No difference between semaglutide, placebo in fibrosis improvement in patients with NASH
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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.
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.”
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.”
Perspective
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Jamile’ Wakim-Fleming, MD
The progressive and continuous rise in obesity rates and consequences on cardiometabolic factors and the liver over the past 25 years have led to multiple studies to understand the pathophysiology and future therapeutic modalities.
Beginning with the STEP trials and in tandem, the FLINT, LEAN, REGENERATE trials, research has shown that glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective in obesity management, type 2 diabetes and fatty liver disease. Hence, their FDA approval to treat obesity and type 2 diabetes.
Fatty liver disease is a complex disease that encompasses fatty liver, fibrosis, NASH and more advanced cirrhosis. While several studies have shown the benefit of GLP-1 RA in resolving fat and some degree of fibrosis, studies in cirrhosis have been scarce and results are inconsistent.
In the study led by Loomba and colleagues at 38 centers in Europe and the U.S., 71 patients with NASH and compensated cirrhosis were eligible to enroll and randomized to receive 2.4 mg semaglutide, which has been FDA-approved for treatment of obesity and type 2 diabetes, weekly for 48 weeks (n = 47) or placebo (n = 24).
Results of the study did not show a significant benefit in improving fibrosis or NASH resolution compared with placebo. However, results did demonstrate significant improvement in weight loss, liver enzymes, triglyceride and very low-density lipoprotein levels without significant side effects. These findings are of major importance to the overall health of the study participants and a steppingstone for longer trial duration.
While it takes about 10 to 15 years for fatty liver to induce cirrhosis, one may speculate that similar studies conducted over at least 72 weeks in individuals with cirrhosis may show benefit in resolution of cirrhosis. More research is needed to find out.
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