Mazdutide Significantly Reduces Liver Fat, Improves Metabolic Markers in MASLD, Obesity

New research reveals the ability of mazdutide, a once-weekly dual agonist of the glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors, to significantly reduce liver fat content, resolve steatosis, and improve metabolic markers in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity.1

Rohit Loomba, MD, MHSc, chief of gastroenterology and hepatology at UC San Diego Health, presented the findings at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025, demonstrating robust improvements in hepatic and metabolic health parameters, including liver fat content, alanine transaminase (ALT), aspartate aminotransferase (AST), and insulin sensitivity.

“In participants with obesity and baseline liver fat content ≥5%, mazdutide resolved steatosis in >60% and >70% of participants with the highest two doses at weeks 32 and 48, respectively,” wrote Loomba and investigators. “LFC reductions were associated with reductions in body weight and with improved insulin sensitivity and lipid metabolism.”

Mazdutide has been investigated for weight management in adults with obesity and for the treatment of type 2 diabetes (T2D) and is currently under clinical evaluation for use to treat MASLD, obstructive sleep apnea, and alcohol use disorder. In October 2025, investigators reported data from DREAMS-3, a phase 3 clinical trial, showing reductions in hemoglobin A1c (-2.03% vs -1.84%) and mean body weight (10.29% vs 6%) in patients with T2D and obesity, compared with semaglutide.2

In the 48-week randomized, placebo-controlled phase 2 obesity trial, investigators aimed to explore changes in ALT, AST, fasting insulin, homeostatic model assessment of insulin resistance (HOMA2-IR), and triglycerides in patients with T2D and obesity. Endpoints were defined as percent change from baseline in liver fat content, the proportion of participants with ≥30%, ≥50%, and ≥70% relative reduction in liver fat content, and the proportion of participants with normal liver fat content (<5%) at weeks 32 and 48.

The patient population included adults with obesity, defined as BMI ≥30 kg/m2, or BMI ≥ 27 kg/m2 with weight-related comorbidities (non-T2D), who were randomly assigned to placebo (n = 36) or once-weekly subcutaneous mazdutide, with dose escalation employed to reach final doses of 6 mg (n = 22), 10 mg (n = 32), or 16 mg (n = 31), respectively.

Baseline characteristics for the 179 participants included a mean age of 47.7 years, BMI 33.8 kg/m2, liver fat content 13.4%, ALT 28.3U/L, and AST 22.9 U/L. Patients included in the MASLD analysis had a baseline liver fat content ≥5% and were assigned to placebo.

By the primary endpoint of 32 weeks, investigators observed reductions in liver fat content across all mazdutide groups compared with placebo (P <.01), with mean percent change from baseline in liver fat content of -53.5% (standard error [SE], 5.4%) with 3/6 mg, -67.7% (SE, 4.0%) with 10 mg, -68.8% (SE, 4.8%) with 16 mg, versus -14.1% (SE, 6.7%) compared with placebo (P <.01).

Investigators noted overall improved liver fat content reductions with mazdutide compared with placebo. A liver fat content reduction of ≥30% was achieved by 74.0% (3/6mg), 84.9% (10mg), and 83.4% (16mg) compared with 24.9% in the placebo group. Normalization of liver fat content <5% occurred in 50.6% (3/6mg), 69.6% (10mg), and 62.7% (16mg) versus 13.0% with placebo. Liver fat content change correlated strongly with weight loss (r=0.73; P <.001)

By week 32 and 48, respectively, >60% and >70% of patients achieved steatosis resolution on ≥10 mg of mazdutide. Higher doses were also associated with improvements in biochemical markers of liver health and metabolic function. The drug significantly reduced ALT (-18.3% to -18.7%), AST (-16.8% to -19.7%), fasting insulin (-46.5% to -53.1%), HOMA2-IR (-46.6% to -47.6%), and triglycerides (-30.9% to -36.2%), while increasing β-hydroxybutyrate (+97.9% to +132.6%).

References

1. Loomba R, Liana B, Harold B, et al. Dual GLP-1 and Glucagon Receptor Agonist, Mazdutide, Resolved Steatosis in >60% of Participants with MASLD and Obesity in a Multicenter, Randomized Phase 2 Trial. Abstract presented at: American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025; November 7-11, Washington, DC.

2. Livingston R. Mazdutide Demonstrates Superiority to Semaglutide in Type 2 Diabetes and Obesity. Hcplive.com. Published October 28, 2025. Accessed November 9, 2025. https://www.hcplive.com/view/mazdutide-demonstrates-superiority-to-semaglutide-in-type-2-diabetes-and-obesity