Semaglutide vs Tirzepatide

Metabolic

Metabolic

FDA Approved

FDA Approved

Semaglutide is a long-acting GLP-1 receptor agonist. Binding the GLP-1 receptor enhances glucose-dependent insulin secretion from pancreatic beta cells, suppresses glucagon release, and slows gastric emptying. It also acts on hypothalamic appetite centers to reduce hunger and caloric intake, driving substantial weight loss in addition to glycemic improvement.

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.

Wegovy (obesity): 0.25 → 0.5 → 1.0 → 1.7 → 2.4 mg SubQ weekly. Ozempic (T2DM): 0.25 → 0.5 → 1.0 → 2.0 mg SubQ weekly. Rybelsus (oral): 3 → 7 → 14 mg daily.

2.5–15 mg once weekly

SubQ or Oral

SubQ

Once weekly (SubQ); once daily (oral)

Once weekly

Per FDA labels, SubQ doses are escalated every 4 weeks to minimize GI adverse effects; 0.25 mg is a starting dose only and is not effective for maintenance. Rybelsus must be taken in the morning on an empty stomach with up to 4 oz (120 mL) of plain water, then no food, drink, or other oral medications for at least 30 minutes. Administer SubQ injections in the abdomen, thigh, or upper arm on the same day each week.

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.