Retatrutide vs Tirzepatide

Metabolic

Metabolic

Research Only

FDA Approved

Retatrutide simultaneously activates three receptors: GLP-1R (appetite suppression, insulin secretion), GIPR (insulin sensitivity, fat metabolism), and glucagon receptor (energy expenditure, hepatic fat reduction). The glucagon receptor component is unique and promotes thermogenesis and fatty acid oxidation beyond what dual agonists achieve.

Tirzepatide is a 39-amino-acid synthetic peptide that co-activates the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. GLP-1R activation enhances glucose-dependent insulin secretion, suppresses glucagon, slows gastric emptying, and reduces appetite via central satiety pathways; GIP receptor agonism appears to augment insulin secretion, improve adipose tissue lipid handling, and may blunt GLP-1-mediated nausea, producing greater A1C and weight-loss effects than selective GLP-1 agonists.

1–12 mg

2.5–15 mg once weekly

SubQ

SubQ

Once weekly

Once weekly

Phase 2 trial used escalating doses up to 12 mg once weekly. Titration schedule similar to other GLP-1 agonists, increasing dose every 4 weeks to minimize GI side effects. Not yet approved — all dosing is from clinical trial data.

Per FDA labels (Mounjaro and Zepbound): start 2.5 mg SC once weekly as a non-therapeutic initiation dose, then increase to 5 mg after 4 weeks. If additional glycemic or weight-loss effect is needed, titrate in 2.5 mg increments every 4 weeks to a maximum of 15 mg once weekly. Zepbound maintenance doses for obesity are 5, 10, or 15 mg weekly; SURMOUNT-OSA used the maximum tolerated dose of 10 or 15 mg weekly. Inject into the abdomen, thigh, or upper arm; rotate sites. Missed doses may be taken within 4 days (96 hours); otherwise skip and resume the weekly schedule. When combined with insulin or sulfonylureas, consider reducing those agents to lower hypoglycemia risk.