Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial
Level 2 - randomized trial
Individual randomized controlled trial
OpenAlex W4382049661 · doi:10.1056/nejmoa2301972
What was done
A phase 2, double-blind, randomized, placebo-controlled trial evaluated once-weekly subcutaneous retatrutide (a triple GIP, GLP-1, and glucagon receptor agonist) in 338 adults with a BMI ≥30 or BMI 27 to <30 plus at least one weight-related condition. Participants were randomly assigned (2:1:1:1:1:2:2) to retatrutide (1 mg, 4 mg starting at 2 mg, 4 mg starting at 4 mg, 8 mg starting at 2 mg, 8 mg starting at 4 mg, or 12 mg starting at 2 mg) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks; secondary end points included weight change at 48 weeks, categorical weight reductions (≥5%, ≥10%, ≥15%), and safety.
What was found
At 24 weeks, least-squares mean body 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% with placebo. At 48 weeks, weight change reached -8.7% (1 mg), -17.1% (combined 4 mg), -22.8% (combined 8 mg), and -24.2% (12 mg) compared with -2.1% for placebo. By 48 weeks, weight loss of ≥5%, ≥10%, and ≥15% occurred in 92%, 75%, and 60% of the 4-mg group; 100%, 91%, and 75% of the 8-mg group; 100%, 93%, and 83% of the 12-mg group; and 27%, 9%, and 2% of the placebo group. The most common adverse events were dose-related gastrointestinal symptoms, mostly mild to moderate, which were partially mitigated by a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter.
Why it matters
This trial shows that triple receptor agonism achieves mean weight reductions up to 24% at 48 weeks, establishing dose-response efficacy and tolerability profiles for phase 3 testing.
Limits
The study is a phase 2 trial with a modest sample size (n=338) distributed across seven intervention and control arms, limiting power to evaluate rare adverse events. The 48-week duration does not provide data on long-term weight maintenance, cardiovascular outcomes, or the long-term clinical consequences of transient heart rate increases.
Cited by
- supports The developmental patent and intellectual property rights for the multi-receptor agonist retatrutide are owned solely by Eli Lilly.