SAN DIEGO—Patients with metabolic dysfunction–associated steatohepatitis fibrosis taking resmetirom who lost at least 5% of their body weight had a higher rate of MASH resolution and more frequent improvement in fibrosis than those who lost less than 5%, according to a post hoc analysis of the MAESTRO-NASH randomized controlled trial.

Presenting the results at The Liver Meeting 2024, Mazen Noureddin, MD, noted that MAESTRO-NASH showed that both 80- and 100-mg doses of resmetirom led to improved MASH resolution and at least a one-stage improvement in liver fibrosis (abstract 0112).

“Historically, we have seen great benefit of resmetirom. The message here is that … if [patients] lose weight, we’re going to see additional benefits to what we have seen before. And you don’t need 10 and 15 [percent weight loss] and nausea and vomiting with GLP-1 inhibitors. You just need 5% and you will get to these [benefits],” said Dr. Noureddin, a professor of medicine at Houston Methodist Hospital.

The benefits seen in those with less weight loss comports with previously seen effects on histology and MRI, according to Dr. Noureddin. “If patients lost more than 5%, the effect was augmented. Up to 60% had MASH resolution, and up to 40% had fibrosis improvement, which is an additional effect if they lose more weight. That was three times better than the placebo,” he added.

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At baseline, 13% to 17% of patients who received resmetirom, all of whom had diabetes, also were taking glucagon-like peptide-1 receptor agonists (GLP-1s) for at least six months before study randomization. At 52 weeks, investigators found no difference in MASH resolution rate or fibrosis improvement between patients with diabetes who were also on GLP-1 or sodium–glucose cotransporter-2 inhibitors and those with diabetes who were not on these drugs. There was also no difference in weight loss between patients taking GLP-1 inhibitors and those not taking them.

Among participants with 5% or greater weight loss, MASH resolution occurred in 50% of the 80-mg resmetirom group, 58% of the 100-mg resmetirom group and 23% of the placebo group. Among patients with less than 5% weight loss, MASH resolution was observed in 25% of the 80-mg group, 30% of the 100-mg group and 7% of the placebo group.

A similar trend was observed for fibrosis improvement: In the group with more than 5% weight loss, fibrosis improvement occurred in 39% of the 80-mg group, 42% of the 100-mg group and 26% of patients taking placebo. In the group with less than 5% weight loss, fibrosis improvement occurred in 28% of the 80-mg group, 31% of the 100-mg group and 13% of the placebo group.

There was an improvement in MRI-derived proton density fat fraction (MRI-PDFF) between weeks 16 and 52 among those with 5% or greater weight loss in both the resmetirom and placebo arms, although those in the resmetirom arm had a greater response. In the resmetirom arm, 98% of those who lost more than 5% weight loss experienced a 30% MRI-PDFF response.

There is a great deal of interest in attributing the effect of GLP-1s on the histologic benefit seen with resmetirom, as well as the general effect of weight loss, according to Monica Tincopa, MD, who moderated the session.

“How do you dissociate that? Does resmetirom specifically contribute to the amount of weight loss achieved? Does it not? I think they’re saying that there’s an additive effect, mechanistically [to weight loss],” said Dr. Tincopa, an associate professor of medicine at UC San Diego Health. “The hypothesis was not that it would specifically cause significant weight loss, but there seems to be an interaction there.”

The results should be useful for patient counseling, Dr. Tincopa said. “That’s one more thing we can tell them. Even at weight-loss percentages that are lower than we would have thought, we see a dramatic improvement in terms of, at least, steatosis,” she added. “For patients who are maybe on the fence about whether or not they want to take this newer drug, that would be one more piece of information that we can tell them. Even if you lose a very small percentage of weight, we can see dramatic improvements.”

—Jim Kling

The study was funded by Madrigal. Dr. Noureddin reported financial relationships with 89bio, Akero, Allergan, Altimmune, Boehringer Ingelheim, Bristol Myers Squibb, ChronWell, CIMA, Conatus, Corcept, CytoDyn, Enanta, Galectin, Genfit, Gilead, GSK, Madrigal, Merck, NorthSea, Novartis, Novo Nordisk, Perspectum, Rivus, Shire, Takeda, Terns, Viking and Zydus. Dr. Tincopa reported no relevant financial disclosures.

This article is from the February 2025 print issue.