In MASH with moderate or advanced liver fibrosis, weekly semaglutide improved histologic steatohepatitis and fibrosis at 72 wk

A planned interim analysis of a randomized, manufacturer-supported trial evaluated 800 patients with biopsy-defined metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis stage 2 or 3 who received once-weekly subcutaneous semaglutide, 0.25 mg titrated to 2.4 mg, or placebo for 72 weeks in addition to standard MASH care. Steatohepatitis resolved without worsening of fibrosis in 62.9% of 534 patients in the semaglutide group and 34.3% of 266 patients in the placebo group, while reduced liver fibrosis without worsening steatohepatitis was reported in 36.8% of the semaglutide group and 22.4% of the placebo group.

The analysis was published on April 30 by the New England Journal of Medicine. The following commentary by Thomas F. Imperiale, MD, FACP, was published in the ACP Journal Club section of Annals of Internal Medicine on Sept. 2.

MASLD (formerly nonalcoholic fatty liver disease) and MASH (formerly nonalcoholic steatohepatitis) are prevalent and steadily increasing. The need for effective therapies is great because MASH may soon be the most common cause of end-stage liver disease globally and liver transplantation in the USA. Weight loss and exercise are the cornerstones of management of MASH, but it is difficult for patients to adopt and maintain. Medications for MASLD and MASH include vitamin E and pioglitazone, which can reverse steatohepatitis but not fibrosis. In a 52-week trial of patients with MASH and stage 2 or 3 fibrosis, resmetirom improved histologic steatohepatitis and fibrosis; results for clinical outcomes are to come.

Semaglutide has improved metabolic and histologic outcomes for MASH in small clinical trials and observational studies. The planned interim analysis by Sanyal and colleagues showed that semaglutide improved weight loss, blood pressure, and metabolic parameters, including lipid and glycated hemoglobin levels, in patients with and without diabetes at 72 weeks. Although the trial was rigorously designed, some concern exists about unblinding due to efficacy (i.e., weight loss), adverse effects, or both, potentially introducing performance bias that could preclude knowing the relative contributions of semaglutide and lifestyle modification. This concern is supported by improvements in both primary outcomes in the placebo group despite weight loss of just 2%.

Improvements in metabolic parameters and liver histology are encouraging, but we await data on cirrhosis-free survival, liver-related events and mortality, and all-cause mortality. Short of direct comparisons among current and emerging therapies, optimal therapy for MASH should include consideration of severity, comorbidities, and cardiovascular risk, with the goal of preventing cardiovascular disease and cancer, the 2 most likely causes of morbidity and mortality in this population.