Semaglutide vs Tirzepatide vs Retatrutide
Comparing 3 compounds by evidence grade, FDA status, mechanism, and key safety considerations: Semaglutide, Tirzepatide, Retatrutide.
| Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
| Evidence grade | Grade A: Approved and proven | Grade A: Approved and proven | Grade B: Human evidence, not approved for this use |
| FDA status | FDA approved Approved as Ozempic (subcutaneous injection, type 2 diabetes), Wegovy (subcutaneous injection 2.4 mg and oral 25 mg tablet, chronic weight management and cardiovascular risk reduction in obesity), and Rybelsus (oral tablet, type 2 diabetes). | FDA approved Approved as Mounjaro (subcutaneous injection, type 2 diabetes) and Zepbound (subcutaneous injection, chronic weight management and, additionally, obstructive sleep apnea in adults with obesity). | Not FDA approved Investigational; Phase 3 TRIUMPH trials ongoing as of June 2026, no NDA submitted. |
| Mechanism | Semaglutide is a GLP-1 receptor agonist that stimulates glucose-dependent insulin secretion, suppresses glucagon, slows gastric emptying, and reduces appetite via central and peripheral GLP-1 receptor activation. | Tirzepatide is a dual GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 receptor agonist, which stimulates insulin secretion, suppresses glucagon, reduces appetite, and slows gastric emptying through activation of both receptor pathways. | Simultaneously activates GLP-1, GIP, and glucagon receptors to suppress appetite, enhance insulin secretion in a glucose-dependent manner, and increase energy expenditure. |
| Key safety | Boxed warning: semaglutide causes thyroid C-cell tumors in rodents at clinically relevant exposures; human relevance is unknown but it is contraindicated in pat... | Boxed warning: tirzepatide causes thyroid C-cell tumors in rats at clinically relevant exposures; human relevance is unknown and the drug is contraindicated in... | As a GLP-1 receptor agonist, retatrutide carries the class risk of thyroid C-cell tumors observed in rodent studies; patients with personal or family history of... |