Resmetirom Shows Consistent Efficacy in MASH Regardless of Concurrent Diabetes Therapy

A new secondary analysis of the MAESTRO-NASH phase 3 trial offers important insights into how resmetirom performs in real-world patients with metabolic-dysfunction–associated steatohepatitis (MASH), particularly among those with type 2 diabetes mellitus (T2DM) who are already taking diabetes treatment.¹

The results, published in Alimentary Pharmacology & Therapeutics, show that resmetirom’s ability to resolve MASH and improve fibrosis remains consistent regardless of background GLP-1 or SGLT2 inhibitor use. At the same time, patients who achieved even modest weight loss—at least 5% over 52 weeks—experienced significantly greater benefits across histology, imaging biomarkers, and non-invasive tests.

Most patients with MASH have multiple metabolic comorbidities, particularly T2DM, making combination treatment strategies an area of growing clinical interest. Resmetirom (Rezdiffra; Madrigal Pharmaceuticals), a liver-targeted, thyroid hormone receptor-β agonist, received accelerated approval in 2024 for adults with F2–F3 fibrosis based on robust improvements in MASH resolution and fibrosis at 52 weeks.² The MAESTRO-NASH trial continues toward a 54-month outcomes readout, but this prespecified subgroup analysis provides a deeper understanding of how the drug performs alongside commonly used diabetes therapies.

Among the 966 randomized patients, roughly two-thirds had T2DM. Of these, 21% were taking GLP-1 receptor agonists and about 20% were using SGLT2 inhibitors at baseline, consistent with modern diabetes-care patterns. These patients typically presented with more advanced metabolic disease and higher cardiovascular risk, including greater prevalence of hypertension, dyslipidemia, and advanced fibrosis. Despite this, they entered the study with stable glycemic control: baseline mean HbA1c was 7.0%, and levels remained unchanged throughout the 52-week treatment period.

The analysis found no evidence that GLP-1 or SGLT2 inhibitor use altered resmetirom’s efficacy. Among patients on stable GLP-1 RA therapy, MASH resolution rates with resmetirom 100 mg reached 39%, closely mirroring the 38% response among patients not taking GLP-1 agents. Fibrosis improvement followed the same pattern, with nearly identical response rates across both subgroups. SGLT2 inhibitor use showed similar consistency, with MASH resolution rates in resmetirom-treated patients on SGLT2 inhibitors overlapping those of patients not on these therapies. In other words, resmetirom’s biological activity on liver inflammation and fibrosis remained intact across a range of metabolic backgrounds.

MRI-proton density fat fraction (MRI-PDFF), a sensitive indicator of hepatic fat reduction, also declined uniformly across subgroups. The 2 doses of resmetirom—80 mg and 100 mg—produced comparable relative fat reductions in patients with or without GLP-1 or SGLT2 therapy, reinforcing that background metabolic medications did not modify drug effect.

However, outcomes diverged for weight loss. Although GLP-1 and SGLT2 therapies were stable and did not produce additional weight reduction during the trial, some participants, regardless of treatment assignment, achieved spontaneous or lifestyle-related weight loss of 5% or more. These individuals experienced strikingly stronger improvements when treated with resmetirom.

“For patients treated with resmetirom, a ≥5% weight loss was associated with higher rates of MASH resolution and fibrosis improvement in resmetirom-treated patients compared with resmetirom-treated patients without weight loss, suggesting that relatively small amounts (≥ 5%) of weight loss enhance the effects of resmetirom on MASH resolution and liver fibrosis improvement.”

Among resmetirom 100 mg recipients with ≥5% weight loss, more than 56% achieved MASH resolution, compared with 34% of those who lost less than 5%. Fibrosis improvement showed the same enhancement: 40.6% versus 31.5%. Imaging findings echoed these patterns. In patients with ≥5% weight loss, liver fat reductions reached up to 69% at Week 52, exceeding the declines seen in those with minimal weight change.

Non-invasive tests also reflected amplified benefit. Patients who lost ≥5% of their body weight were more likely to achieve meaningful reductions in liver stiffness on VCTE elastography. In the resmetirom 100 mg group, nearly 65% of weight-loss responders achieved at least a 25% reduction in liver stiffness at 52 weeks, compared with less than 45% among those who lost under 5%.

Importantly, a mediation analysis confirmed that resmetirom’s improvement in MASH and fibrosis is not driven by weight loss, but rather enhanced by it. Weight change contributed little to the drug’s direct effect, meaning resmetirom remains effective independent of weight trends, but patients who do lose weight experience additive gains.

Safety outcomes remained consistent across all metabolic subgroups. Gastrointestinal side effects, such as diarrhea and nausea, were slightly more common with resmetirom but were not intensified by GLP-1 RA use, despite their overlapping side-effect profiles.

References

1. Noureddin M, Rinella M, Taub R, et al. Effects of resmetirom on metabolic-dysfunction associated steatohepatitis in patients with weight loss and/or diabetes taking glucagon-like peptide-1 receptor agonists and other diabetes therapies: a secondary analysis of the MAESTRO-NASh trial. Aliment Pharmacol Ther. Published online October 23, 2025. doi:10.1111/apt.70382
2. Madrigal Pharmaceuticals announces FDA approval of Rezdiffra™ (resmetirom) for the treatment of patients with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis. Madrigal. Published March 14, 2024. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-fda-approval-rezdiffratm