Editor's Note: It is estimated that 25% of adults worldwide are affected by metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is characterized by at least 5% liver fat content in individuals who do not consume alcohol or consume very little. MASLD represents the liver manifestation of metabolic syndrome and is closely associated with obesity, insulin resistance, and type 2 diabetes (T2DM). About 20% to 30% of MASLD patients progress to metabolic dysfunction-associated steatohepatitis (MASH), characterized by steatosis, inflammation, and hepatocellular ballooning, with or without fibrosis. It is estimated that 20% of MASH patients will further develop end-stage liver disease. A weight loss of 3% to 5% can improve MASLD, while a weight loss of ≥10% is associated with MASH regression and fibrosis regression, indicating the critical role of obesity in the progression of these diseases. Recently, a study published in the Journal of Hepatology suggests that a GLP-1R/GCGR dual agonist may provide an effective treatment for MASLD and obesity.Background and Objectives
GLP-1R agonist-based methods have achieved over 10% weight loss and have led to MASH regression even without fibrosis improvement. Since GLP-1R is not expressed in the liver, the effect of GLP-1R agonists on liver fat content (LFC) is indirect, driven by weight loss and subsequent fat reduction, making LFC a major driver of MASH and liver fibrosis.
Unlike GLP-1R, GCGR is abundantly present in the liver. Glucagon has direct effects on the liver, including stimulating hepatic β-oxidation of fatty acids and reducing lipogenesis. It is hypothesized that combining GLP-1R and GCGR agonists, known as dual agonists, can achieve greater fat reduction levels than using GLP-1 drugs alone.
This study was a randomized, double-blind, placebo-controlled trial aimed at evaluating the effect of the GLP-1R/GCGR dual agonist pemvidutide on LFC in MASLD subjects.
Methods
Participants were aged 18-65 years with a BMI of ≥28.0 kg/m². Researchers used magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to identify participants with LFC ≥10%, who were then randomized in a 1:1:1:1 ratio to receive 1.2 mg, 1.8 mg, or 2.4 mg of pemvidutide or placebo, administered via weekly subcutaneous injections for 12 weeks. Participants were stratified by baseline T2DM status. The primary endpoint was the percentage change in LFC from baseline after 12 weeks of treatment.
Results
The study enrolled 94 participants who were randomized and dosed. The median baseline BMI and LFC were 36.2 kg/m² and 20.6%, respectively. The average baseline weight was 98.2-105.1 kg, the average baseline BMI was 35.3-36.9 kg/m², the average baseline LFC was 20.2%-23.8%, and the average baseline ALT was 32.4-39.5 IU/L. About 29% of participants had baseline T2DM.
At week 12, all pemvidutide groups showed significant reductions in LFC compared to baseline. The 1.2 mg pemvidutide group saw an absolute reduction in LFC of 8.9% (95% CI: -12.4% to -5.4%), a relative reduction of 46.6% (95% CI: -63.7% to -29.6%). The 1.8 mg group had an absolute reduction of 14.7% (95% CI: -18.0% to -11.4%), a relative reduction of 68.5% (95% CI: -84.4% to -52.5%). The 2.4 mg group had an absolute reduction of 11.3% (95% CI: -15.3% to -7.4%), a relative reduction of 57.1% (95% CI: -76.1% to -38.1%). The placebo group showed an absolute reduction of only 0.2% (95% CI: -3.4% to 3.1%), a relative reduction of 4.4% (95% CI: -20.2% to 11.3%).
The proportion of participants with a relative reduction in LFC of ≥30% at week 12 was 65.0% (1.2 mg), 94.4% (1.8 mg), and 85.0% (2.4 mg), compared to 4.2% in the placebo group (P<0.0001). Additionally, 40.0% (P=0.001), 72.2% (P<0.0001), and 70.0% (P<0.0001) of participants in the 1.2 mg, 1.8 mg, and 2.4 mg pemvidutide groups, respectively, achieved a ≥50% reduction in LFC, while no participants in the placebo group reached this endpoint. Normalization of liver fat, defined as LFC ≤5%, was achieved by 20.0% (P=0.0266) in the 1.2 mg group, 55.6% (P<0.0001) in the 1.8 mg group, and 50.0% (P=0.0003) in the 2.4 mg group, with no participants in the placebo group reaching this level.
Overall, the 1.8 mg pemvidutide group had the highest proportion of participants benefiting, with the most weight loss (-4.3%; P<0.001), the greatest reduction in ALT levels (-13.8 IU/L; P=0.029), and the largest absolute change in iron-corrected T1 relaxation time (cT1) (-75.9 ms; P=0.002).
Pemvidutide was well-tolerated at all doses, with no serious or severe adverse events.
Conclusion
In MASLD subjects, weekly pemvidutide treatment significantly reduced LFC, liver inflammation markers, and body weight compared to placebo.
Researchers’ Comments
MASLD and MASH are closely related to overweight and obesity, with obesity-related liver fat excess being a key driver of these diseases. GLP-1R agonists reduce weight through centrally and peripherally mediated appetite suppression. Unlike GLP-1R agonists, GCGR agonists act directly on the liver, stimulating fatty acid oxidation and inhibiting lipogenesis, providing a more effective mechanism for reducing LFC than weight loss alone. This study demonstrates that weekly pemvidutide treatment significantly reduces LFC, liver inflammatory activity, and body weight, indicating that pemvidutide could be an effective treatment for MASH and obesity.
