Disentangling Weight Loss-Dependent and Independent Effects of Survodutide on Liver Outcomes in MASH: Insights from a Phase 2 Mediation Analysis

Highlight

• Survodutide treatment in MASH patients demonstrates significant improvements in liver histology and non-invasive fibrosis/inflammation markers.

• Mediation analysis indicates that improvements in inflammation and fibrosis endpoints are largely weight loss-independent, suggesting direct drug effects.

• Steatosis-related improvements are primarily driven by weight reduction, highlighting distinct mechanistic pathways.

• Findings point to a potential role for glucagon receptor agonism in direct hepatic benefits beyond weight loss.

Study Background

Metabolic dysfunction-associated steatohepatitis (MASH), formerly termed nonalcoholic steatohepatitis (NASH), represents a progressive liver disease characterized by inflammation, hepatocellular injury, and varying degrees of fibrosis. With growing prevalence linked to obesity and type 2 diabetes, MASH constitutes a major cause of chronic liver disease and cirrhosis worldwide, driving significant morbidity and mortality. Effective pharmacotherapies remain an unmet need, especially those that can target both steatosis and fibrosis without relying solely on weight loss, which can be difficult to achieve and maintain.

Survodutide is a novel dual agonist with activity at glucagon and GLP-1 receptors, which has demonstrated promising metabolic and liver-directed effects in a phase 2 randomized controlled trial (NCT04771273) in patients with MASH. The dual receptor activation strategy is hypothesized to confer benefits from improved metabolic regulation, weight loss, and direct hepatic effects due to glucagon receptor engagement.

Study Design

This post hoc causal mediation analysis used data from a phase 2, randomized, placebo-controlled trial evaluating survodutide in participants with biopsy-confirmed MASH with fibrosis stage F2-F3. The analysis included 170 participants with paired baseline and end-of-treatment liver biopsies after 48 weeks. Dose arms of survodutide were pooled. The main objectives were to quantify the proportion of the total treatment effect on liver endpoints mediated through weight reduction (indirect effect) versus direct pharmacologic effects independent of weight loss (direct effect).

The mediation model incorporated treatment status (survodutide versus placebo) as the exposure variable, percentage weight change from baseline as the mediator, and controlled for baseline body weight, type 2 diabetes status, and fibrosis stage. Endpoints analyzed included histological outcomes related to MASH resolution, fibrosis improvement, and non-invasive tests (NITs) associated with inflammation, fibrosis, and steatosis such as AST, Enhanced Liver Fibrosis (ELF™) score, MRI-proton density fat fraction (MRI-PDFF), and FibroScan® Controlled Attenuation Parameter™ (CAP).

Key Findings

The mediation analysis revealed a heterogeneous pattern regarding the contribution of weight reduction to liver outcome improvements:

Histological Endpoints

• Resolution of MASH without worsening fibrosis: Weight reduction mediated approximately 66.7% of the total treatment effect, indicating that two-thirds of the benefit was attributable to weight loss whereas one-third was a direct drug effect.

• Improvement in MASH without worsening fibrosis: Similarly, 71.8% of the treatment effect was mediated by weight loss.

• Improvement in fibrosis without worsening MASH: Only 36.3% of the effect was weight loss-dependent, suggesting that improvement in fibrosis was primarily driven by weight-independent mechanisms possibly related to direct glucagon receptor agonism.

Non-Invasive Test Endpoints

• For inflammation and fibrosis markers, less than 50% of the treatment effect was mediated by weight loss: AST (16.5%) and ELF score (38.6%).

• In contrast, steatosis-related endpoints exhibited a stronger dependence on weight reduction, with MRI-PDFF and CAP showing mediated effects of 58.2% and 77.4%, respectively.

These results delineate that while weight loss contributes substantially to improvements in steatosis and some aspects of MASH resolution, reductions in liver inflammation and fibrosis appear to be significantly weight-independent.

Expert Commentary

This mediation analysis offers important insights into the mechanisms by which survodutide exerts its hepatoprotective effects in patients with MASH. The distinct differential mediation underscores the complexity of MASH pathology and response to treatment. The preponderance of direct effects on fibrosis improvement supports the therapeutic potential of glucagon receptor agonism in modulating liver fibrosis independent of weight loss.

These findings align with emerging literature highlighting the non-metabolic benefits of glucagon receptor activation, including modulation of hepatic stellate cell activity, anti-inflammatory effects, and altered hepatic energy metabolism. Understanding these direct pathways is crucial for developing effective MASH therapies, especially for patients unable to achieve significant weight loss.

Limitations of this analysis include its post hoc nature and the generalizability constrained by inclusion criteria focusing on F2-F3 fibrosis. Confirmation in larger, prospective studies with longer follow-up is warranted to validate the durability and clinical relevance of the direct effects observed.

Conclusion

Survodutide improves liver histological and non-invasive markers of inflammation, fibrosis, and steatosis in MASH, with a differential contribution of weight reduction-dependent and -independent mechanisms. The predominance of weight-independent effects on fibrosis and inflammatory endpoints suggests direct hepatic actions, likely via glucagon receptor agonism, distinct from weight loss-mediated benefits. These findings enhance mechanistic understanding and support the therapeutic potential of dual receptor agonists targeting multiple disease pathways in MASH.

Future research should aim to elucidate the molecular underpinnings of these direct effects, optimize dosing strategies, and evaluate long-term clinical outcomes in diverse MASH populations.

Funding and ClinicalTrials.gov

The phase 2 trial (NCT04771273) was supported by institutional and industry collaborators involved in the development of survodutide. Specific funding details were not provided in the mediation analysis report.

References

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4. Ratziu V, et al. Noninvasive tests and biomarkers for NASH and fibrosis assessment. Hepatology. 2020;72(3):741-755.