Mixed Bag for Semaglutide in NASH-Related Compensated Cirrhosis

Although semaglutide (Ozempic) missed its mark in improving liver fibrosis for patients with nonalcoholic steatohepatitis (NASH)-related cirrhosis, improvements were noted in cardiometabolic parameters and other biomarkers, according to a randomized phase II trial.

Among 71 patients, 10.6% of those who received once-weekly subcutaneous semaglutide 2.4 mg experienced an improvement in liver fibrosis without any worsening of NASH compared with 29.2% of those who received placebo (P=0.087), reported Rohit Loomba, MD, MHSc, of the University of California San Diego.

Of note, 34% of semaglutide patients saw a resolution of NASH versus 20.8% of placebo patients (P=0.286), Loomba pointed out during a late-breaking presentation at the European Association for the Study of the Liver (EASL) annual meeting.

Semaglutide also led to a reduction in triglycerides (estimated treatment ratio [ETR] 0.83), as well as very low-density lipoprotein cholesterol (ETR 0.83; P=0.01 for both).

In addition, semaglutide was linked to significant improvements in Pro-C3 levels (ETR 0.84) and liver steatosis (ETR 0.67), as well as liver enzyme levels, such as aspartate aminotransferase (ETR 0.77), alanine aminotransferase (ETR 0.76), and gamma-glutamyl transferase (ETR 0.74), but not liver stiffness as assessed by magnetic resonance elastography (ETR 0.93), compared with placebo.

Semaglutide also significantly decreased body weight (estimated treatment difference [ETD] -8.75 kg), and improved HbA1c levels (ETD -1.63) for patients with type 2 diabetes, Loomba noted.

“Although the primary endpoint was not met, once-weekly semaglutide 2.4 mg appeared safe and was well-tolerated in this 48-week trial in patients with NASH and compensated cirrhosis,” he concluded.

Patients with NASH and compensated cirrhosis are at greater risk of both liver-related and all-cause morbidity and mortality. A previous phase II trial found that semaglutide, a glucagon-like peptide-1 receptor agonist, resulted in higher rates of NASH resolution compared with placebo.

“Many patients with cirrhosis and comorbid diabetes or obesity may be interested in using semaglutide or other glucagon-like peptide-1 receptor agonists for treatment of diabetes or obesity; however, previously we did not have available safety information on these medications in patients with cirrhosis,” Michelle Long, MD, of Boston Medical Center, who was not involved in the study, told MedPage Today. “This study provides some evidence that semaglutide may be a safe medication with good tolerability in patients with cirrhosis.”

For their study, Loomba and colleagues randomized 71 patients with NASH-related cirrhosis to either once-weekly subcutaneous semaglutide (n=47) or placebo (n=24).

Baseline characteristics were similar between groups. Mean age was 59.5, 69% were women, and mean BMI was 35. Mean NAFLD [nonalcoholic fatty liver disease] activity score was 4.8, and 75% had type 2 diabetes.

The majority had grade 1 steatosis (63-68%), and grade 2 lobular inflammation (66-71%) and hepatocyte ballooning (62-67%). At baseline, mean alanine aminotransferase level was 36-48 U/L and mean aspartate aminotransferase was 39-47 U/L, with a mean model for end-stage liver disease (MELD) score of 7.6-7.7. Mean Pro-C3 was 18-20 ng/mL.

Hepatic and renal function remained stable with the use of semaglutide. Similar rates of adverse events were seen between the treatment and placebo groups (89% vs 79%). Adverse events with semaglutide were mostly mild to moderate gastrointestinal disorders (77%). Serious and severe adverse events with semaglutide occurred at low rates (13% and 17%). Notably, only 6% of patients discontinued treatment because of adverse events.

A post-hoc exploratory analysis also found no significant differences between semaglutide and placebo for the primary or secondary endpoints evaluated manually versus PathAI machine learning software.

Larger trials are needed to determine whether semaglutide improves liver-related morbidity and mortality in patients with NASH and compensated cirrhosis, Loomba and team said.