Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial.
Level 2 - randomized trial
Phase 2 randomized, double-blind, placebo-controlled trial
PubMed 37366315 · doi:10.1056/NEJMoa2301972
What was done
A phase 2, double-blind, randomized, placebo-controlled trial evaluated subcutaneous retatrutide at various doses (1 mg, 4 mg [starting at 2 mg or 4 mg], 8 mg [starting at 2 mg or 4 mg], or 12 mg [starting at 2 mg]) versus placebo administered once weekly for 48 weeks in 338 adults with a BMI ≥30 or BMI 27 to <30 with a weight-related condition. The primary end point was percentage change in body weight from baseline to 24 weeks; secondary end points included 48-week percentage weight change, categorical weight loss thresholds (≥5%, ≥10%, ≥15%), and safety.
What was found
At 24 weeks, least-squares mean percentage weight change was -7.2% (1 mg), -12.9% (combined 4 mg), -17.3% (combined 8 mg), and -17.5% (12 mg) versus -1.6% for placebo. At 48 weeks, weight changes were -8.7% (1 mg), -17.1% (combined 4 mg), -22.8% (combined 8 mg), and -24.2% (12 mg) versus -2.1% for placebo. By 48 weeks, weight loss of ≥15% occurred in 60% of the 4-mg, 75% of the 8-mg, and 83% of the 12-mg groups versus 2% for placebo. Gastrointestinal adverse events were the most common and were dose-related; dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter.
Why it matters
This trial demonstrates that triple agonism of GIP, GLP-1, and glucagon receptors with retatrutide achieves substantial, dose-dependent weight reductions exceeding 24% at 48 weeks in obesity.
Limits
The study was a phase 2 trial with a modest sample size (n=338) and 48 weeks of follow-up, leaving long-term maintenance, hard clinical outcomes, and rare adverse events unmeasured.