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Semaglutide Increases NASH Resolution but Does Not Improve Fibrosis Stage
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In this 72-week phase II trial, 320 patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) and liver fibrosis were randomized to receive semaglutide at 0.1 mg, 0.2 mg, or 0.4 mg, or to placebo. NASH resolution was achieved with no worsening of fibrosis in 40% of patients in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group. Average weight loss was 13% in the 0.4-mg group and 1% in the placebo group. Nausea, constipation, and vomiting were more frequently reported in the 0.4-mg group compared with the placebo group.
- These data demonstrate that semaglutide treatment leads to significantly increased NASH resolution compared with placebo; however, no difference in fibrosis stage improvement was observed.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known.
METHODS
We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients.
RESULTS
In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P=0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed.
CONCLUSIONS
This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942. opens in new tab.)
Additional Info
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Diabetes
There currently are no drugs approved by the FDA for treatment of nonalcoholic steatohepatitis (NASH). This phase II study provides evidence of the safety and efficacy of semaglutide, a glucagon-like peptide-1 (GLP-1) agonist, in the treatment of NASH. A different GLP-1 agonist, liraglutide, had also previously been shown to be superior to placebo in resolution of NASH without worsening of fibrosis.1 The findings in this study suggest a class effect, leading to several practical implications.
Both semaglutide (albeit in lower doses than those investigated) and liraglutide are approved for the treatment of diabetes, with NASH present in about 60% to 70% of those patients (conversely, 20% of patients with NASH also have diabetes).2 Hence, when choosing an anti-diabetes drug in this group of patients, a GLP-1 agonist should be prioritized.
Over 50% of patients with NASH have obesity.2 In this study, semaglutide 0.4 mg subcutaneously daily led to a 13% total body weight loss on average, a rate which is similar to those in a phase II study for weight loss in patients with obesity without DM.3 It is known that a total body weight loss of 7% or more leads to significant improvement in NASH without worsening of fibrosis.4 It is unclear if the effect seen in this study was independent of weight loss, but it suggests that semaglutide is an effective anti-obesity medication and should also be prioritized in patients treated for obesity who have comorbid NASH.
References
Primary Care
Semaglutide for NASH
There are currently no FDA-approved drugs for nonalcoholic steatohepatitis (NASH). This industry-sponsored study studied 302 patients with NASH and fibrosis. The primary endpoints were resolution of NASH and fibrosis. A liver biopsy was completed at baseline and after 72 weeks. There were three doses of semaglutide (0.1, 0.2, and 0.4 mg) studied against placebo. The patients were started at 0.05 mg and increased to 0.1 mg after 1 week. The higher-dose groups were increased weekly by 0.1 mg until 0.2 or 0.4 mg was reached.
Dosage
# of Subjects
% Resolution
Body Wt.
ALT
Placebo
80
17%
-1%
-19%
0.1 mg semaglutide
80
40%
-5%
-37%
0.2 mg semaglutide
78
36%
-9%
-42%
0.4 mg semaglutide
82
59%
-13%
-53%
The table above summarizes the results after 72 weeks of treatment. Unfortunately, there was no improvement in fibrosis compared with placebo.
Think of glucagon-like peptide-1 (GLP-1) agonists as the “I am full hormones.” They trick the body into thinking it just ate. When we eat, glucagon is released to slow transit of the stomach so the body can absorb the nutrients. Slowing transit can cause nausea as if someone just ate a large meal. This also helps explain the main side effects in this study, which were nausea (42%), decreased appetite (22%), constipation (22%), vomiting (15%), and abdominal pain (7%). This is also the reason one needs to slowly titrate up the dose.
This class of medications are most effective for their effects on weight loss. Previous studies have shown that weight loss is the primary treatment for resolving NASH. Unfortunately, these studies also did not show improvement in fibrosis.1 This is why it is also vital to improve nutrition. A study of the Mediterranean diet was found to have a positive effect on NASH even without weight loss.2
Semaglutide and other GLP-1 agonists will be useful tools to treat NASH. But the health mantra continues: Good nutrition with less sugar to maintain an ideal weight with exercise to push sugar into the muscles is the gold standard that will cure this preventable disease.
References