Semaglutide vs Tirzepatide vs Retatrutide: Research Comparison
Semaglutide, tirzepatide and retatrutide are three long-acting peptides from the same research field, but they act on a different number of receptors. Semaglutide targets one (GLP-1), tirzepatide targets two (GIP and GLP-1) and retatrutide targets three (GIP, GLP-1 and glucagon). This page compares their receptor profiles, structure, chemical data and development status.
For in vitro research use only. Not for human or animal use. Nothing on this page is medical advice.
The short answer
The main difference is how many hormone receptors each peptide activates:
- Semaglutide is a single agonist of the GLP-1 receptor.
- Tirzepatide is a dual agonist of the GIP and GLP-1 receptors.
- Retatrutide is a triple agonist of the GIP, GLP-1 and glucagon receptors.
All three are modified peptides with a fatty-acid chain that binds albumin, which gives them a much longer half-life than the natural hormones they are based on. Semaglutide and tirzepatide are approved prescription medicines; retatrutide is still investigational.
Side-by-side comparison
Semaglutide
≈ 4113.6 g/mol · 31 aa
A GLP-1 analogue with 94% sequence similarity to native human GLP-1, modified for resistance to enzyme breakdown and albumin binding.
Regulatory status ↓Tirzepatide
≈ 4813.5 g/mol · 39 aa
A single peptide based on the GIP sequence that also activates the GLP-1 receptor. First described as LY3298176.
Tirzepatide guide →Retatrutide
≈ 4731 g/mol · 39 aa
A single peptide that activates GIP, GLP-1 and glucagon receptors. First described as LY3437943.
Retatrutide guide →Receptor profile
| Receptor | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| GLP-1 receptor | ✓ | ✓ | ✓ |
| GIP receptor | — | ✓ | ✓ |
| Glucagon receptor | — | — | ✓ |
| Agonist type | Single | Dual | Triple |
The three receptors explained
- GLP-1 receptorActivated by glucagon-like peptide-1, an incretin hormone released from the gut. Studied for its role in glucose-dependent insulin secretion, gastric emptying and appetite signalling in the brain.
- GIP receptorActivated by glucose-dependent insulinotropic polypeptide, the second main incretin hormone. Studied in insulin secretion and in fat-tissue biology. Combining GIP and GLP-1 activity is the basis of tirzepatide.
- Glucagon receptorActivated by glucagon, a hormone from the pancreas. Studied for its effects on liver metabolism and energy expenditure. Adding glucagon-receptor activity is what makes retatrutide a triple agonist.
Researchers use these compounds to explore how activating one, two or three of these receptors changes metabolic signalling in cell and animal models, and how the receptors interact with each other.
Chemical data
| Property | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Class | GLP-1 receptor agonist | GIP / GLP-1 receptor agonist | GIP / GLP-1 / glucagon receptor agonist |
| Development code | NN9535 | LY3298176 | LY3437943 |
| Length | 31 amino acids | 39 amino acids | 39 amino acids |
| Molecular formula | C187H291N45O59 | C225H348N48O68 | C221H342N46O68 |
| Molecular weight | ≈ 4113.6 g/mol | ≈ 4813.5 g/mol | ≈ 4731 g/mol |
| CAS number | 910463-68-2 | 2023788-19-2 | 2381089-83-2 |
| Fatty-acid chain | C18 fatty diacid | C20 fatty diacid | C20 fatty diacid |
| Reported half-life | ≈ 7 days | ≈ 5 days | ≈ 6 days |
| Form (research grade) | Lyophilised powder | Lyophilised powder | Lyophilised powder |
Half-life values are approximate figures reported in published pharmacokinetic studies and are included for comparison of molecular design only.
Structural design
The three peptides share the same basic engineering ideas, applied to different starting sequences:
- Different backbonesSemaglutide is built on the GLP-1 sequence. Tirzepatide and retatrutide are built on a GIP-based sequence that has been modified so a single molecule can activate more than one receptor.
- Aib substitutionsAll three include α-aminoisobutyric acid (Aib), a non-natural amino acid that protects the peptide from breakdown by the enzyme DPP-4.
- Fatty-acid chainA fatty diacid attached through a linker lets the peptide bind reversibly to albumin in blood, which slows clearance and extends half-life.
- Receptor balanceTirzepatide and retatrutide are designed with a specific balance of activity at each receptor, rather than equal potency at all of them.
Development and regulatory status
| Compound | Developer | Status |
|---|---|---|
| Semaglutide | Novo Nordisk | Approved prescription medicine for metabolic conditions in the UK, EU and US. |
| Tirzepatide | Eli Lilly | Approved prescription medicine for metabolic conditions in the UK, EU and US. |
| Retatrutide | Eli Lilly | Investigational. Phase 3 (TRIUMPH) trial results were reported in 2026, but it is not approved as a medicine anywhere. |
Approved medicines are prescription-only and are supplied through licensed pharmacies. Research-grade peptides are not medicines: the material we supply is sold strictly for in vitro laboratory research and is not intended for human or animal use.
For a closer look at the two Eli Lilly compounds, see our retatrutide vs tirzepatide comparison.
Limitations of the evidence
- Few published studies compare all three compounds directly under the same conditions.
- Receptor potency figures depend on the assay and cell system used, so values from different studies are not always comparable.
- Results from cell and animal models do not necessarily translate to humans.
- Long-term data for retatrutide is still being collected in ongoing trials.
Quality and testing
Every batch of tirzepatide and retatrutide we supply is independently tested for purity by Janoshik using HPLC before it is released for sale. Read more on our Quality & Testing page.
Storage and handling in the lab
All three peptides are handled in a similar way:
- Store lyophilised powder at −20 °C, protected from light and moisture, for long-term stability.
- Allow the vial to reach room temperature before opening to reduce condensation.
- Once reconstituted for experiments, keep refrigerated (2–8 °C) and avoid repeated freeze–thaw cycles.
- Avoid vigorous shaking; lipidated peptides can aggregate or stick to surfaces.
Research-grade tirzepatide and retatrutide
Tirzepatide and retatrutide are available for laboratory research through our official store, sterling-research.com.
Related research compounds
Frequently asked questions
What is the main difference between semaglutide, tirzepatide and retatrutide?
The number of receptors they activate. Semaglutide activates the GLP-1 receptor only, tirzepatide activates the GIP and GLP-1 receptors, and retatrutide activates the GIP, GLP-1 and glucagon receptors.
Why is retatrutide called a triple agonist?
Because a single retatrutide molecule activates three hormone receptors: GIP, GLP-1 and glucagon. Tirzepatide is called a dual agonist because it activates two of them.
What does the glucagon receptor add in retatrutide?
Glucagon-receptor activity is studied for its effects on liver metabolism and energy expenditure. It is the feature that distinguishes retatrutide from tirzepatide.
Why do these peptides last so long compared with natural hormones?
All three carry a fatty-acid chain that binds reversibly to albumin in blood, and they include non-natural amino acids that resist breakdown by the DPP-4 enzyme. Natural GLP-1 lasts only minutes, while these peptides have reported half-lives of several days.
Is retatrutide approved in the UK?
No. Retatrutide is an investigational compound. Phase 3 trial results were reported in 2026, but it is not a licensed medicine in the UK, EU or US.
Are research-grade peptides the same as the approved medicines?
No. Approved medicines are prescription-only products made and regulated as medicines. Research-grade peptides are supplied strictly for in vitro laboratory research and are not for human or animal use.
References
- Lau J, et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem. 2015;58(18):7370–7380.
- Coskun T, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018;18:3–14.
- 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;34(9):1234–1247.
- Jastreboff AM, et al. Triple–hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. 2023;389:514–526.
This page is for scientific information only. Sterling Peptides Ltd supplies research peptides strictly for in vitro laboratory research. Not for human or animal use, and not for diagnostic or therapeutic purposes. Questions: contact@sterling-research.com