Ask the author session

The global landscape of metabolic dysfunction-associated steatotic liver disease (MASLD) and its more progressive form, metabolic dysfunction-associated steatohepatitis (MASH), is evolving at an unprecedented pace. For years, therapeutic options for individuals living with liver fat accumulation, inflammation, and fibrosis were limited primarily to lifestyle interventions. Today, targeted medical therapies are demonstrating remarkable clinical efficacy.

Among the most promising novel therapeutics is survodutide, a first-in-class dual glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor agonist. Recently published in Nature Medicine, the results of the pivotal Phase 3 SYNCHRONIZE-MASLD trial highlight the extraordinary potential of this molecule to clear hepatic fat and promote weight loss.

To unpack these clinical findings, the Swiss NASH Foundation is pleased to highlight an insightful “Ask the Author” video interview featuring lead study investigator Prof. Lee Kaplan, Director of the Obesity and Metabolism Institute in Boston. Below, we explore the science behind survodutide, the key trial outcomes, and why this study represents a major step forward for the global liver health community.

👉 You can watch the full interview below between Prof. Lee Kaplan and Prof. Jean-François Dufour — don’t miss it.

1. Unlocking Dual Agonism: GLP-1 and Glucagon Working in Harmony

Survodutide represents a novel class of metabolic therapeutics designed to engage two distinct biological pathways simultaneously: the GLP-1 receptor and the glucagon receptor. While GLP-1 receptor agonists have transformed obesity and type 2 diabetes management by enhancing satiety and glycemic control, adding glucagon receptor activation introduces a direct, powerful driver of liver lipid metabolism.

As Prof. Lee Kaplan explains in his interview, survodutide is engineered with a specific 8:1 balance—exhibiting eightfold greater potency at the GLP-1 receptor than at the glucagon receptor. This calibrated ratio is crucial: it delivers the metabolic benefits of glucagon on liver metabolism while preventing the disruption of blood glucose homeostasis that high-dose glucagon activation might otherwise trigger.

The synergistic mechanism operates across key physiological pathways:

  • GLP-1 Receptor Agonism: Suppresses central appetite, improves insulin secretion, delays gastric emptying, and reduces body weight.
  • Glucagon Receptor Agonism: Stimulates hepatic energy expenditure, increases mitochondrial fatty acid oxidation, and directly accelerates the clearance of accumulated lipids from hepatocytes.

2. Rigorous Trial Design: Target Population and “At-Risk MASLD”

The SYNCHRONIZE-MASLD trial was a randomized, double-blind, placebo-controlled Phase 3 study conducted over 48 weeks across clinical sites in the United States and Spain. The study evaluated 216 adult participants (131 female and 85 male) with obesity—defined as a body mass index (BMI) of ≥30 kg/m², or ≥27 kg/m² with at least one obesity-related complication—and confirmed at-risk MASLD.

A notable strength of the trial was its pragmatic recruitment framework. Rather than requiring invasive liver biopsies for all participants, the study team adopted a clinical definition termed “at-risk MASLD”:

  • Non-Invasive Qualification (~90% of cohort): Participants were identified using non-invasive liver tests (NITs) indicating a high probability of liver inflammation or progressive MASH.
  • Biopsy Confirmation (~10% of cohort): A subset had pre-existing biopsy confirmation of MASH.

Participants were randomized in a 2:1 ratio to receive once-weekly subcutaneous injections of survodutide 6.0 mg (146 participants) or placebo (70 participants). The trial established two co-primary endpoints evaluated from baseline to week 48: achieving a ≥30% reduction in liver fat content (LFC) measured by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF), and the percentage change in overall body weight.

3. Key Efficacy Findings: Deep Liver Fat Clearance and Weight Loss

The SYNCHRONIZE-MASLD trial met both co-primary endpoints with high statistical significance (P < 0.0001 across all primary analyses). Survodutide demonstrated clear superiority over placebo in both liver fat reduction and weight reduction.

The table below outlines the primary efficacy results at 48 weeks using both the efficacy estimand (evaluating treatment response while on study drug) and the treatment regimen estimand (evaluating all randomized participants regardless of treatment adherence):

Endpoint / Clinical MetricSurvodutide 6.0 mgPlaceboStatistical Significance
≥30% Liver Fat Reduction (Efficacy Estimand)84.2%24.3%P < 0.0001
≥30% Liver Fat Reduction (Treatment Regimen)68.5%28.6%P < 0.0001
Mean Body Weight Change (Efficacy Estimand)-12.2%-1.0%P < 0.0001
Mean Body Weight Change (Treatment Regimen)-8.7%-1.4%P < 0.0001

Beyond meeting the baseline 30% reduction threshold, survodutide induced rapid and profound reductions in liver fat. As highlighted by Prof. Kaplan, a majority of patients receiving survodutide achieved a 50% loss of liver fat, and a substantial majority achieved a 70% loss of liver fat.

4. Why Glucagon Agonism Changes the Game for MASH Resolution

Understanding the clinical thresholds of liver fat clearance is essential for evaluating the therapeutic impact of next-generation liver treatments. In hepatology research, specific degrees of liver fat reduction correlate directly with histological improvements:

  • 30% Liver Fat Reduction: Corresponds with meaningful clinical improvement in MASH inflammation and ballooning.
  • 50% Liver Fat Reduction: Correlates with histological regression of liver fibrosis.
  • 70% Liver Fat Reduction: Representative of full normalization of liver fat content.

Prof. Kaplan notes that while established GLP-1 receptor agonists (such as semaglutide) and dual GLP-1/GIP agonists (such as tirzepatide) effectively improve MASH through weight loss and metabolic modulation, they rarely achieve the rapid 50% to 70% liver fat clearance seen with glucagon-containing dual or triple agonists. The direct hepatic action of glucagon agonism provides a distinct metabolic advantage, accelerating fat exit from liver cells far beyond what weight loss alone typically delivers.

5. Safety, Tolerability, and the Future Pipeline

Evaluating the safety profile of intensive metabolic therapy is paramount for long-term patient management. In the SYNCHRONIZE-MASLD trial:

  • Adverse Events: The most frequent side effects reported with survodutide were gastrointestinal (such as nausea and diarrhea), occurring predominantly during the initial dose-escalation phase and generally ranging from mild to moderate severity.
  • Gallstone Risk Evaluation: Rapid fat mobilization from the liver raised theoretical questions regarding increased biliary cholesterol output and gallstone formation. However, across a pooled dataset of approximately 1,800 patients in three Phase 3 trials (covering obesity with diabetes, obesity without diabetes, and MASLD), survodutide treatment was not associated with an increased risk of gallstones.

The Road Ahead: The LIVERAGE Program

The findings from SYNCHRONIZE-MASLD serve as a stepping stone toward dedicated histological outcomes trials. Boehringer Ingelheim and Zealand Pharma are advancing the LIVERAGE clinical trial program—a suite of biopsy-driven Phase 3 studies specifically evaluating MASH resolution and fibrosis improvement. Top-line results from the LIVERAGE program are anticipated in late 2027 or early 2028.

Additionally, data from a massive Cardiovascular Outcomes Trial (CVOT) enrolling 5,500 patients will provide further insights into the broader systemic and cardiometabolic protection offered by survodutide.

6. Watch the Full “Ask the Author” Video Interview

We invite all members of the Swiss NASH Foundation community, patients, clinicians, and researchers to watch the complete “Ask the Author” video interview with Prof. Lee Kaplan to hear his full analysis of the trial design, mechanism of action, and future clinical implications.

The Swiss NASH Foundation remains committed to bringing you the latest scientific breakthroughs, expert commentary, and educational resources in steatotic liver disease. Stay connected with our platform for future clinical updates and video features.

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