Highlights
- Resmetirom, a first-in-class THR-β agonist, maintains robust efficacy in MASH resolution and fibrosis improvement regardless of background therapy with GLP-1 receptor agonists (GLP-1 RA) or SGLT2 inhibitors.
- The addition of ≥5% weight loss to Resmetirom (100 mg) therapy significantly boosts MASH resolution rates from 33.8% to 56.6%, demonstrating a potent synergistic effect between lifestyle/metabolic intervention and THR-β agonism.
- Liver fat reduction (MRI-PDFF) and liver stiffness (VCTE) showed greater improvements in patients achieving weight loss while on Resmetirom, underscoring the value of a multi-modal therapeutic approach.
- Findings suggest Resmetirom can serve as a cornerstone therapy in a heterogeneous patient population already managed for type 2 diabetes and obesity.
Background: The Evolution of MASH Therapeutics
Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), has long represented a critical unmet need in clinical hepatology. As a progressive liver disease characterized by steatosis, inflammation, and ballooning, MASH is a leading cause of cirrhosis and hepatocellular carcinoma globally. Until recently, therapeutic options were limited to lifestyle modifications and off-label use of insulin sensitizers or antioxidants.
The primary challenge in treating MASH lies in its complex pathophysiology, which is inextricably linked to obesity, insulin resistance, and dyslipidemia. The emergence of Resmetirom—an oral, liver-directed, thyroid hormone receptor beta (THR-β) selective agonist—marked a pivotal shift. By targeting the THR-β pathway, Resmetirom restores hepatic fat metabolism and reduces lipotoxicity. The landmark Phase 3 MAESTRO-NASH trial (NCT03900429) provided the evidence base for Resmetirom’s approval, meeting primary histological endpoints at 52 weeks. However, in the current clinical landscape where GLP-1 RAs and SGLT2 inhibitors (SGLT2i) are frequently prescribed for comorbidities, understanding the interaction between these agents and Resmetirom is essential for clinical decision-making.
Key Content: Evidence Synthesis from the MAESTRO-NASH Trial
Core Findings of the Phase 3 MAESTRO-NASH Primary Analysis
The primary analysis of the MAESTRO-NASH trial involved 966 patients with biopsy-confirmed MASH and fibrosis stages F1B, F2, or F3. Patients were randomized 1:1:1 to 80 mg Resmetirom, 100 mg Resmetirom, or placebo. At week 52, histological outcomes were significantly superior in the Resmetirom groups:
- MASH Resolution: Achieved in 25.9% (80 mg) and 29.9% (100 mg) of patients compared to 9.7% in the placebo group (P < 0.001).
- Fibrosis Improvement: Reduction of at least one stage occurred in 24.2% (80 mg) and 25.9% (100 mg) of patients versus 14.2% in the placebo group (P < 0.001).
- Lipid Profile: Significant reductions in LDL-C (up to 16.3%) were observed, highlighting the extra-hepatic cardiovascular benefits of THR-β agonism.
Secondary Analysis: Interaction with GLP-1 RAs and SGLT2i
A secondary analysis was conducted to determine if the efficacy of Resmetirom was influenced by the use of standard-of-care diabetes medications. At baseline, approximately 13% to 17% of the cohort (all with Type 2 Diabetes) were on stable GLP-1 RA or SGLT2i therapy.
The data revealed that Resmetirom’s therapeutic effect was independent of these background medications. Patients on GLP-1 RAs or SGLT2is showed similar rates of MASH resolution and fibrosis improvement compared to those not on these therapies. Crucially, the trial design required stable dosing of these medications, meaning the liver benefits observed were attributable to the addition of Resmetirom rather than a new initiation of GLP-1 therapy. This finding is vital for clinicians managing diabetic patients with advanced fibrosis, as it confirms that Resmetirom provides additive value to existing metabolic regimens.
The Impact of Weight Loss: A Potent Synergy
Perhaps the most clinically significant finding from the secondary analysis was the impact of weight loss (defined as ≥5% from baseline). While Resmetirom itself is not primarily a weight-loss drug, a subset of patients achieved weight loss through lifestyle efforts or background therapy.
When combined with 100 mg of Resmetirom, weight loss of ≥5% resulted in dramatically enhanced outcomes:
- Histological MASH Resolution: 56.6% in the weight-loss group vs. 33.8% in those with <5% weight loss.
- Fibrosis Improvement: 40.6% vs. 31.5%, respectively.
- Non-invasive Biomarkers: MRI-PDFF (liver fat) reduction was -69% in the weight-loss group compared to -46% in the <5% group. Liver stiffness reduction was also more pronounced (-4.6 kPa vs. -2.3 kPa).
Expert Commentary: Clinical Applicability and Mechanistic Insights
The MAESTRO-NASH secondary analysis provides a roadmap for the “precision medicine” era of MASH treatment. The data suggest that THR-β agonism and GLP-1 receptor agonism target different but complementary pathways. While GLP-1 RAs primarily address the systemic metabolic drivers (satiety, insulin secretion, weight loss), Resmetirom directly targets hepatic metabolism and lipotoxicity.
The controversy in MASH management often centers on whether weight loss alone is sufficient. These results suggest that while weight loss is a powerful tool, its combination with Resmetirom offers a synergistic effect that exceeds the sum of its parts. For the clinician, this justifies a “dual-track” strategy: prioritizing lifestyle and metabolic control while simultaneously initiating Resmetirom to address the established hepatic injury and fibrosis.
Furthermore, the safety profile—with serious adverse events being similar across groups—supports the use of Resmetirom in complex patients with multiple comorbidities. The higher frequency of transient GI symptoms (nausea, diarrhea) with Resmetirom should be managed through patient education, especially when co-administered with GLP-1 RAs which carry similar side-effect profiles.
Conclusion
The MAESTRO-NASH trial and its secondary analysis establish Resmetirom as a foundational therapy for MASH with fibrosis. Its efficacy is robust across various metabolic backgrounds, including patients on GLP-1 RAs and SGLT2 inhibitors. Most importantly, the dramatic improvement in histological and biomarker outcomes in patients achieving ≥5% weight loss highlights a therapeutic ceiling that can only be reached through combined pharmacological and lifestyle interventions. Future research should focus on the long-term cardiovascular and hepatic outcomes of these combination strategies, but the current evidence strongly supports Resmetirom as a versatile and effective component of modern MASH care.
References
- Harrison SA, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024;390(6):497-509. PMID: 38324483.
- Noureddin M, et al. Effects of Resmetirom on Metabolic-Dysfunction Associated Steatohepatitis in Patients With Weight Loss and/or Diabetes Taking GLP-1 Receptor Agonists and Other Diabetes Therapies: A Secondary Analysis of the MAESTRO-NASH Trial. Aliment Pharmacol Ther. 2025;62(11-12):1089-1099. PMID: 41127972.
