Drug development for non-alcoholic steatohepatitis (NASH), also known as metabolic dysfunction-associated steatohepatitis (MASH), has been surprisingly challenging1. As per the widely accepted “multi-hit hypothesis”, the initial strikes are fat accumulation and insulin resistance. This triggers inflammation and stress in the liver cells, which struggle to cope with the excess fat; the liver cell’s mitochondria are particularly vulnerable to damage. Chronic inflammation prompts specialized liver cells to produce scar tissue, leading to fibrosis of the liver. The fibrotic remodeling can progress from mild (stage F1) to cirrhosis (stage F4) if left unchecked2. Thus, to effectively treat MASH, a drug must address three key conditions: fat accumulation, inflammation, and fibrosis. Since fibrosis is the most compelling predictor of outcomes, current and future therapies must focus on improving fibrosis by indirectly reducing pro-fibrotic inflammatory signaling or directly abrogating fibrosis. However, so far, no therapeutic drugs have been able to meet all these requirements, especially when it comes to improving fibrosis.

Resmetirom: acts on the MASH and fibrosis regression by intrahepatic path

Resmetirom is an orally administered, liver-targeted thyroid hormone receptor-β (THRβ) selective agonist. The FDA’s approval of resmetirom changes the MASH drug development landscape for the better after years of failed programs3. The drug activates THRβ, a nuclear hormone receptor predominantly expressed in the liver and acts as a key regulator of metabolic pathways in this organ. The exact mechanisms through which activation of THRβ improves MASH are still unclear but are known to control fat synthesis, regulate fatty acid oxidation, regulate cholesterol metabolism, improve mitochondrial function, and reduce inflammation and fibrosis. In a phase III randomized controlled trial, 966 patients with mild-to-moderate MASH (stage F1b, F2 or F3) were randomly assigned to once-daily oral treatment with 80 mg or 100 mg resmetirom or placebo for 52 weeks4. MASH resolution, defined by histological analysis of biopsy samples, with no worsening of fibrosis, was observed in 25.9% of the 80 mg group and 29.9% of the 100 mg group, compared to 9.7% in the placebo group (P < 0.001). Treatment was associated with fibrosis improvement by at least one stage with no worsening in non-alcoholic fatty liver disease (NAFLD) activity score in 25% of resmetirom recipients versus just under 15% in the placebo group. Additionally, the study found that resmetirom was safe and well-tolerated, with no significant difference in the primary endpoint of incidence of treatment-emergent adverse events between the groups. The most frequent adverse events associated with resmetirom were diarrhea and nausea. The key secondary endpoints demonstrated significant reductions in atherogenic lipid levels and liver stiffness over 52 weeks in the 80 mg and 100 mg resmetirom. However, it is noteworthy that resmetirom showed an improvement in certain liver pathology measurements in only 25–30% of patients.

GLP-1 agonists: act on the metabolism upstream by extrahepatic path

The emergence of glucagon-like peptide-1 (GLP-1) agonists as a treatment option for diabetes and obesity has prompted their examination in patients with MASH5. Encouraging results from phase IIa and IIb studies have paved the way for phase III clinical trials6. Both GLP-1 agonists and resmetirom have indirect anti-inflammatory and anti-fibrotic effects through their metabolic action. As there is no meaningful expression of GLP-1 receptors on hepatocytes, the major effect of GLP-1 agonists on MASH is likely to be indirect and may be related to a reduction in calorie intake, body weight and insulin resistance, all of which would lead to reduced liver lipid accumulation and hepatic inflammation7,8. Additionally, semaglutide failed to improve fibrosis in the study, casting doubt over whether it can tackle fibrosis. It is unclear whether the effects on weight are sufficient, by themselves, to enable fibrosis regression. Longer treatment might be needed for the improvement in liver fat and metabolic features to translate into improved fibrosis via slowing disease progression. In February 2024, top-line results from another phase II trial were released9. Survodutide, a glucagon/GLP-1 dual agonist, met its primary endpoint of histological improvement in MASH at 48 weeks and also demonstrated a statistically significant improvement in fibrosis, a secondary endpoint.

Resmetirom and GLP-1 agonists for MASH: complementary rather than exclusive

Resmetirom exhibits promising results as a specific treatment for MASH. Nevertheless, GLP-1 agonists are regarded as the primary contenders. Some even suggest that GLP-1 agonists might have the potential to supplant MASH therapy in its entirety. GLP-1 agonists act on the metabolism upstream of the liver manifestations, but this does not mean they solve all problems, such as fibrotic liver injury. Challenges regarding GLP-1 agonists include anti-fibrosis, long-term tolerability, and regaining weight. GLP-1 agonists, which primarily target extrahepatic mechanisms to ameliorate metabolic disorders, when used in conjunction with resmetirom, focusing on intrahepatic mechanisms, offer a complementary approach in the management of MASH and liver fibrosis. This combination harnesses divergent mechanisms of action, thereby providing a synergistic strategy in addressing the multifaceted nature of these conditions (Fig. 1). First, it is difficult for GLP-1 agonists to achieve anti-fibrosis effects because the major effect of GLP-1 agonists on MASH is likely to be indirect by extrahepatic path. Second, semaglutide has been shown to be ineffective in patients with compensated MASH-related cirrhosis10. It is, therefore, important to have liver-specific treatments for patients who have already advanced liver disease. Third, one of the biggest challenges in weight management is the rebound effect that can occur after discontinuing GLP-1 medication. Resmetirom, as an oral medication, is a promising solution as it is safe and well-tolerated for long-term use and provides more convenience and accessibility for patients who may be afraid of injections. Four, resmetirom confers significant advantages to patient cohorts who do not meet the indication of GLP-1 therapies, including individuals who have already attained weight reduction and populations not afflicted with diabetes. Additionally, the FDA’s accelerated approval of resmetirom does not require a biopsy diagnosis in the prescribing information. This facilitates flexible use by clinicians and patient acceptance.

Fig. 1: Combined Resmetirom and GLP-1 Agonists Approach to MASH Treatment.
figure 1

Abbreviation: GLP-1: glucagon-like peptide-1; MASH: metabolic dysfunction-associated steatohepatitis.

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Conclusion

As the “multi-hit hypothesis” holds, combining the therapeutic approaches of GLP-1 agonists with resmetirom seems like a promising strategy by targeting the multifaceted pathophysiology of MASH, which may lead to improved patient outcomes. While the “synergy” makes sense, it is still theoretical until proven in dedicated trials or, suboptimally, from data in real-world studies.