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Phase 2 RCT (dose-finding, double-blind, placebo-controlled) · PMID 37385275

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

24.2% mean body weight loss with retatrutide 12mg at 48 weeks

Last updated · 2023 · Jastreboff AM, Kaplan LM, Frías JP, et al. · New England Journal of Medicine
Key findings
  • 24.2% mean body weight loss with retatrutide 12mg at 48 weeks
  • 100% of participants on 8mg and 12mg doses lost ≥5% body weight
  • 83% on 12mg lost ≥15% body weight
  • Highest weight loss for any anti-obesity drug at Phase 2
  • 338 adults with obesity enrolled

Summary

This landmark Phase 2 dose-finding trial evaluated retatrutide, the first triple GIP/GLP-1/glucagon receptor agonist, for obesity treatment. The study enrolled 338 adults with BMI ≥30 (or ≥27 with comorbidity) without diabetes. Participants were randomized to retatrutide at various doses (0.5mg, 1mg, 2mg, 4mg, 8mg, 12mg weekly) or placebo for 48 weeks.

Key Findings

  • Dose-dependent weight loss at 48 weeks:
    • 1mg: -8.7%
    • 4mg: -17.1%
    • 8mg: -22.8%
    • 12mg: -24.2%
    • Placebo: -2.1%
  • Weight loss trajectory had not plateaued at 48 weeks in higher doses — suggesting further weight loss possible with longer treatment
  • 100% of participants on 8mg and 12mg lost ≥5% body weight
  • 83% on 12mg lost ≥15% body weight
  • 63% on 12mg lost ≥20% body weight
  • Significant improvements in metabolic parameters (HbA1c, lipids, blood pressure)
  • GI adverse events: nausea (24-34%), diarrhea (18-22%), vomiting (8-13%) — comparable to GLP-1 RAs
  • Mild dose-dependent heart rate increase (+2-4 bpm)
  • No serious safety signals identified

Relevance to Retatrutide

This is THE landmark study for retatrutide and one of the most important papers in obesity pharmacotherapy. The 24.2% weight loss at 48 weeks exceeded all prior anti-obesity medications — surpassing even Tirzepatide‘s 22.5% at 72 weeks (SURMOUNT-1) in a shorter time frame. The fact that weight loss curves had not plateaued suggests the ceiling may be even higher with longer treatment. The Phase 3 TRIUMPH program was launched based on these results. The triple agonist approach — adding glucagon receptor activation to GIP/GLP-1 — validated the hypothesis that direct energy expenditure stimulation (via glucagon) provides additional weight loss beyond appetite suppression alone.

Citation

Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972.

See Also

View on PubMed · PMID 37385275 →