Retatrutide: Everything We Know About the Triple Agonist

What Is Retatrutide?

Retatrutide is a triple hormone receptor agonist developed by Eli Lilly. Unlike semaglutide (which targets GLP-1 only) or tirzepatide (GLP-1 + GIP), retatrutide activates three receptors simultaneously: GLP-1, GIP, and glucagon.

This triple mechanism is why it produced the highest weight loss ever recorded in a clinical trial.

Phase 2 Results

The Phase 2 trial (published in NEJM, 2023) enrolled 338 participants over 48 weeks:

• 24.2% body weight loss at the highest dose (12mg)
• 100% of participants on 12mg lost at least 5%
• 93% lost at least 10%
• 83% lost at least 15%
• 63% lost at least 20%

For context, semaglutide achieves ~15% and tirzepatide ~22% in their respective trials.

How It Works

The three receptors each contribute differently:

• GLP-1: Suppresses appetite, slows gastric emptying
• GIP: Enhances insulin sensitivity, may improve bone density
• Glucagon: Increases energy expenditure, directly reduces liver fat

The glucagon component is what makes retatrutide unique — it actually increases your metabolic rate rather than just reducing intake.

Side Effects

Similar GI profile to other GLP-1s:

• Nausea (16-22% depending on dose)
• Diarrhea (14-20%)
• Constipation (8-12%)
• Vomiting (9-12%)

Side effects were most common during dose escalation and generally resolved within 2-3 weeks.

Titration Schedule

The Phase 2 protocol:

1. 1mg for 4 weeks
2. 2mg for 4 weeks
3. 4mg for 4 weeks
4. 8mg for 4 weeks
5. 12mg maintenance

When Will It Be Available?

Phase 3 trials are ongoing. Expected FDA approval: 2027-2028. Some researchers are already using it through research chemical suppliers, though this carries risks without medical supervision.

Should You Wait for Retatrutide?

If you're currently on semaglutide or tirzepatide and getting good results, there's no reason to wait. If you've plateaued on maximum doses of current medications, retatrutide may eventually be an option — but it's still 1-2 years from approval.