Retatrutide as a triple agonist
A "triple agonist" is a single drug that switches on three different receptors. Retatrutide is one peptide, with a fatty-acid chain attached that keeps it in the blood for about 6 days, and it activates the receptors for three gut and pancreas hormones.[2][3] Lilly reports its potency at each receptor, measured in the lab against the body's own hormone:[1]
| Receptor | Natural hormone | Retatrutide compared with it |
|---|---|---|
| GIP receptor | GIP | 8.9 times more potent |
| GLP-1 receptor | GLP-1 | 2.5 times less potent |
| Glucagon receptor | Glucagon | 2.9 times less potent |
So retatrutide leans on the GIP receptor, while still acting on the other two. The NEJM phase 2 paper describes the same profile.[2]
What each receptor does
Each receptor contributes something different. This is how Lilly's medical information summarizes their roles:[1]
| Receptor | Main actions |
|---|---|
| GLP-1 | Boosts insulin release when glucose is high, adjusts glucagon release, slows stomach emptying, increases fullness signals in the brain |
| GIP | Boosts insulin release when glucose is high; also reduces food intake and regulates fat metabolism |
| Glucagon | Best known for raising liver glucose output when blood sugar is low; also reduces food intake, affects energy use and fat metabolism, and delays stomach emptying |
Why the glucagon receptor was added
The glucagon receptor is what sets retatrutide apart from tirzepatide. Lilly says preclinical and early-phase data suggest retatrutide may "promote maintenance of energy expenditure during weight loss" and "enhance lipid metabolism".[1] These are early findings, not proven effects in large human trials. How much the glucagon component adds on top of GIP and GLP-1 in people has not been separated out in the published phase 3 results.
The naming background, including why some people call it "GLP-3", is on what is retatrutide.
What the mechanism looks like in trials
The trials measured the results of these actions, not the receptors themselves:
| Effect | What was measured | Trial |
|---|---|---|
| Less food intake, weight loss | −25.0% body weight on 12 mg vs −3.9% on placebo, 80 weeks[4] | TRIUMPH-1 |
| Fat loss | Total fat mass −23.2% on 12 mg vs −4.5% on placebo, 36 weeks (DXA scans)[5] | Phase 2 diabetes substudy |
| Blood sugar | HbA1c up to −2.02 points vs −0.01 on placebo, 24 weeks[6] | Phase 2 diabetes |
| Slower stomach emptying (side effects) | Nausea 42.4% on 12 mg vs 14.8% on placebo[4] | TRIUMPH-1 |
| Heart rate | Dose-related rise that peaked around week 24[2] | Phase 2 obesity |
In the body-composition substudy, the share of weight lost as lean tissue was similar to other obesity treatments, according to the authors.[5] Details: retatrutide side effects (including muscle) and retatrutide heart rate.
What is still unknown
- How much each receptor contributes to the weight loss in people.
- Whether the energy-expenditure effect seen in early studies holds in long-term treatment.
- Long-term heart and kidney outcomes. A 10,000-person outcomes trial is due to complete its main phase in 2029.[7]
The weight-loss figures by dose are on the retatrutide results page.
Frequently asked questions
How does retatrutide work?
It activates three hormone receptors at once (GIP, GLP-1 and glucagon), which together reduce appetite, raise insulin release when glucose is high and affect fat metabolism.[1]
Why is retatrutide called a triple agonist?
Because one molecule switches on three receptors. Semaglutide acts on one (GLP-1) and tirzepatide on two (GIP and GLP-1).[2]
What does the glucagon receptor do in retatrutide?
Lilly says glucagon-receptor activity may help maintain energy expenditure during weight loss and enhance fat metabolism, based on preclinical and early-phase data.[1]
Does retatrutide burn fat or muscle?
Mostly fat, in the one published scan study: fat mass fell 23.2% on 12 mg vs 4.5% on placebo in people with type 2 diabetes. The lean share of weight lost was similar to other obesity treatments; muscle strength was not measured.[5]
Sources
- What is the mechanism of action of retatrutide?
- Jastreboff AM et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial
- Urva S et al. LY3437943, a GIP, GLP-1 and glucagon receptor agonist, in type 2 diabetes: phase 1b
- Jastreboff AM et al. Retatrutide for obesity (TRIUMPH-1)
- Coskun T et al. Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2 randomised trial
- Rosenstock J et al. Retatrutide in people with type 2 diabetes: a phase 2 trial
- Retatrutide studies (NCT04881760, NCT05929066, NCT05931367, NCT06662383, NCT07629401 and others)