Editorial: Feeling better about NASH

Romero Gomez et al¹ described a post hoc analysis of health-related quality of life (QOL) measures in patients with non-cirrhotic NASH undergoing treatment with semaglutide in a phase 2 clinical trial. The main results were that semaglutide is associated with significantly greater rates of NASH resolution, and with no worsening of fibrosis than with placebo.²

In this sub-study, QOL was assessed using the SF-36 questionnaire, measuring both physical and mental domains. Briefly, the authors found a significant improvement in the physical (but not mental) domains, expressed as the physical component summary score (PCS), after 72 weeks of treatment with semaglutide. Interestingly, this was most marked in those with histological improvement—specifically, histological resolution of NASH. Also of interest, PCS improved in all study participants with NASH resolution, whether on semaglutide or placebo. The greatest improvement in QOL occurred in the domains of bodily pain, physical functioning and limitations due to physical health problems—the strongest correlation being with improvement in bodily pain.

Significant improvement was seen with the dose of 0.4 mg per day but not with the two lower doses used. This is consistent with the primary outcome of this study in which only the highest dose was associated with histologic improvement compared to placebo.

The question arising from this study is how exactly improvements in QOL occurred. It was not purely a direct effect of semaglutide—improvements in QOL scores were also seen in placebo recipients achieving NASH resolution. It was not purely due to weight loss—PCS scores improved significantly with 0.4 mg of semaglutide, even when adjusted for weight loss. It was not due to the presence of, or improvement in, advanced liver disease. This study included only subjects with moderate degrees of hepatic fibrosis (F2 and F3) and excluded those with cirrhosis. Could it be that less inflammation in the liver is translated to a decrease in pain sensitisation? This is consistent with the finding from this study that, at baseline, physical symptoms correlated best with hepatic inflammation but not with the presence or degree of steatosis or fibrosis. Clearly, further work will be needed to sort this out.

Improvements in QOL have also been seen with other drugs being developed for the treatment of NASH, including obeticholic acid and resmetirom.^3-5 These findings raise the question of whether improvement in symptoms or QOL could be, in and of themselves, a suitable therapeutic goal in non-cirrhotic NASH. While NASH is generally thought to be a minimally symptomatic disease, studies such as this one show that patients with NASH do have physical symptoms. While improving these symptoms might be a worthy goal, we still seem to be waiting for a therapy that mitigates the liver disease itself. Ideally, any new therapies should also address the coexisting metabolic disorders associated with NASH (i.e., glucose intolerance, obesity and hyperlipidaemia). Finally, a therapy that also makes patients feel better while taking care of the items listed above would seem to be a great benefit.

ACKNOWLEDGEMENTS

None.

AUTHOR CONTRIBUTIONS

Adrian Di Bisceglie: Writing – original draft (equal).

LINKED CONTENT

This article is linked to Romero Gomez et al papers. To view these articles, visit https://doi.org/10.1111/apt.17598 and https://doi.org/10.1111/apt.17641