Different Mechanisms
Semaglutide (Ozempic/Wegovy) activates one receptor: GLP-1R. Single agonist.
Tirzepatide (Mounjaro/Zepbound) activates two: GLP-1R + GIPR. Dual agonist ('twincretin').
GLP-1 suppresses appetite and stimulates insulin. GIP enhances fat metabolism and insulin sensitivity through distinct pathways. Two mechanisms > one.
Weight Loss Data
Semaglutide (STEP): 15–17% mean weight loss at 68 weeks. ~30% of patients lost ≥20%.
Tirzepatide (SURMOUNT): 22.5% mean weight loss. 63% of patients lost ≥20%.
That's ~5 percentage points more — clinically meaningful.
Retatrutide — a triple agonist (GLP-1/GIP/Glucagon) showed 24.2% weight loss in Phase II. Phase III ongoing.
Engineering Differences
Semaglutide: GLP-1 backbone, Aib8 (DPP-4 resistance), C18 fatty diacid (albumin binding), t½ ≈7 days.
Tirzepatide: GIP backbone engineered to cross-react with GLP-1R, C20 fatty diacid, t½ ≈5 days.
Side Effects
Both: nausea (25-44%), vomiting, diarrhea. Same thyroid C-cell warning. Weight regain after stopping (~2/3 regained within 1 year for semaglutide).
Bottom Line
Tirzepatide wins on weight loss data. Semaglutide has more long-term data, broader coverage, and an oral option. Both are dramatically better than any prior obesity medication.