Survodutide in adults with obesity and metabolic dysfunction-associated steatotic liver disease: SYNCHRONIZE-MASLD, a randomized, double-blind, placebo-controlled phase 3 trial

This multicenter phase 3 trial evaluated the glucagon receptor/GLP-1R dual agonist survodutide in participants with obesity and at-risk MASLD as determined by MASLD and evidence of liver inflammation and/or fibrosis using NITs or liver biopsy-confirmed MASH. In most participants, baseline values of NITs were most consistent with early disease characterized by excess liver fat and inflammation, with no or only mild-to-moderate fibrosis. In this population, survodutide resulted in a greater proportion of participants achieving ≥30% reduction in LFC assessed by MRI-PDFF than placebo, with six in 10 participants achieving normalization of LFC (

A relative reduction of ≥30% in MRI-PDFF-assessed LFC has been shown to be associated with a higher likelihood of histologic improvement and MASH resolution28, and, for people with MASH and fibrosis stage F2–F3, a ≥50% reduction in LFC has correlated with fibrosis regression29. In the present trial, a substantial proportion of participants experienced these levels of reduction in MRI-PDFF-assessed LFC with survodutide: 84.2% had a reduction of ≥30%, 75.3% had a reduction of ≥50% and 55.5% had a reduction of ≥70%. These findings are consistent with the previously reported phase 2 trial of survodutide in people with biopsy-confirmed MASH and fibrosis stage 1–3, in which 87.0% of participants treated with survodutide (6.0 mg) versus 19.7% treated with placebo had a ≥30% relative reduction in MRI-PDFF-assessed LFC over 48 weeks24. Furthermore, 61.0% of participants in the present trial had LFC 30, these data suggest the potential for survodutide treatment to support meaningful improvement in several of the proposed drivers of MASH and hepatic fibrosis, addressing an area of high unmet need11,20.

Based on mean values of liver fibrosis biomarkers at baseline, the study population could be classified as having fibrosis ranging from absent to mild or moderate at baseline. The mean baseline FIB-4 score was 1.3, which, in published clinical practice guidelines, is a requirement for further testing, and liver stiffness by MRE (mean 2.8 kPa) reflected a very low likelihood of fibrosis (advanced fibrosis is likely at ≥3.63 kPa and unlikely at 2,9. There were no differences in liver stiffness assessed by MRE between the survodutide and placebo groups at week 48. Although the lack of improvement in MRE could reflect a lack of biological effect of the treatment, the low baseline value of liver stiffness as assessed by MRE likely generated a ‘floor effect’ that hampered the ability of MRE to detect meaningful changes in this endpoint31. Similar findings were reported in a phase 1 trial of semaglutide in people with MASH who had a mean MRE-assessed liver stiffness of 2.95−3.08 kPa at baseline. The authors of that report also hypothesized that the sensitivity of MRE may be reduced in people with less severe liver fibrosis32. By contrast, liver stiffness as assessed by VCTE, which was indicative of mild-to-moderate fibrosis at baseline (advanced fibrosis is likely at ≥12 kPa and unlikely at 2,9, was reduced after survodutide treatment compared to placebo at week 48. BMI is an important determinant of discordance between MRE and VCTE for fibrosis staging, raising the possibility of fibrosis overestimation by VCTE33. However, the ELF score, which is a marker of extracellular matrix turnover and fibrogenesis, at baseline also reflected mild-to-moderate fibrosis (advanced fibrosis is likely at ≥9.8 and unlikely at 2,9 and showed an absolute reduction of 0.34 after 48 weeks of treatment with survodutide. Improvements in NITs related to liver inflammation, including cT1, ALT and AST, and in liver volume as assessed by MRI were observed after survodutide treatment. An absolute reduction in cT1 of ≥80 ms from baseline was previously shown to correspond to a histological 2-point decrease in the nonalcoholic fatty liver disease activity score (NAS)34. Collectively, these findings suggest that early and effective treatment may reduce LFC in people with obesity and at-risk MASLD, with the potential for a direct effect of survodutide on the liver to reduce inflammation and either suppress fibrosis progression or promote fibrosis regression.

The broader range of pharmacological actions resulting from dual receptor agonism with survodutide could provide clinical advantages over GLP-1R monoagonist therapies for MASH35. In a previous analysis of a phase 2 trial in MASH and fibrosis, survodutide demonstrated early and sustained improvements in serological biomarkers versus placebo36,37. In a mediation analysis from a MASH phase 2 trial with survodutide, NIT endpoints related to improvements in liver inflammation and fibrosis (for example, ELF score, ALT and AST) were shown to be predominantly weight loss independent, consistent with the potential for complementary additive or synergistic effects of glucagon receptor agonism on the liver36. The ongoing LIVERAGE phase 3 clinical trial program of survodutide for the treatment of MASH with moderate-to-advanced fibrosis (stage F2–F3) and for the treatment of MASH-associated compensated cirrhosis (stage F4) will assess the effects of survodutide on a more advanced MASH population38,39.

Because people with MASLD/MASH have a substantially increased risk of major adverse cardiovascular outcomes, it is noteworthy that survodutide treatment in this population is associated with improvements in several key markers of cardiovascular risk, including SBP, DBP, lipids, HOMA-IR, hsCRP, uric acid and HbA1c40. The reduction in body weight in this trial is similar to other MASLD/MASH trials with a mixed T2D population24,32. An improvement in LFC may have led to these improved metabolic functions and decreased cardiometabolic risk40. In ASCOT, a randomized controlled trial in the UK, participants with hypertension treated with blood pressure-lowering and lipid-lowering medications had fewer cardiovascular events 10 years after the trial ended41. This suggests that effective treatment of MASLD early in the disease course, along with improvement in cardiometabolic parameters, may prevent progression of cardiovascular disease and reduce the risk of future cardiac events. The mechanisms through which survodutide mediates its effects on liver and cardiometabolic health remain to be fully elucidated. However, the results of this study suggest that survodutide has the potential to exert beneficial effects on obesity and liver disease through multiple mechanisms. Direct actions of glucagon receptor agonism in the liver include increased fatty acid oxidation, which may enhance liver fat clearance; there is also a potential for liver-targeted effects that enhance the beneficial effect on obesity and body fat regulation23,35,42,43,44,45.

Glucagon receptor agonism and GLP-1R agonism have opposing effects on blood glucose levels; therefore, the optimal balancing of these receptors in dual agonists is important for the maintenance of glucose homeostasis. Survodutide has an eight-fold greater activation of the human GLP-1R than the glucagon receptor in vitro23. A previous phase 2 trial in participants with T2D found an improvement in HbA1c with survodutide26. In the present study, we demonstrate a reduction in body weight and improvements in liver and cardiometabolic health, including glucose-related parameters, with no imbalance of hyperglycemic events overall, a pattern consistent with survodutide having an optimized balance of glucagon receptor and GLP-1R activation that supports metabolic benefits without compromising glucose regulation.

Survodutide treatment was associated with a safety profile consistent with other medications that include GLP-1R agonist activity. Adverse gastrointestinal events were the most frequently reported and were the most common cause of treatment discontinuation. These adverse effects occurred most commonly during the dose-escalation period and resolved with longer exposure to the drug. Because tolerability early in the treatment course could be a key determinant of treatment persistence, efforts to further decrease gastrointestinal intolerance would be beneficial. The protocol for this study initially allowed limited flexibility in dose escalation. Although the protocol was amended to enhance flexibility of dosing, the change likely took place too late in this study to have a meaningful effect on participant tolerance. The variability in tolerance to the prescribed dose-escalation protocol underscores the importance of individualized dose management during the early phase of treatment to achieve optimal therapeutic benefit, the approach most commonly taken with other medications containing GLP-1R agonist activity in real-world clinical practice46,47,48. Other ongoing studies in the phase 3 SYNCHRONIZE obesity program, including SYNCHRONIZE-CVOT, and studies in the ongoing LIVERAGE program have allowed for greater dose flexibility. There were no adjudication-confirmed cases of drug-induced liver injury, acute pancreatitis, pancreatic cancer or thyroid cancer in the survodutide group. At week 52, survodutide was associated with a modest mean increase in heart rate relative to placebo, consistent with previous reports for other drugs containing GLP-1R agonist activity24,25, without evidence of clinically relevant QTcF prolongation.

The present study was conducted in participants with obesity and what we have defined as at-risk MASLD, as determined by liver steatosis in the absence of secondary causes of hepatic fat accumulation and evidence of inflammation and/or fibrosis by one or more widely used NITs. Although most participants did not meet formal criteria for MASH, they are representative of patients in clinical practice likely to be considered for treatment based primarily on NITs. A recent US real-world study reported that liver biopsy was performed in only 10% of patients with newly diagnosed MASH12, similar to the proportion with biopsy-confirmed MASH in this trial. The inclusion of participants based on NITs without a requirement for biopsy, and the beneficial effects of survodutide in the population studied, provide support for the efficacy and safety of this treatment for people with MASLD who have not yet progressed to advanced fibrosis or cirrhosis, which is the profile of most patients with MASLD/MASH seen in the broader medical community11.

Limitations of this study include its relatively short duration (48 weeks), which precluded assessment of longer-term efficacy and safety outcomes. Additionally, the global reach of the trial was limited because of rapid recruitment among research sites in the United States, restricting participating sites to only two countries (United States and Spain), where recruited participants were mostly White, limiting the generalizability. Other ongoing studies in the SYNCHRONIZE program are evaluating the effects of survodutide in people with broader ethnic and racial representation.

In conclusion, this phase 3 trial demonstrated clinically meaningful reductions in LFC and body weight after 48 weeks of treatment with weekly survodutide 6.0 mg in participants with obesity and at-risk MASLD. These results in participants whose disease was predominantly defined by NITs have high relevance for clinical practice. Improvements in LFC, body weight and multiple markers of liver and cardiometabolic health with survodutide treatment in participants with early-stage MASLD suggest that this therapeutic agent has important benefits for reducing liver inflammation and cardiometabolic risk and underscore its potential for improving long-term outcomes in people with obesity and metabolic liver disease.