Semaglutide, tirzepatide, retatrutide and cagrilintide compared

Why these four are compared

Semaglutide, tirzepatide, retatrutide and cagrilintide are routinely discussed together, and the grouping is reasonable up to a point. All four are single-chain peptides of 31 to 39 residues, all four carry a fatty diacid that binds serum albumin and gives a half-life measured in days, and all four have been studied in large or growing clinical programmes in obesity and type 2 diabetes. The grouping breaks down at the receptor: three act on incretin-family receptors and the fourth on amylin receptors, a different pharmacological system, so "GLP-1 family" is a convenience rather than a classification.

This guide sets the four side by side on receptor targets, backbone, substitutions, lipidation, half-life, molecular weight, development and UK licensing status, headline trial figures and bench handling. Every figure is taken from the primary literature cited in the four monographs, which carry the full accounts: semaglutide, tirzepatide, retatrutide and cagrilintide.

All four are supplied by BuyUK Peptides as research chemicals for in-vitro laboratory use only. Nothing on this page is dosing or administration guidance; trial doses appear only as facts about the trials.

Receptor targets

The clearest axis of comparison is receptor pharmacology.

Semaglutide is a selective agonist at the glucagon-like peptide-1 receptor (GLP-1R) and does not act at the GIP or glucagon receptors [1, 2]. It is the reference compound of the class, and the comparator in the trials that established the newer molecules.

Tirzepatide is a dual agonist at the glucose-dependent insulinotropic polypeptide receptor (GIPR) and GLP-1R [3]. Willard and colleagues characterised it as imbalanced and biased: at GIPR it behaves much like native GIP, while at GLP-1R it is a weaker agonist that favours cAMP signalling over β-arrestin recruitment [4].

Retatrutide adds a third receptor, the glucagon receptor (GCGR), to GIPR and GLP-1R [5]. Coskun and colleagues report roughly balanced activity at GCGR and GLP-1R in vitro and greater activity at GIPR, so it is, like tirzepatide, deliberately weighted towards the GIP receptor [5].

Cagrilintide is not an incretin at all. It is an analogue of amylin, the pancreatic hormone co-secreted with insulin, and it acts at the amylin receptors, which are complexes of the calcitonin receptor with one of three receptor activity-modifying proteins (RAMPs), and at the calcitonin receptor itself [6, 7, 8]. Because of that second activity it is sometimes classed as a dual amylin and calcitonin receptor agonist rather than a pure amylin mimetic [6, 8].

All four receptor systems are class B G-protein-coupled receptors, and the standard in-vitro readout for each is cAMP accumulation in a cell line expressing the relevant receptor. For cagrilintide the assay must specify which calcitonin receptor–RAMP complex is expressed, because potency differs between them [7, 8].

Backbone origin

The four peptides descend from three different native sequences.

Semaglutide is built on GLP-1(7-37), the active fragment of the human incretin, and keeps the native numbering, so its first residue is histidine 7 [1, 2].

Tirzepatide and retatrutide are both built on native GIP rather than GLP-1. The tirzepatide discovery paper describes a GIP-derived sequence engineered to take on GLP-1 receptor activity [3], and retatrutide extends the approach with substitutions that confer glucagon receptor activity as well [5]. That shared lineage is why the two are structurally closer to each other than either is to semaglutide.

Cagrilintide is built on human amylin, a 37-residue member of the calcitonin peptide family, by way of pramlintide. Native amylin forms amyloid fibrils readily in solution, and pramlintide, the one amylin analogue to reach the clinic, suppressed that by borrowing three prolines from rat amylin; cagrilintide keeps those prolines and adds further changes [6, 8].

Key substitutions

The common problem for the three incretin peptides is dipeptidyl peptidase-4 (DPP-4), which cleaves the native hormones at the second residue within minutes of release. All three answer it with 2-aminoisobutyric acid (Aib) near the N-terminus: semaglutide at position 8 in GLP-1 numbering, which is the second residue of the chain [1, 2]; tirzepatide at positions 2 and 13 [3]; and retatrutide at positions 2 and 20, with an α-methyl-L-leucine at position 13 [5]. Semaglutide also replaces lysine 34 with arginine, so that only one lysine remains for acylation; the substitution has no apparent effect on receptor binding [2].

Cagrilintide's substitutions address a different problem, fibrillation, and are more extensive. Against human amylin it carries N14E, V17R, A25P, S28P, S29P and Y37P. The three prolines are pramlintide's; the glutamate and arginine are attributed in the structural literature to resisting fibril formation and stabilising the N-terminal helix through an intramolecular salt bridge, and the C-terminal proline replaces the native tyrosine [6, 8]. Cagrilintide also retains the Cys2–Cys7 disulfide bridge conserved across the calcitonin family, which none of the incretin peptides has [6].

Lipidation

All four are protracted by the same principle: a fatty diacid attached through a linker to a lysine binds reversibly to serum albumin and shields the peptide from renal clearance and enzymatic attack. The details differ.

Semaglutide carries a C18 fatty diacid on lysine 26, through one γ-glutamyl unit and two 8-amino-3,6-dioxaoctanoic acid (OEG) units [1, 2]. Lau and colleagues report that this combination gave the best balance of albumin affinity and receptor potency among the derivatives tested, at the cost of roughly three-fold lower GLP-1 receptor affinity than liraglutide [1].

Tirzepatide carries a C20 fatty diacid on lysine 20, through a γ-glutamyl and two-OEG linker [3, 4].

Retatrutide carries a C20 fatty diacid on lysine 17, through a γ-glutamyl and AEEA linker [5]. AEEA, 2-[2-(2-aminoethoxy)ethoxy]acetic acid, is the same chemical unit as OEG under a different name, so the difference from tirzepatide is the number of spacer units and the position of the acylated lysine rather than the chemistry of the spacer.

Cagrilintide is the outlier. Its C20 fatty diacid is attached through a γ-glutamyl linker to the α-amine of the N-terminal lysine, not to a side chain in the middle of the sequence [8].

The diacid makes every one of these molecules amphipathic, which drives the handling behaviour discussed below.

Half-life and molecular weight

The published human half-lives are of the same order for all four. Semaglutide's discovery paper reports around 165 hours, and the licensed product's summary of product characteristics gives it as approximately one week [1]. Tirzepatide's half-life is around five days [3, 4]. Retatrutide's was measured at about six days in the multiple ascending dose study [9]. Cagrilintide's was estimated at 159 to 195 hours, roughly seven to eight days, in the phase 1b study with semaglutide [10]. All four were therefore taken into the clinic at once-weekly intervals.

Average molecular weights run from 4113.58 g/mol for semaglutide through 4409.1 for cagrilintide and 4731.3 for retatrutide to 4813.45 for tirzepatide; tirzepatide and retatrutide differ by about 82 Da. A certificate may report a monoisotopic or deconvoluted electrospray mass instead of the average, and should say which.

Comparison table

Trial figures are mean or least-squares mean change from baseline in the named arm; placebo arms and other doses are in the next section.

Development stage and UK licensing status

The four compounds fall into two regulatory groups.

Semaglutide and tirzepatide are the active ingredients of licensed prescription-only medicines in the United Kingdom: semaglutide as Ozempic and Rybelsus for type 2 diabetes and Wegovy for weight management, tirzepatide as Mounjaro for both. The research-grade peptides sold here are the same molecules chemically, but they are not those medicines: they are not manufactured under a marketing authorisation, are not formulated with the licensed excipients, are not sterile unless the certificate says so, and carry no therapeutic claim.

Retatrutide and cagrilintide are investigational, with no marketing authorisation in the UK, the EU or the US. Retatrutide's phase 3 TRIUMPH programme began reporting topline results in 2026, and the sponsor intends to submit for US regulatory review in the first quarter of 2027 [15, 16]. Cagrilintide has been studied mainly in fixed combination with semaglutide as CagriSema; a submission for that combination was made to the US Food and Drug Administration in December 2025, and the head-to-head REDEFINE 4 trial against tirzepatide did not meet its non-inferiority endpoint [17]. Press-release figures for both programmes have not yet appeared in peer-reviewed form and should be read as provisional.

Our guide to the UK rules on research compounds explains why the position of a research-grade copy of a licensed medicine differs from that of an unlicensed investigational compound.

Headline trial figures

The figures below come from different populations, durations and estimands and were not designed to be compared with one another; the only direct comparisons in the set are SURPASS-2 (tirzepatide against semaglutide 1 mg) and REDEFINE 1 and 4 (CagriSema against semaglutide and tirzepatide respectively).

Semaglutide. In STEP 1, 1,961 adults with obesity or overweight and without diabetes received semaglutide 2.4 mg once weekly or placebo for 68 weeks. Mean body-weight change was −14.9% against −2.4% [11]. In SELECT, 17,604 adults with cardiovascular disease and without diabetes had a lower rate of the primary cardiovascular composite on semaglutide 2.4 mg than on placebo (hazard ratio 0.80) [18].

Tirzepatide. In SURMOUNT-1, 2,539 adults with obesity or overweight and without diabetes received tirzepatide 5, 10 or 15 mg once weekly or placebo for 72 weeks. Mean body-weight change was −15.0%, −19.5% and −20.9% respectively against −3.1% [12]. In SURPASS-2, in type 2 diabetes, all three tirzepatide doses gave greater HbA1c and weight reduction than semaglutide 1 mg over 40 weeks [19].

Retatrutide. In the phase 2 obesity trial, 338 adults received retatrutide 1, 4, 8 or 12 mg once weekly or placebo for 48 weeks. Least-squares mean weight change was −8.7%, −17.1%, −22.8% and −24.2% against −2.1% [13]. The TRIUMPH-1 phase 3 topline, in 2,339 adults over 80 weeks, reported −19.0%, −25.9% and −28.3% at 4, 9 and 12 mg against −2.2% [15]. The phase 2 programme also recorded a dose-related rise in heart rate and skin hyperaesthesia in 7% of retatrutide participants, findings not reported in the same way for the other three compounds [13].

Cagrilintide. As monotherapy in the phase 2 dose-finding trial, 706 adults with overweight or obesity received cagrilintide at 0.3 to 4.5 mg once weekly, liraglutide 3.0 mg daily or placebo for 26 weeks; weight change ranged from −6.0% to −10.8% across the cagrilintide doses against −9.0% with liraglutide and −3.0% with placebo [14]. In REDEFINE 1, 3,417 adults received cagrilintide–semaglutide 2.4 mg/2.4 mg, either component alone, or placebo for 68 weeks; weight change was −20.4% with the combination, −14.9% with semaglutide alone, −11.5% with cagrilintide alone and −3.0% with placebo [20].

Across all four programmes the most common adverse events were gastrointestinal, principally nausea, diarrhoea and vomiting, concentrated during dose escalation [11, 12, 13, 14]. Cagrilintide's monotherapy trial additionally reported dose-dependent injection-site reactions and anti-drug antibodies in 46 to 73% of participants by week 26 [14].

Research-handling differences

At the bench the four compounds behave as what they are: large amphipathic peptides carrying a hydrophobic diacid. The common rules apply to all of them: store the sealed vial at 2–8 °C for routine use or −20 °C for longer, protect from light, let a cold vial reach room temperature before opening, add solvent down the side of the vial and swirl rather than shake, use low-binding plasticware and PES or PVDF rather than nylon filters, and allow a minute or two of gentle swirling for dissolution. The storage and stability guide sets out the general principles and the reconstitution calculator gives volumes for a target concentration. The differences follow from the chemistry above.

Semaglutide has a free C-terminal carboxylate and an acidic diacid, so it dissolves most readily at neutral or mildly basic pH and tends to come out of solution as the pH falls; the licensed formulations are buffered at pH 7.4 for this reason. Assay potency depends strongly on the albumin content of the medium, and the discovery paper reports receptor affinities both with and without albumin for that reason [1].

Tirzepatide handles much like semaglutide, with an amidated C-terminus. The licensed product's label supports in-use storage of the clinical solution at room temperature for up to 21 days, which is the closest thing to a published in-use stability claim available for any of the four.

Retatrutide is somewhat more hydrophobic than tirzepatide because of its glucagon-derived substitutions, and in our experience benefits from a slightly longer dissolution time and buffers at or above neutral pH. It has no licensed product label to borrow a stability claim from. Its synthesis is demanding, so the certificate's impurity profile deserves closer attention: a mass roughly 340 Da short of theory indicates loss of the diacid, and 86 Da short is consistent with a missing Aib.

Cagrilintide needs the most care. It is an amylin analogue engineered against fibrillation, but the sensible assumption is that it will aggregate under conditions a GLP-1-class peptide would tolerate. Do not vortex; agitation and air–water interfaces promote nucleation in amylin-family peptides, and once fibrils have formed they do not redissolve. Prepare only the volume needed, inspect before each use, discard anything cloudy or viscous, and do not freeze reconstituted solutions. Its disulfide adds a certificate check the others lack: a mass two daltons above theory suggests the bridge is reduced.

The receptor table is the firm ground. What the GIP receptor contributes to tirzepatide's effect [4], what the glucagon component adds in retatrutide [5] and why cagrilintide is additive with semaglutide [20] remain open questions, which is the reason these compounds are worth studying side by side in the same assay rather than through literature values.

References

1. Lau J, Bloch P, Schäffer L, et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. Journal of Medicinal Chemistry. 2015;58(18):7370–7380. doi:10.1021/acs.jmedchem.5b00726.
2. Knudsen LB, Lau J. The discovery and development of liraglutide and semaglutide. Frontiers in Endocrinology. 2019;10:155. doi:10.3389/fendo.2019.00155. PMID 31031702.
3. Coskun T, Sloop KW, Loghin C, 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. Molecular Metabolism. 2018;18:3–14. doi:10.1016/j.molmet.2018.09.009. PMID 30473097.
4. Willard FS, Douros JD, Gabe MBN, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17):e140532. doi:10.1172/jci.insight.140532.
5. Coskun T, Urva S, Roell WC, 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 Metabolism. 2022;34(9):1234–1247.e9. doi:10.1016/j.cmet.2022.07.013. PMID 35985340.
6. Kruse T, Hansen JL, Dahl K, et al. Development of cagrilintide, a long-acting amylin analogue. Journal of Medicinal Chemistry. 2021;64(15):11183–11194. doi:10.1021/acs.jmedchem.1c00565. PMID 34288673.
7. Christopoulos G, Perry KJ, Morfis M, et al. Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product. Molecular Pharmacology. 1999;56(1):235–242. doi:10.1124/mol.56.1.235.
8. Cao J, Belousoff MJ, Johnson RM, et al. Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors. Nature Communications. 2025;16:3389. doi:10.1038/s41467-025-58680-y.
9. Urva S, Coskun T, Loh MT, et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. The Lancet. 2022;400(10366):1869–1881. doi:10.1016/S0140-6736(22)02033-5.
10. Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. The Lancet. 2021;397(10286):1736–1748. doi:10.1016/S0140-6736(21)00845-X. PMID 33894838.
11. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). New England Journal of Medicine. 2021;384(11):989–1002. doi:10.1056/NEJMoa2032183. PMID 33567185.
12. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). New England Journal of Medicine. 2022;387(3):205–216. doi:10.1056/NEJMoa2206038.
13. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. New England Journal of Medicine. 2023;389(6):514–526. doi:10.1056/NEJMoa2301972. PMID 37366315.
14. Lau DCW, Erichsen L, Francisco AM, et al. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. The Lancet. 2021;398(10317):2160–2172. doi:10.1016/S0140-6736(21)01751-7. PMID 34798060.
15. Eli Lilly and Company. Lilly's triple agonist, retatrutide, delivered powerful weight loss in pivotal Phase 3 obesity trial (TRIUMPH-1). Press release, 21 May 2026. investor.lilly.com.
16. Eli Lilly and Company. Lilly's triple agonist, retatrutide, successful in two additional Phase 3 obesity trials, delivering significant improvements in weight and A1C (TRIUMPH-2 and TRIUMPH-3). Press release, 23 July 2026. investor.lilly.com.
17. Novo Nordisk A/S. Company announcement: CagriSema REDEFINE 4 head-to-head trial results versus tirzepatide. Form 6-K filed with the US Securities and Exchange Commission, 23 February 2026. sec.gov filing.
18. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). New England Journal of Medicine. 2023;389(24):2221–2232. doi:10.1056/NEJMoa2307563.
19. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2). New England Journal of Medicine. 2021;385(6):503–515. doi:10.1056/NEJMoa2107519.
20. Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered cagrilintide and semaglutide in adults with overweight or obesity (REDEFINE 1). New England Journal of Medicine. 2025;393(7):635–647. doi:10.1056/NEJMoa2502081. PMID 40544433.

This monograph summarises the published literature for laboratory researchers. It is not medical advice, and nothing on this site is for human or veterinary use.