Editorial: Feeling better about NASH—Authors' reply

Abstract

We would like to comment on the excellent editorial by Dr. Di Bisceglie discussing our study on quality of life (QoL) outcomes in patients with non-alcoholic steatohepatitis (NASH) and fibrosis stage (F) 2-3 who were treated with semaglutide or placebo in a phase 2 randomised trial. 1,2 The association between NASH and QoL has been largely addressed. Fatigue, together with pruritus, sleep disorders, abdominal pain, anxiety and somnolence, is common in patients with NASH. These patient-reported outcomes promoted an impairment in health-related QoL (HRQoL). 3 Hepatic fibrosis is a major driver of poor HRQoL, but there is also an association with inflammation and female sex.Dr. Di Bisceglie raises the question of the mechanism(s) by which improvements in QoL may have occurred with once-daily semaglutide 0.4 mg, and in patients with resolution of NASH in both arms, postulating that reduced liver inflammation may be relevant for improving QoL. This naturally leads to consideration of potential mechanistic links between the liver and brain. Could semaglutide promote changes in the liver that affect perceptions of bodily pain? And, if so, which biomarkers could help to evaluate this? Fatty liver disease is associated with brain inflammation, and monocarboxylate transporter-1 has recently been identified as a potential mechanistic link between steatosis and alterations in brain chemistry. 4 Semaglutide is currently being studied in brain disorders due to its potential ability to improve neuroinflammation. 5 Nevertheless, more research on a potential modifying effect of semaglutide on biomarkers could help to further elucidate liver-brain mechanisms in NASH.Dr. Di Bisceglie correctly notes that, as well as improving symptoms related to QoL, a therapy that mitigates liver disease itself is still needed for patients with NASH. It is therefore worth reiterating the primary outcome of this trial, namely that once-daily semaglutide 0.4 mg led to significantly greater rates of NASH resolution without worsening of fibrosis than placebo over 72 weeks. 6 As mentioned by Dr. Di Bisceglie, semaglutide was associated with reductions in body weight and glycated haemoglobin. In a phase 2 trial in patients with NASH and cirrhosis (F4), once-weekly semaglutide 2.4 mg led to similar metabolic improvements, although the primary endpoint of fibrosis improvement without worsening of NASH was not met. 7 It is thus also probable that the final effect on QoL in these patients depends on three factors: semaglutide, NASH resolution, and improvement in metabolic parameters. Including patient-reported outcome and HRQoL analyses in clinical trials could allow us to better understand the effect of these drugs on the overall health of people living with non-alcoholic fatty liver disease.