Phase 2 MASLD/MASH Substudy (Liver Fat Analysis)

Study Overview

The liver fat substudy of the Phase 2 obesity trial used magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to measure liver fat. It enrolled 98 participants with metabolic dysfunction-associated steatotic liver disease (MASLD) and at least 10% liver fat at baseline. The primary endpoint was the relative change in liver fat at 24 weeks. Results were published by Sanyal et al. in Nature Medicine on June 10, 2024.

Background

MASLD/MASH Epidemic

Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD) affects approximately 25-30% of the global adult population. Its progressive form, metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Until the March 2024 approval of resmetirom (Rezdiffra), there were no approved pharmacological treatments.

Glucagon Receptor and Liver Fat

The glucagon receptor component of retatrutide’s triple agonism is hypothesized to be a key driver of hepatic fat reduction:

• Glucagon promotes hepatic lipid oxidation (fat burning in liver cells)
• Glucagon suppresses de novo lipogenesis (new fat creation in the liver)
• Glucagon increases hepatic energy expenditure
• These direct effects on the liver add to the indirect benefits of weight loss

Results

MRI-PDFF Findings

Liver fat fell in a dose-dependent way. Mean relative change from baseline, and the share of participants with normal liver fat (below 5%):

All retatrutide doses differed from placebo at both time points. At 48 weeks, 89% (8 mg) and 93% (12 mg) had normal liver fat. Fewer participants had scans at 48 weeks (8-9 per group) than at 24 weeks (14-17 per group). Liver fat reductions tracked changes in body weight, abdominal fat and measures of insulin sensitivity.

Comparison with Other Therapies

Retatrutide cut liver fat far more than other approaches:

• Resmetirom (approved for MASH): ~30-35% relative reduction
• Semaglutide 2.4 mg: ~40-50% relative reduction
• Tirzepatide 15 mg: ~50-55% relative reduction
• Retatrutide 12 mg: -82.4% relative change at 24 weeks (Phase 2 substudy)

MASH Resolution Indicators

Liver biopsies were not performed in this substudy, so it cannot show whether MASH resolves. Most participants appeared to have simple steatosis rather than advanced fibrosis. Biopsy-based trials are needed to answer that question.

Significance

These results led directly to the SYNERGY clinical trial program, a dedicated Phase 3 effort testing retatrutide specifically for MASLD/MASH with liver fibrosis. The 4,500-participant SYNERGY-Outcomes trial will assess liver histology endpoints and long-term clinical outcomes.

Publication

Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nature Medicine. 2024;30:2037-2048.