Issue: May 2023
Fact checked byHeather Biele

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April 03, 2023
2 min read
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No difference between semaglutide, placebo in fibrosis improvement in patients with NASH

Issue: May 2023
Fact checked byHeather Biele
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Key takeaways:

  • Semaglutide did not significantly improve fibrosis or achieve resolution in patients with NASH and compensated cirrhosis.
  • Adverse events were mild to moderate, with no new safety concerns reported.
Perspective from Jamile’ Wakim-Fleming, MD

Although semaglutide did not “significantly improve” fibrosis in patients with nonalcoholic steatohepatitis and compensated cirrhosis, notable improvements were reported in cardiometabolic parameters and markers of liver fat and injury.

“Previous studies in patients with NASH and stage 2 or 3 fibrosis have shown that semaglutide can improve NASH resolution over 72 weeks. However, there are limited data whether any therapy is effective in patients with NASH cirrhosis,” Rohit Loomba, MD, MHSc, director of hepatology and the NAFLD Research Center and vice chief of gastroenterology at the University of California, San Diego, told Healio. “Patients with NASH-related cirrhosis are at high risk for dying from liver diseases.”

“GLP-1 analogue exposure among patients with compensated cirrhosis who suffer from morbid obesity and type 2 diabetes for the treatment of diabetes appears to be well-tolerated and may be safe.” Rohit Loomba, MD

He continued: “We wanted to assess whether glucagon-like peptide-1 (GLP-1) analogues will be able to reverse features of NASH-cirrhosis and also the validity and clinical utility of endpoints, whether histologic or noninvasive, in assessing improvements in cirrhosis due to NASH with semaglutide vs. placebo. We also wanted to assess safety and tolerability of semaglutide in this population.”

In a double-blind, placebo-controlled phase 2 trial published in The Lancet Gastroenterology & Hepatology, Loomba and colleagues enrolled 71 patients (69% women; mean age, 59.5 years) with biopsy-confirmed NASH-related cirrhosis and a BMI of at least 27 kg/m2 between June 2019 and April 2021. Participants received once-weekly subcutaneous semaglutide 2.4 mg (n = 47) or placebo (n = 24). Mean BMI was 34.9 kg/m2 and 75% of patients had diabetes.

The primary outcome of interest was the proportion of patients with improved liver fibrosis without worsening of NASH.

After 48 weeks, researchers observed “no statistically significant” difference in improved liver fibrosis among patients in the semaglutide group (11%) compared with the placebo group (29%; 0R = 0.28; 95% CI, 0.06-1.24). They also reported no difference in NASH resolution between groups (34% vs. 21%; OR = 1.97; 95% CI, 0.56-7.91).

Although a lower proportion of patients achieved NASH resolution and improved liver fibrosis at 48 weeks with semaglutide compared with placebo, this difference was not significant (6% vs. 13%; OR = 0.48; 95% CI, 0.06-3.91).

Compared with placebo, a greater proportion of patients in the semaglutide group had improvements in steatosis grade (45% vs. 33%), liver steatosis from baseline (estimated treatment ratio = 0.67; 95% CI, 0.51-0.88) and liver fat volume. More patients in the study group had at least a 30% reduction in steatosis (49% vs. 13%; OR = 6.58; 95% CI, 1.63-39.31) at 48 weeks.

Researchers reported similar trends between groups in adverse events (89% vs. 79%) and serious adverse events (13% vs. 8%).

“Future trials with larger sample sizes will be needed to determine whether semaglutide alone or in combination with other liver-targeted agents will improves outcomes such as liver-related morbidity and mortality in patients with NASH and compensated cirrhosis,” Loomba said. “GLP-1 analogue exposure among patients with compensated cirrhosis who suffer from morbid obesity and type 2 diabetes for the treatment of diabetes appears to be well-tolerated and may be safe. Further studies are needed in this study population.”