic events occurred among 6% of the low, 5% of the intermediate, and 7% of the high dose groups compared with 2% of the placebo cohort.

Liver failure is the fourth leading cause of death for patients with diabetes, according to the Verona Diabetes Study published in 1999. Approximately 35% of patients with nonalcoholic steatohepatitis will develop liver fibrosis, end-stage liver disease or hepatocellular carcinoma. It is estimated that non-alcoholic fatty liver disease affects 45-75% of patients with type 2 diabetes and 20-30% of western countries in general.

This study was limited by its timeline, it remains unclear what effects semaglutide will have long-term, the authors wrote.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Newsome P N, Buchholtz K, Cusi K, et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. New England Journal of Medicine. March 25, 2021;384(12):1113-1124. doi:10.1056/NEJMoa2028395.