Semaglutide vs Tirzepatide vs Retatrutide Compared

Semaglutide, tirzepatide and retatrutide represent three successive designs in incretin-based peptide research: a single agonist, a dual agonist and a triple agonist. Two are approved prescription medicines; one remains investigational. This article compares their receptor targets, structures and the trial programmes that define each.

Side-by-side summary

	Semaglutide	Tirzepatide	Retatrutide
Receptor targets	GLP-1R	GIPR + GLP-1R	GLP-1R + GIPR + GCGR
Length	31 residues	39 residues	39 residues
Design basis	Analogue of native GLP-1(7–37)	Engineered peptide based on the GIP sequence	Engineered single peptide with three-receptor activity
Lipidation	C18 fatty diacid	C20 fatty diacid	C20 fatty diacid
Reported half-life	~7 days	~5 days	~6 days
Key programmes	SUSTAIN, STEP, SELECT	SURPASS, SURMOUNT	Phase 2; phase 3 TRIUMPH
Status	Approved prescription medicine	Approved prescription medicine	Investigational

The three receptor targets

GLP-1 receptor

The GLP-1 receptor is a class B G protein-coupled receptor. Its activation drives glucose-dependent insulin secretion, suppresses glucagon release, slows gastric emptying and acts on central appetite pathways. Native GLP-1 is cleaved by DPP-4 within minutes, which is why research analogues are engineered for stability.

GIP receptor

Glucose-dependent insulinotropic polypeptide (GIP) is the second incretin hormone. GIP receptors are expressed in pancreatic islets, adipose tissue and the brain. Its contribution in combination with GLP-1 agonism is still being characterised; notably, both GIPR agonism and GIPR antagonism are under clinical investigation in separate programmes.

Glucagon receptor

The glucagon receptor regulates hepatic glucose output and lipid metabolism. In rodent models, glucagon receptor agonism increases energy expenditure, which is the rationale for adding it to incretin agonism. Balancing this against its glucose-raising effect is a central design problem for triple agonists.

Structural differences

Semaglutide shares about 94% sequence homology with native human GLP-1. Three changes define it: aminoisobutyric acid (Aib) at position 8 for DPP-4 resistance, arginine in place of lysine at position 34, and a C18 fatty diacid attached to lysine 26 through a hydrophilic linker. The diacid binds serum albumin, which extends half-life. Theoretical molecular weight is about 4,113.6 Da.

Tirzepatide is a 39-residue linear peptide based on the GIP sequence, containing two Aib residues and a C20 fatty diacid on lysine 20. Coskun et al. (2018) described it as "imbalanced": affinity at GIPR comparable to native GIP, but weaker at GLP-1R than native GLP-1. Theoretical molecular weight is about 4,813.5 Da.

Retatrutide is a 39-residue single peptide containing several non-proteinogenic residues and a fatty diacid moiety, engineered to activate GLP-1, GIP and glucagon receptors (Coskun et al., 2022). It is one molecule, not a mixture of three.

Trial landscape

Semaglutide: STEP and SELECT

STEP 1 (Wilding et al., 2021) enrolled 1,961 adults with overweight or obesity without diabetes. Mean body-weight change at 68 weeks was −14.9% with semaglutide versus −2.4% with placebo. SELECT (Lincoff et al., 2023) enrolled 17,604 adults with established cardiovascular disease and overweight or obesity, and reported a 20% relative reduction in major adverse cardiovascular events (hazard ratio 0.80).

Tirzepatide: SURMOUNT

SURMOUNT-1 (Jastreboff et al., 2022) enrolled 2,539 adults. Mean body-weight change at 72 weeks reached −20.9% in the highest study arm versus −3.1% with placebo. SURMOUNT-5 (Aronne et al., 2025) is the first head-to-head obesity trial against semaglutide, reporting −20.2% versus −13.7% at 72 weeks.

Retatrutide: phase 2 and phase 3

The phase 2 trial (Jastreboff et al., 2023) enrolled 338 adults with obesity. Mean body-weight change at 48 weeks reached −24.2% in the highest study arm versus −2.1% with placebo. The phase 3 TRIUMPH programme is evaluating retatrutide across obesity and related conditions; check ClinicalTrials.gov for current status and readouts.

Reading these numbers carefully

• Cross-trial comparison is weak evidence. Populations, durations, titration schedules and baseline weights differ. Only SURMOUNT-5 compares two of these molecules directly.
• Phase 2 and phase 3 are not equivalent. Retatrutide's figures come from a smaller, shorter trial than STEP 1 or SURMOUNT-1.
• Mechanism is partly unresolved. The individual contribution of GIP and glucagon agonism in humans is still being separated from the GLP-1 component.

Notes on research-grade material

Approved products are prescription medicines manufactured under drug GMP. Research-grade peptide supplied for in vitro and animal work is a different product with a different purpose. Identity should be confirmed by mass spectrometry against the theoretical mass, because lipidated peptides of this size are complex to synthesise and purify. See our guide to reading a certificate of analysis.

References

• Lau J, Bloch P, Schäffer L, et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem. 2015;58(18):7370–7380.
• Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384:989–1002.
• Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389:2221–2232.
• 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. Mol Metab. 2018;18:3–14.
• Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387:205–216.
• Aronne LJ, et al. Tirzepatide as compared with semaglutide for the treatment of obesity. N Engl J Med. 2025.
• 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 Metab. 2022;34(9):1234–1247.
• Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. 2023;389:514–526.