Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial

Summary

Randomized, double-blind, placebo-controlled phase 2a substudy of the 48-week retatrutide phase 2 obesity trial, published in Nature Medicine. It included 98 participants from that trial who had metabolic dysfunction-associated steatotic liver disease (MASLD) and at least 10% liver fat. They were randomly assigned to once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg) or placebo for 48 weeks. The primary endpoint was the mean relative change in liver fat at 24 weeks. Retatrutide lowered liver fat by roughly 43% to 82% depending on dose, versus essentially no change on placebo, and most participants on the higher doses reached normal liver fat.

Key Findings

• Mean relative change in liver fat at 24 weeks: -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), -82.4% (12 mg) vs +0.3% (placebo); all P < 0.001 vs placebo
• Normal liver fat (<5%) at 24 weeks: 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg) vs 0% (placebo)
• Liver-fat reductions were significantly related to changes in body weight, abdominal fat, and metabolic measures associated with improved insulin sensitivity and lipid metabolism
• For context, the parent 48-week obesity study reported weight reductions of 22.8% (8 mg) and 24.2% (12 mg)

Methodology

Substudy of the retatrutide phase 2 obesity trial, registered at ClinicalTrials.gov (NCT04881760). Participants with MASLD and ≥10% liver fat (n = 98) were randomized to 48 weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg) or placebo. The primary outcome was the mean relative change from baseline in liver fat at 24 weeks.

Limitations

• 98 participants split across five arms
• The primary endpoint is at 24 weeks; the abstract does not report liver-fat results beyond that point
• The abstract reports liver fat content only, not fibrosis, inflammation (MASH), or biopsy findings
• Liver-fat reductions tracked weight loss, so the abstract does not separate liver-specific effects from weight-loss effects
• Phase 2 data that need confirmation in larger trials

Relevance to Content

Human RCT data supporting a liver-health angle for retatrutide beyond weight loss. Present it as phase 2 liver-fat data, not as evidence that retatrutide treats MASH or fibrosis, and not as a head-to-head comparison with semaglutide or tirzepatide (the trial had no active comparator).

See Also

• Parent compound: Retatrutide
• Semaglutide
• Tirzepatide