Ask VialBase
RCT · PMID 37351564

Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial — VialBase Research

high

Last updated · 2023 · Jastreboff, A.M., Kaplan, L.M., Frias, J.P., Wu, Q., Du, Y., Gurbuz, S., Coskun, T., Haupt, A., Milicevic, Z., Hartman, M.L. · New England Journal of Medicine
Key findings
  • Retatrutide 12mg produced 24.2% mean weight loss at 48 weeks
  • Triple GIP/GLP-1/glucagon agonist mechanism
  • Weight loss still trending downward at 48 weeks — plateau not reached

Summary

This phase 2 dose-finding trial evaluated retatrutide, the first triple-hormone receptor agonist (GIP/GLP-1/glucagon), in adults with obesity without diabetes. Retatrutide produced unprecedented weight loss of up to 24.2% at 48 weeks, with the weight loss curve still declining — suggesting even greater losses with longer treatment.

Key Findings

  • Mean weight loss at 48 weeks: -8.7% (1mg), -17.1% (4mg), -22.8% (8mg), -24.2% (12mg) vs -2.1% (placebo)
  • At 12mg: 100% of participants achieved ≥5% weight loss; 83% achieved ≥20%
  • Weight loss curves had not plateaued at 48 weeks — suggesting further loss with continued treatment
  • Triple agonism (GIP + GLP-1 + glucagon) represents a mechanistic advance over dual agonism
  • Glucagon receptor agonism adds thermogenic/metabolic effects beyond appetite suppression
  • GI adverse events similar in nature to GLP-1 RAs; mostly mild-moderate

Methodology

Phase 2, double-blind, placebo-controlled, dose-finding RCT. 338 adults with BMI ≥30 (or ≥27 with comorbidity) without diabetes. Randomized to retatrutide (1mg, 4mg, 8mg, or 12mg) or placebo weekly for 48 weeks. Multiple dose escalation regimens tested.

Limitations

  • Phase 2 trial — smaller sample size than phase 3 STEP/SURMOUNT trials
  • 48-week duration — plateau not reached, so maximum weight loss unknown
  • Safety profile needs larger/longer studies to fully characterize
  • Glucagon agonism raises theoretical concerns about lean mass loss and hepatic effects
  • No active comparator (semaglutide or tirzepatide)

Relevance to Content

The most impressive weight loss data to date for any obesity pharmacotherapy. Essential for forward-looking content about next-generation treatments. The triple-agonist mechanism provides a compelling narrative about incretin evolution: GLP-1 (semaglutide) → GIP/GLP-1 (tirzepatide) → GIP/GLP-1/glucagon (retatrutide). Phase 3 trials ongoing.

See Also

View on PubMed · PMID 37351564 →