Semaglutide Improves Liver Fibrosis in New Trial Analysis

Two separate phase 3 trials show that semaglutide improved fatty liver disease and reduced hospitalizations related to cardiovascular risk in obese patients. Novo Nordisk’s semaglutide is marketed as Ozempic to treat patients with diabetes and Wegovy is marketed for weight loss.

In the ongoing ESSENCE trial, 37% of the 800 adults with metabolic dysfunction-associated steatohepatitis (MASH) and moderate-to-advanced liver fibrosis achieved improvement in liver fibrosis with no worsening of steatohepatitis compared with 22.5% of patients on placebo. Additionally, 62.9% of people treated achieved resolution of steatohepatitis with no worsening of liver fibrosis compared with 34.1% on placebo.

MASH — also called nonalcoholic steatohepatitis (NASH) — is a severe form of fatty liver disease. It is a leading cause of liver-related mortality, especially for those with hypertension and type 2 diabetes and affects between 1.5% and 6.5% of U.S. adults. The number of people in advanced stages of the disease is expected to double by 2030.

Martin Holst Lange

“Among people with overweight or obesity, one in three live with MASH. This has a serious impact on their health and represents a significant unmet need,” Martin Holst Lange, executive vice president and head of Development at Novo Nordisk, said in a news release.

Part 1 of the ESSENCE trial evaluated the effect of once-weekly semaglutide 2.4 mg on liver tissue (histology) compared with placebo on top of standard of care for the first 800 randomized people at 72 weeks.

Novo Nordisk expects to file for regulatory approvals in the United States and European Union in the first half of 2025. Company officials said detailed results will be presented at an upcoming conference. In part 2 of the ESSENCE trial, semaglutide 2.4 mg is being evaluated to determine if it can lower liver-related clinical events compared with placebo at 240 weeks. Results of part 2 are expected in 2029.

Related: Providing Access to Rezdiffra for NASH and the Therapies to Come

Earlier this year, the FDA granted accelerated approval for Rezdiffra (resmetirom), the first drug approved specifically for MASH. Traditionally, treatments that have been used for MASH have included lifestyle modification and off-label use of therapies such as semaglutide or tirzepatide (marketed as Mounjaro for diabetes and Zepbound for weight loss).

Rezdiffra, developed by Madrigal Pharmaceuticals, is an oral therapy to treat advanced liver fibrosis, and it launched with a wholesale acquisition cost of $47,400 per year. As of Sept. 30, 2024, coverage for Rezdiffra was in place for more than 80% of commercial lives covered by health insurance in the United States, according to a company news release. Rezdiffra is being assessed in the MAESTRO-NASH OUTCOMES trial the treatment of patients with compensated cirrhosis, which is an earlier, asymptomatic stage of liver disease.

In a separate Novo Nordisk trial, the SELECT phase 3 cardiovascular outcomes trial, an exploratory post hoc analysis showed semaglutide 2.4 mg reduced hospital admissions and overall length of hospital stay for adults with obesity or who were overweight with established cardiovascular disease (CVD) and without diabetes.

Obesity increases the risk of cardiovascular disease, including heart attack and stroke, while also contributing to the progression of other cardiovascular risk factors including elevated blood pressure and cholesterol.

The analysis of SELECT indicated that a lower percentage of patients taking semaglutide experienced a first hospital admission for any indication versus placebo and for serious adverse events. In addition, the number of total hospitalizations was lower in the semaglutide group versus placebo for all indications.

Safety data collected in the SELECT trial was limited to serious adverse events (including death), adverse events leading to discontinuation, and adverse events of special interest. In the trial 16% of semaglutide 2.4 mg-treated patients and 8% of placebo-treated patients, respectively, discontinued the study drug due to an adverse event. The most common adverse event leading to discontinuation was gastrointestinal disorders, occurring in 10% of patients in the semaglutide group and 2% in the placebo group

These results were presented during an oral session at the annual ObesityWeek conference. The trial, initiated in 2018, enrolled 17,604 adults and was conducted in 41 countries at more than 800 investigator sites.

Related: Wegovy Cuts Risk of Serious Cardiovascular Events By 20% in Those Without Diabetes, Study Finds

Data from the SELECT trial on the impact of semaglutide on cutting cardiovascular risk was first presented last year at the American Heart Association Scientific Sessions. The trial enrolled 17,604 adults aged 45 years or older with obesity and established cardiovascular disease with no prior history of diabetes.