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

This landmark Phase 2 trial by Jastreboff, Kaplan, Frías, and colleagues, published in the New England Journal of Medicine, evaluated retatrutide — the first triple-hormone-receptor agonist — for the treatment of obesity. Retatrutide activates three receptors simultaneously: GIP, GLP-1, and glucagon, representing a novel approach beyond the dual-agonist mechanism of tirzepatide.

The researchers conducted a randomized, double-blind, placebo-controlled, dose-finding study in 338 adults with obesity (BMI of 30 or higher, or 27 or higher with at least one weight-related condition). Participants received weekly subcutaneous injections of retatrutide at doses ranging from 1 mg to 12 mg, or placebo, for 48 weeks.

The results were unprecedented. Participants receiving the highest dose (12 mg) achieved a mean weight reduction of 24.2% of body weight at 48 weeks — surpassing the results of any approved anti-obesity medication. Remarkably, 100% of participants in this group achieved at least 5% weight loss, and the majority lost substantially more. Dose-dependent reductions were observed across all treatment groups, with meaningful weight loss seen even at lower doses.

Gastrointestinal side effects (nausea, diarrhea, vomiting, constipation) were the most common adverse events, consistent with the incretin class. These were most frequent during the dose-escalation phase and generally decreased over time. The addition of glucagon receptor activation appeared to enhance weight loss through increased energy expenditure without introducing unexpected safety concerns. This trial established retatrutide as a potentially transformative therapy for obesity and triggered rapid advancement into Phase 3 studies.