Retatrutide and tirzepatide are both Eli Lilly peptides, both 39 amino acids long, and both built on a GIP receptor agonist backbone. The difference is one receptor: retatrutide also activates the glucagon receptor. This post compares the two compounds on structure, receptor pharmacology, clinical data and regulatory status, and explains why cross-trial comparisons between them need care.
This article is for research and educational purposes. Retatrutide is an investigational compound with no marketing authorisation. Torsena supplies research peptides for in-vitro and ex-vivo laboratory use only.
Retatrutide vs tirzepatide at a glance
| Characteristic | Retatrutide | Tirzepatide |
|---|---|---|
| Developer code | LY3437943 | LY3298176 |
| Receptor targets | GIP, GLP-1, glucagon | GIP, GLP-1 |
| Class | Triple agonist | Dual agonist |
| Peptide length | 39 amino acids | 39 amino acids |
| Backbone | GIP-based | GIP-based |
| Molecular formula | C221H342N46O68 | C225H348N48O68 |
| Molecular weight | 4731.33 Da | 4813.53 Da |
| CAS number | 2381089-83-2 | 2023788-19-2 |
| Lipidation | Fatty diacid | C20 fatty diacid |
| Regulatory status | Investigational, US filing planned Q1 2027 | Approved in the US and EU |
Structure: close relatives
Both peptides share the same length and a GIP-derived scaffold, and both carry a fatty diacid side chain that binds serum albumin and extends their persistence in experimental and clinical settings. The amino acid substitutions in retatrutide are what give it meaningful glucagon receptor activity while keeping strong GIP and GLP-1 engagement.
Receptor pharmacology: the glucagon difference
Tirzepatide acts at the GIP and GLP-1 receptors. Retatrutide acts at both of those and at the glucagon receptor. In cAMP accumulation assays in HEK293 cells expressing the human receptors, retatrutide’s reported EC50 values are 0.0643 nM at GIP, 0.775 nM at GLP-1 and 5.79 nM at glucagon, so it is most potent at GIP and least potent at glucagon.
The glucagon axis is the reason researchers study the two compounds side by side. GLP-1 and GIP signaling are mainly associated with insulin secretion, gastric emptying and appetite pathways. Glucagon receptor signaling is associated with energy expenditure, hepatic glycogenolysis and hepatic lipid oxidation. Retatrutide is designed to combine those effects in one molecule, which a mixture of separate agonists cannot replicate at a fixed ratio.
Clinical data: what the trials report
Tirzepatide’s pivotal obesity trial, SURMOUNT-1, reported mean weight reduction of up to about 21% at 72 weeks. Retatrutide’s pivotal obesity trial, TRIUMPH-1, reported 28.3% at 80 weeks in its highest dose arm, and 30.3% at 104 weeks in a study extension. Retatrutide’s other Phase 3 trials are covered in our summary of all five retatrutide Phase 3 results.
| Trial | Compound | Duration | Highest reported mean weight reduction |
|---|---|---|---|
| SURMOUNT-1 | Tirzepatide | 72 weeks | About 21% |
| Phase 2 (NEJM 2023) | Retatrutide | 48 weeks | 24.2% |
| TRIUMPH-1 | Retatrutide | 80 weeks | 28.3% |
Why these numbers are not a direct comparison
The figures above come from separate trials with different durations and different populations. TRIUMPH-1 participants started at a higher average BMI than SURMOUNT-1 participants, around 40 against 38, and populations with higher baseline weight can show larger percentage reductions. TRIUMPH-1 also ran eight weeks longer. The gap between the two compounds is therefore suggestive, not established.
Lilly is running a trial that compares retatrutide with tirzepatide directly, with completion expected around the end of 2026. That trial will be the first real answer to which compound produces the larger effect under the same conditions.
Safety profile
Both compounds show the gastrointestinal adverse event pattern typical of incretin-based agents, mainly nausea, diarrhea and constipation, more frequent during dose escalation. Tirzepatide’s safety profile is well characterised from years of approved use. Retatrutide’s is still being established, and TRIUMPH-1 also reported dysesthesia, a skin sensation change, which is not a typical feature of tirzepatide data.
Research applications
In laboratory research, the two compounds are often used together to isolate the contribution of the glucagon receptor. Because they share a backbone and lipidation strategy, differences observed between them in metabolic, hepatic or energy expenditure models point more cleanly to glucagon receptor engagement than a comparison with a structurally unrelated agonist would.
Frequently asked questions
Is retatrutide stronger than tirzepatide?
Retatrutide’s trials report larger mean weight reductions than tirzepatide’s, but no head-to-head results have been published yet, and the existing trials differ in population and duration.
What is the main difference between retatrutide and tirzepatide?
Retatrutide activates the glucagon receptor in addition to the GIP and GLP-1 receptors that tirzepatide targets.
Are retatrutide and tirzepatide made by the same company?
Yes. Both were developed by Eli Lilly. Tirzepatide is marketed as Mounjaro and Zepbound, while retatrutide remains investigational.
Is retatrutide approved?
No. Lilly plans to submit retatrutide to the FDA in Q1 2027. It has no marketing authorisation anywhere.
References
Coskun T, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss. Cell Metab. 2022;34(9):1234-1247.
Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity. N Engl J Med. 2023;389(6):514-526.
Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216.
Eli Lilly and Company. TRIUMPH-1 topline results, 21 May 2026.
Related: Retatrutide research peptide · Tirzepatide research peptide · Retatrutide Phase 3 results