Semaglutide vs Tirzepatide vs Retatrutide
Semaglutide, tirzepatide and retatrutide are lipidated incretin-based peptides with one, two and three receptor targets. Semaglutide and tirzepatide are FDA-approved; retatrutide is investigational. This page compares their mechanisms, structures, trial programs and status.
These three peptides represent successive steps in incretin-based drug design. Semaglutide is a selective agonist of the glucagon-like peptide-1 (GLP-1) receptor. Tirzepatide is a single peptide that activates both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the GLP-1 receptor. Retatrutide adds glucagon receptor agonism to the GIP and GLP-1 activities.
All three use fatty-acid side chains that bind serum albumin, which slows clearance and allows infrequent administration. Semaglutide and tirzepatide are FDA-approved and have large published phase 3 programs. Retatrutide remains investigational. Its manufacturer reported positive TRIUMPH phase 3 results and plans a regulatory submission, but the drug is not approved.
Side-by-side
| Attribute | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Receptor targets | GLP-1 receptor | GIP and GLP-1 receptors | GIP, GLP-1 and glucagon receptors |
| Sequence basis | GLP-1 analogue | GIP-based sequence engineered for dual activity | GIP-based sequence engineered for triple activity |
| Albumin-binding modification | C18 fatty diacid on a lysine via a linker | C20 fatty diacid on a lysine via a linker | Fatty diacid on a lysine via a linker |
| Non-standard residues | Aib at position 2 to resist DPP-4 | Includes Aib residues | Includes Aib and other non-standard residues |
| Developer | Novo Nordisk | Eli Lilly | Eli Lilly |
| Major trial programs | SUSTAIN (type 2 diabetes), STEP (obesity), SELECT (cardiovascular outcomes) | SURPASS (type 2 diabetes), SURMOUNT (obesity) | TRIUMPH (phase 3) |
| FDA status | Approved (Ozempic, Wegovy, Rybelsus) | Approved (Mounjaro, Zepbound) | Investigational; BLA submission planned for Q1 2027 |
| Compounding | Check current FDA compounding guidance | Check current FDA compounding guidance | FDA has stated it cannot be used in compounding |
| Analytical pitfalls | Confirm lipidated mass; aggregation of lipidated peptide | Confirm lipidated mass; aggregation; long sequence increases impurity load | Confirm lipidated mass; no pharmacopeial reference standard |
One, two or three receptors
Semaglutide acts only at the GLP-1 receptor, which mediates glucose-dependent insulin secretion, slower gastric emptying and appetite effects. Tirzepatide adds GIP receptor agonism, and its balance of activity is weighted differently at the two receptors than either native hormone. Retatrutide adds glucagon receptor agonism, which is studied for its effects on energy expenditure and liver fat. The exact contribution of each receptor to the clinical effects of the multi-agonists is still being studied.
Shared structural strategy
All three peptides combine amino acid substitutions that resist dipeptidyl peptidase-4, such as aminoisobutyric acid, with a fatty diacid attached to a lysine side chain through a hydrophilic linker. The lipid chain binds reversibly to serum albumin, which protects the peptide from renal clearance and enzymatic breakdown. Analytically this makes them more demanding than simple peptides: identity testing must confirm the full lipidated mass, and lipidated peptides can aggregate or adsorb to surfaces.
Clinical programs and status
Semaglutide's programs include SUSTAIN in type 2 diabetes, STEP in obesity and SELECT, a cardiovascular outcomes trial. Tirzepatide's include SURPASS in type 2 diabetes and SURMOUNT in obesity. Retatrutide's phase 3 program is TRIUMPH. Results for approved drugs are described in their labels and trial publications. Retatrutide has no approved label, and the FDA has stated it cannot be used in compounding.
Frequently asked questions
What is the difference between semaglutide, tirzepatide and retatrutide?
They differ mainly in receptor targets. Semaglutide activates the GLP-1 receptor, tirzepatide activates both GIP and GLP-1 receptors, and retatrutide activates GIP, GLP-1 and glucagon receptors. All three are lipidated peptides that bind albumin for extended circulation. Semaglutide and tirzepatide are FDA-approved; retatrutide is investigational.
Is retatrutide FDA approved?
No. Retatrutide is investigational and not FDA-approved. In July 2026 Eli Lilly said it plans to submit a biologics license application in the first quarter of 2027 following positive TRIUMPH phase 3 results. The FDA has stated that retatrutide cannot be used in compounding.
Why are these peptides lipidated?
A fatty diacid attached to a lysine side chain lets the peptide bind reversibly to serum albumin. This protects it from rapid kidney clearance and enzymatic breakdown and greatly extends its time in circulation compared with native incretin hormones, which are cleared within minutes.
Full entries
- Semaglutide
Semaglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist. It is FDA-approved for type 2 diabetes (Ozempic, Rybelsus) and chronic weight management (Wegovy).
- Tirzepatide
Tirzepatide is a once-weekly peptide that activates both the GIP and GLP-1 receptors. It is FDA-approved for type 2 diabetes (Mounjaro) and chronic weight management (Zepbound).
- Retatrutide
Retatrutide is an investigational once-weekly peptide that activates the GIP, GLP-1 and glucagon receptors. It is not FDA-approved; Eli Lilly plans a BLA submission in Q1 2027 after phase 3 results.
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