Resmetirom Maintains Efficacy for MASH Irrespective of GLP-1 RA, SGLT2i Use

Findings from a prespecified analysis of the phase 3 MAESTRO-NASH trial are shedding light on the effects of resmetirom 80 or 100 mg or placebo in patients with type 2 diabetes with a background of stable GLP-1 baseline therapy or sodium-glucose cotransporter 2 inhibitors (SGLT2i) therapy and the effect of ≥ 5% weight loss on liver histology endpoints.1

Among trial participants with type 2 diabetes, data showed rates of metabolic-dysfunction associated steatohepatitis (MASH) resolution and fibrosis improvement were comparable between those who were treated with GLP-1 RA and SGLT2i and resmetirom and those who received resmetirom alone. Of note, small amounts of weight loss were found to enhance the effects of resmetirom on MASH resolution, liver fibrosis improvement, and noninvasive tests of efficacy, suggesting a potential complementary mechanism to increase response rates to resmetirom treatment.1

“Both SGLT2i and GLP-1 RA have been shown to provide long-term cardiovascular and renal benefits, including lowering of events in cardiovascular outcome trials and reducing progression of heart failure and renal disease,” Mazen Noureddin, MD, MSc, chief scientific officer of Summit Clinical Research, and colleagues wrote.1 “The safe and efficacious use of combinations of these agents with resmetirom is an important outcome of this subpopulation analysis.”

On March 14, 2025, the US Food and Drug Administration (FDA) granted accelerated approval to resmetirom (Rezdiffra) for noncirrhotic nonalcoholic steatohepatitis (NASH), now known as MASH, with moderate to advanced fibrosis, making it the first and only treatment to receive approval for the progressive liver disease. In August 2025, the Agency approved semaglutide (Wegovy) injection 2.4 mg as the second treatment for MASH following years of speculation about the benefits of GLP-1 RAs for liver health.2,3

In the randomized, double-blind, placebo-controlled, phase 3 MAESTRO-NASH trial evaluating the efficacy of resmetirom in patients with biopsy-confirmed MASH and fibrosis, investigators conducted a prespecified analysis of the effects of resmetirom or placebo on a background of stable GLP-1 baseline therapy for ≥ 6 months prior to randomization or SGLT2i therapy and the effect of ≥ 5% weight loss on liver histology endpoints. Specifically, they examined changes in liver histology, MRI-proton density fat fraction (MRI-PDFF), and liver stiffness after 52 weeks of treatment.1

The primary analysis population included 966 patients with baseline fibrosis stages of F1B, F2, or F3 and NAFLD Activity Score ≥ 4 based on central pathologist scoring. Of these patients, 647 had type 2 diabetes and 319 did not. Weight was required to be stable (< 5% change in 3 months), and doses of GLP-1 RA and SGLT2i were required to be stable for ≥ 6 months and ≥ 30 days, respectively, prior to eligibility biopsy.1

At baseline, 13%–17% of patients in the treatment groups were on stable doses of GLP-1 RA (80 mg resmetirom, n = 54; 100 mg resmetirom, n = 41; placebo, n = 42). Additionally, 11%–17% of patients were on stable SGLT2i treatment (80 mg resmetirom, n = 55; 100 mg resmetirom, n = 39; placebo, n = 36).1

Investigators noted no weight loss above baseline occurred with GLP-1 RA or SGLT2i therapy and that SGLT2 and GLP-1 RA treated patients showed similar rates of MASH resolution and fibrosis improvement in combination with resmetirom compared with patients not on these therapies.1

In the 80 and 100 mg resmetirom groups, respectively, patients achieving ≥ 5% weight loss had 50.0% (placebo-corrected % difference, 22.0%; 95% CI, 2.9% to 41.2%) and 56.6% (28.4%; 95% CI, 10.3% to 46.5%) response rates for MASH resolution compared with resmetirom patients with < 5% weight loss who had 27.6% (20.4%; 95% CI, 14.1% to 26.7%) and 33.8% (26.5%; 95% CI, 20.1% to 32.9%) response rates for MASH resolution. In the 80 and 100 mg resmetirom groups, respectively, patients achieving ≥ 5% weight loss had 38.6% (11.2%; 95% CI, −6.8% to 29.1%]) and 40.6% (12.0%; 95% CI, −5.0% to 29.0%) response rates for fibrosis improvement compared to patients with < 5% weight loss who had 27.6% (13.0%; 95% CI, 6.3% to 19.7%) and 31.5% (16.7%; 95% CI, 9.9% to 23.5%) response rates for fibrosis improvement.1

Further analysis revealed additional differences in MRI-PDFF reduction (−69% vs −46%), and liver stiffness reduction after 52 weeks of treatment (−4.6 kPa vs −2.3 kPa) between patients treated with resmetirom 100 mg with weight loss ≥ 5% and those with weight loss < 5%.1

“For patients with T2DM, the rates of MASH resolution and fibrosis improvement were comparable between those who were treated with GLP-1 RA and SGLT2i and resmetirom and those who received resmetirom alone. Relatively small amounts (≥ 5%) of weight loss enhance the effects of resmetirom on MASH resolution, liver fibrosis improvement, and non-invasive tests of efficacy, suggesting a potential complementary mechanism to increase response rates to resmetirom treatment,” investigators concluded.1

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. doi:10.1111/apt.70382

2. Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed October 24, 2025. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash

3. Brooks A. FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASH. HCPLive. August 15, 2025. Accessed October 24, 2025. https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-injection-2-4-mg-for-noncirrhotic-mash