Semaglutide, tirzepatide, R3TA: these three peptides belong to the same family, that of incretin receptor agonists. They are at the heart of research into the regulation of metabolism, appetite and weight. What sets them apart comes down to one question: how many receptors do they activate?
Incretins, starting point
After a meal, the intestine releases hormones called incretins. The two main ones are the GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). They stimulate insulin secretion depending on blood sugar levels, and GLP-1 slows stomach emptying while promoting the feeling of satiety.
In its natural state, GLP-1 is degraded within a few minutes by an enzyme, DPP-4. Synthetic analogues are modified to resist it: their action lasts much longer.
Semaglutide: a receptor
Developed by Novo Nordisk, semaglutide only activates GLP-1 receptor. A fatty acid chain allows it to bind to blood albumin, which greatly prolongs its duration of action. It is authorized as a medicine in many countries.
Tirzepatide: two receptors
tirzepatide activates both the GIP receptor and that of GLP-1. We speak of a double agonist. It too is authorized as a medicine in several countries.
R3TA: three receptors
The R3TA adds a third receptor: that of glucagon. It is a triple agonist, hence its nickname “R3”. The results of its phase 2 trial were published in 2023 in the New England Journal of Medicine, and it is the subject of a phase 3 trial program.
| Molecule | Target receptors | Developer |
|---|---|---|
| Semaglutide | GLP-1 | Novo Nordisk |
| Tirzepatide | GIP, GLP-1 | |
| R3TA | GIP, GLP-1, glucagon |
Why add the glucagon receptor?
Glucagon is best known for raising blood sugar levels. But its receptor also intervenes in the energy expenditure and in the use of fats by the liver. The hypothesis studied with R3TA is to associate these effects with those of GLP-1 and GIP, which compensate for the action of glucagon on blood sugar.
What to remember
- The three molecules mimic intestinal hormones, incretins.
- Semaglutide targets one receptor, tirzepatide two, R3TA three.
- R3TA is the most recent; it is still being studied in clinical trials.
- For research, its purity is verified by HPLC and its identity by mass spectrometry: see our guide for read a certificate of analysis.
Fact sheet
- Semaglutide
- 1 receptor: GLP-1
- Tirzepatide
- 2 receptors: GIP and GLP-1
- R3TA (retatrutide)
- 3 receptors: GIP, GLP-1 and glucagon
- Published dosing schedule
- One injection a week for all three molecules
- Regulatory status
- Semaglutide and tirzepatide authorised; retatrutide in phase 3
What the research says
Summary of published data, written by the PeptidLab team. It describes molecules studied in the laboratory or in clinical trials: nothing here is an indication for use.
2021Phase 3N Engl J Med
STEP 1 (semaglutide 2.4 mg): average weight loss of 14.9% at 68 weeks, versus 2.4% on placebo.
2022Phase 3N Engl J Med
SURMOUNT-1 (tirzepatide): up to 20.9% weight loss at 72 weeks with 15 mg, versus 3.1% on placebo.
2022PreclinicalCell Metab
Discovery of retatrutide (LY3437943): in animals, adding glucagon agonism increases energy expenditure on top of reduced appetite.
2023Phase 2N Engl J Med
Retatrutide in 338 adults with obesity or overweight: up to 24.2% weight loss at 48 weeks with 12 mg, versus 2.1% on placebo.
These figures come from different trials, with different populations, doses and durations: they cannot be compared directly.
Safety: what studies report
- For all three molecules, the most common adverse effects are digestive and increase with the dose.
- In the phase 2 trial of retatrutide, a dose-dependent rise in heart rate was observed, most marked around week 24.
Sources
Links to PubMed or to the original document. Articles in English.
- Wilding JPH et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med, 2021. PubMed
- Jastreboff AM et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med, 2022. PubMed
- Coskun T et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab, 2022. PubMed
- Jastreboff AM et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med, 2023. PubMed
Updated October 2026.
Frequently asked questions
Is R3TA newer than tirzepatide?
Yes. Semaglutide targets one receptor, tirzepatide two, and the newer R3TA targets three: GLP-1, GIP and glucagon.
What is an agonist?
A molecule that binds to a receptor and activates it, mimicking the action of the natural hormone.
Why is R3TA called “R3”?
It's a common nickname, referring to his three target receptors. We also encounter “reta”, or the deformation “ratatouille”.
This guide has an informative and scientific purpose. PeptidLab products are intended exclusively for laboratory research and are not intended for human or animal consumption.
