Semaglutide vs. tirzepatide vs. retatrutide
Head-to-head on mechanism, trial weight loss, side effects, cardiometabolic outcomes, and current availability.
Mechanism
- Semaglutide — GLP-1 receptor agonist. Single-receptor.
- Tirzepatide — dual agonist: GIP + GLP-1.
- Retatrutide — triple agonist: GIP + GLP-1 + glucagon. The glucagon component likely adds a thermogenic / energy-expenditure effect on top of the appetite-suppressing effects of GIP and GLP-1.
Trial weight loss (68–72 weeks, highest dose)
| Drug | Trial | Dose | Weight loss (vs placebo-adjusted) |
|---|---|---|---|
| Semaglutide | STEP 1 (Wilding, 2021) | 2.4 mg/wk | ~14.9% vs ~2.4% placebo |
| Tirzepatide | SURMOUNT-1 (Jastreboff, 2022) | 15 mg/wk | ~20.9% vs ~3.1% placebo |
| Retatrutide | TRIUMPH-1 Ph2 (Jastreboff, 2023) | 12 mg/wk (48 wk) | ~24.2% vs ~2.1% placebo |
Note: TRIUMPH-1 was Phase 2 and shorter duration than the Phase 3 comparators; weight loss likely would have continued.
Cardiovascular / cardiometabolic outcomes
- Semaglutide — SELECT trial (Lincoff, 2023) showed a 20% relative reduction in MACE in adults with established cardiovascular disease and overweight/obesity without diabetes.
- Tirzepatide — SURMOUNT-MMO (cardiovascular outcomes trial in obesity) underway; results expected. SURPASS program showed strong glycemic outcomes in T2D but no MACE superiority trial yet.
- Retatrutide — Phase 3 program includes cardiovascular outcomes trial (TRIUMPH-OUTCOMES); no results yet.
Side effect profile
All three have qualitatively similar GI profiles dominated by nausea, vomiting, diarrhea, and constipation. Rates scale with dose and taper over time. Retatrutide additionally showed modest heart rate increases in TRIUMPH, likely related to the glucagon component.
Availability and access
- Semaglutide — FDA-approved (Wegovy, Ozempic, Rybelsus). Widely available.
- Tirzepatide — FDA-approved (Zepbound, Mounjaro). Previously on shortage list; status evolves.
- Retatrutide — not yet FDA-approved. Available only via trial enrollment.
Compounded versions of semaglutide and tirzepatide, legal when FDA-designated a shortage, have become a significant market. Compounding status depends on current FDA shortage declarations and is subject to change.
Bottom line
By Phase 3 weight loss data, tirzepatide > semaglutide. Early Phase 2 data suggests retatrutide may exceed tirzepatide in magnitude, but we await Phase 3 confirmation and cardiovascular outcomes. For CV-focused use cases with robust outcomes data, semaglutide remains the leader (SELECT).