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Semaglutide alone or in combination regimens shows promise for NASH

Liz Highleyman
18 December 2020

Semaglutide, a medication approved to treat type 2 diabetes, increased the likelihood of improvement in non-alcoholic steatohepatitis (NASH) without worsening liver fibrosis, researchers reported at the AASLD virtual Liver Meeting.

What's more, combining semaglutide with two other drugs – firsocostat and cilofexor – led to greater improvements in various measures of fibrosis, metabolism and liver health.

Non-alcoholic fatty liver disease (NAFLD) and its more severe form, NASH, are responsible for a growing burden of advanced liver disease worldwide. Linked to obesity and diabetes, NAFLD/NASH is increasingly recognised as a manifestation of the metabolic syndrome. The build-up of fat in the liver triggers cell death and inflammation, which over time can lead to fibrosis, cirrhosis, liver cancer and liver failure. 



A non-invasive test, used instead of a biopsy, to measure the stiffness or elasticity of the liver using an ultrasound probe.

With no approved therapies, lifestyle modification and weight loss are currently the mainstays of NAFLD/NASH management. Developing medications for NAFLD and NASH has been challenging, and several drugs that appeared promising in early studies did not show significant benefits in larger trials. Given the multiple biological processes that play a role in the development of NAFLD/NASH, many experts think optimal treatment may require combining drugs with different mechanisms of action.

Semaglutide monotherapy

Prof. Philip Newsome of Birmingham Biomedical Research Centre presented results from an international phase II trial of semaglutide (Ozempic, from Novo Nordisk) for people with NASH. The findings were also published in the New England Journal of Medicine.

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that mimics the action of natural GLP-1, which increases insulin secretion and plays a role in appetite regulation and glucose and lipid metabolism.

The study enrolled people with biopsy-confirmed NASH, mild to advanced liver fibrosis (stage F1 to F3), an NAFLD activity score of 4 or higher and body mass index (BMI) greater than 25, indicating overweight or obesity. About 60% were women, nearly 80% were White and the mean age was 55 years. Nearly two-thirds had diabetes and half had advanced fibrosis.

Participants were randomly assigned to receive one of three doses of semaglutide (0.1, 0.2 or 0.4mg) or a placebo administered by subcutaneous injection once daily for 72 weeks. (There is also an oral formulation of semaglutide [Rybelsus] that was not used in this study.) Liver biopsies were performed at baseline and at the end of the study.

The primary study endpoint, assessed in the 230 patients with stage F2 or F3 fibrosis, was NASH resolution with no worsening of fibrosis. Improvement in fibrosis with no worsening of NASH was a secondary endpoint. (Some other NASH trials look at these endpoints in the reverse order.)

Significantly more participants taking any dose of semaglutide experienced NASH resolution (40%, 36% and 59%, respectively, in the 0.1, 0.2, and 0.4mg dose groups) compared with the placebo arm (17%).

The proportion of people with fibrosis improvement was statistically similar in all groups: 46%, 32% and 43% in the three semaglutide dose groups compared with 31% in the placebo group. However, fewer people assigned to semaglutide experienced liver fibrosis progression: 10%, 8% and 5% in the three dose groups versus 19% in the placebo group. The remaining participants either saw no change or had missing data.

People randomised to semaglutide saw greater improvements in fibrosis biomarkers, liver enzyme levels (ALT, AST and GGT) and liver stiffness according to FibroScan imaging. In addition, people taking semaglutide lost more weight (-13% with the highest dose compared to just -1% in the placebo group).

People who used semaglutide also had improvements in various metabolic measures including average glucose level (as measured by HbA1c tests) and lipid profiles. Harmful cholesterol, triglycerides and free fatty acid levels declined, while beneficial HDL cholesterol rose.

Treatment was generally well tolerated and the safety profile was consistent with use of semaglutide as a diabetes treatment. The most common adverse events were gastrointestinal symptoms, including nausea, vomiting, diarrhoea and constipation, which occurred more often with semaglutide, especially in the highest dose group. Treatment-related severe adverse events were rare (4% or less).

Newsome concluded that semaglutide led to a higher rate of NASH resolution without fibrosis worsening. He suggested the lack of significant improvement in fibrosis could mean that this takes longer and might become apparent with extended follow-up.

Semaglutide combination regimens

In another phase II study, Dr Naim Alkhouri of Arizona Liver Health and colleagues compared regimens of semaglutide alone or in combination with Gilead Science's firsocostat, cilofexor or both.

Firsocostat (GS-0976) is an acetyl-CoA carboxylase (ACC) inhibitor; ACC is involved in lipogenesis, or conversion of carbohydrates to fatty acids in the liver. Cilofexor (GS-9674) is a nonsteroidal farnesoid X receptor (FXR) agonist; FXR regulates bile acid synthesis and plays a role in lipid and glucose metabolism.

As reported at the recent Digital International Liver Congress, the ATLAS trial showed that firsocostat, cilofexor and the apoptosis signal-regulating kinase 1 inhibitor selonsertib (GS-4997), alone or in combination regimens, failed to significantly improve liver fibrosis without worsening NASH. However, one combo in particular – firsocostat plus cilofexor – led to improvements in other measures of fibrosis and liver health.

The present study design was similar to that of ATLAS, but substituted semaglutide for selonsertib, which was found to be ineffective in the phase III STELLAR 3 and 4 trials presented at last year's Liver Meeting.

The trial included 108 people with NASH and stage F2 to F3 fibrosis according to biopsies or an MRI liver fat fraction of 10% or higher and a liver stiffness measurement of 7 kPa according to FibroScan. About 70% were women, a third to a half were Hispanic or Latino (a group with a higher prevalence of NASH) and the median age was 54 years. A majority were overweight or had obesity and more than half had diabetes.

Participants were randomised to receive semaglutide in one of the following regimens for 24 weeks:

  • semaglutide monotherapy
  • semaglutide plus 20mg firsocostat
  • semaglutide plus 30mg cilofexor
  • semaglutide plus 100mg cilofexor
  • semaglutide plus 20mg firsocostat plus 30mg cilofexor.

Semaglutide was given as a once-weekly injection at escalating doses ranging from 0.24mg to 2.4mg. Firsocostat and cilofexor were taken orally once daily.

All groups lost weight, with percentage loss ranging from -7% to -10%. MRI liver fat fraction decreased more in all the combination groups (-10% to -13%, with the greatest loss in the triple therapy arm) compared with the semaglutide monotherapy group (-9%).

Liver stiffness declined in all groups, with the greatest improvement seen in the triple therapy arm. Enhanced liver fibrosis (ELF) score, a composite index of fibrosis biomarkers, showed similar improvement across all treatment groups. FAST score, another composite measure, showed greater improvement in the combination groups, especially those containing firsocostat.

The combination groups saw greater improvements in ALT, AST and the biomarker cytokeratin 18 (CK18). The largest drops in ALT occurred in the dual and triple regimens containing firsocostat.

All treatment groups had similar improvements in glycaemic parameters including HbA1c, plasma glucose and insulin levels. Looking at lipid changes, harmful LDL cholesterol increased in the group taking the higher dose of cilofexor – though it did not change in the lower dose group – and triglycerides rose in the groups that used firsocostat.

The combination therapies were generally safe and well tolerated. Rates of moderate or worse side effects ranged from 14% to 32%, but few people stopped treatment due to adverse events. Gastrointestinal symptoms were again most common, with about two-thirds of participants reporting nausea in the triple therapy group. Mild pruritus, or itching, was reported by a small number of people taking cilofexor.

In patients with NASH, combinations of semaglutide with cilofexor or firsocostat may provide additional benefits compared with semaglutide alone, Alkhouri and colleagues concluded.


Newsome PN et al. Efficacy and safety of subcutaneous semaglutide once-daily versus placebo in patients with non-alcoholic steatohepatitis. AASLD Liver Meeting, abstract 10, 2020.

Alkhouri N et al. Safety and efficacy of combination therapies including semaglutide, cilofexor, and firsocostat in patients with NASH. AASLD Liver Meeting, abstract LO2, 2020.