Tirzepatide vs Retatrutide vs Semaglutide: how they compare
Semaglutide, tirzepatide and retatrutide are three of the most studied peptides in metabolic research. They share a design idea, a hormone-like peptide built to last for days instead of minutes, but each one activates a different set of receptors. That single difference explains most of what sets them apart in the published trials.
At a glance
| Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
| Receptors activated | GLP-1 | GIP + GLP-1 | GIP + GLP-1 + glucagon |
| Type | Single agonist | Dual agonist | Triple agonist |
| Half-life in humans | About 1 week | About 5 days | About 6 days |
| Regulatory status | Approved (since 2017) | Approved (since 2022) | Investigational, not approved |
| Landmark weight trial | STEP 1: −14.9% vs −2.4% placebo (68 weeks) | SURMOUNT-1: up to −20.9% vs −3.1% placebo (72 weeks) | TRIUMPH-1 (phase 3): up to −28.3% vs −2.2% placebo (80 weeks)* |
The trial figures are mean changes in body weight in the highest-dose groups of each study. The studies differ in length, population and design, so the numbers show the scale of each effect rather than a direct ranking. *Topline result reported by the manufacturer.
The three receptors
- GLP-1 receptor: the target of glucagon-like peptide-1, a gut hormone released after meals. In research it is linked to glucose-dependent insulin release, slower gastric emptying and reduced food intake.
- GIP receptor: the target of glucose-dependent insulinotropic polypeptide, the other main incretin hormone. It also acts on insulin release and is studied for its effects on fat tissue and on the tolerability of GLP-1 signalling.
- Glucagon receptor: glucagon raises blood glucose, but it also increases energy expenditure and fat breakdown in the liver. Adding it to a GLP-1 and GIP agonist is the idea behind retatrutide.
Semaglutide: the GLP-1 reference
Semaglutide is an analogue of human GLP-1 with about 94% sequence similarity to the natural hormone. Two changes make it last: an amino-acid substitution at position 8 protects it from the enzyme DPP-4, which breaks down natural GLP-1 within minutes, and a fatty-acid side chain lets it bind to albumin in the blood, which slows its clearance to a half-life of about a week.
It is the most established of the three, approved for type 2 diabetes in 2017 and for weight management in 2021. In the STEP 1 trial, adults with obesity lost a mean 14.9% of body weight over 68 weeks, against 2.4% with placebo. In research it is the usual benchmark for GLP-1 receptor activity.
Tirzepatide: dual GIP and GLP-1
Tirzepatide is a single 39-amino-acid peptide built on the GIP sequence and engineered to activate both the GIP and GLP-1 receptors. Like semaglutide it carries a fatty-acid chain for albumin binding, giving a half-life of about five days. Pharmacology studies describe it as an "imbalanced" agonist: it acts more like natural GIP at the GIP receptor than like GLP-1 at the GLP-1 receptor.
In SURMOUNT-1, mean weight loss after 72 weeks reached 20.9% in the highest-dose group, against 3.1% with placebo. It is also the only one of the three with head-to-head data against semaglutide (see below).
Retatrutide: adding glucagon
Retatrutide (development code LY3437943) is a single peptide that activates the GIP, GLP-1 and glucagon receptors. The glucagon component is meant to add an effect on energy expenditure and liver fat on top of the appetite and insulin effects of the other two.
In its phase 2 obesity trial, mean weight loss after 48 weeks reached 24.2% in the highest-dose group, against 2.1% with placebo, and had not yet levelled off when the study ended. A substudy in participants with excess liver fat reported large reductions in liver fat content.
The phase 3 programme (TRIUMPH) has since reported its first results. In May 2026 the manufacturer announced that in TRIUMPH-1, in adults with obesity, mean weight loss after 80 weeks reached 28.3% in the highest-dose group, against 2.2% with placebo. Retatrutide is still investigational: it has not been approved for any use.
Head-to-head results
- SURPASS-2 compared tirzepatide with semaglutide in type 2 diabetes. Tirzepatide produced larger reductions in blood glucose (HbA1c) and in body weight at every dose tested.
- SURMOUNT-5 compared them in obesity without diabetes. After 72 weeks, mean weight loss was 20.2% with tirzepatide against 13.7% with semaglutide.
- No published trial has yet compared retatrutide directly with either of them.
Choosing a compound for a study
- Semaglutide when you need a well-characterised GLP-1-only reference, or a comparator with the most published data behind it.
- Tirzepatide to study what GIP receptor activity adds to GLP-1 signalling.
- Retatrutide to study the contribution of glucagon receptor activity, for example energy expenditure or liver fat.
All three are supplied as lyophilised (freeze-dried) powder. Unopened vials keep best in the freezer at −20 °C, away from light and moisture. After reconstitution, keep them refrigerated at 2–8 °C.
References
- Wilding JPH et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med 2021;384:989–1002.
- Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med 2022;387:205–216.
- Jastreboff AM et al. Triple–hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med 2023;389:514–526.
- Frías JP et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2). N Engl J Med 2021;385:503–515.
- Aronne LJ et al. Tirzepatide as compared with semaglutide for the treatment of obesity (SURMOUNT-5). N Engl J Med 2025.
- Willard FS et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight 2020;5(17):e140532.
- Eli Lilly and Company. Topline results of the TRIUMPH-1 phase 3 trial of retatrutide in obesity. Press release, 21 May 2026.
- Sanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease. Nat Med 2024.