Mechanism of action
Semaglutide is a selective GLP-1 receptor agonist. Long-acting analog with side-chain modifications extending half-life to ~7 days. Tirzepatide is the first dual GIP/GLP-1 agonist — a single peptide activating both incretin receptors. The GIP component amplifies the weight-reducing effect through complementary mechanisms in adipose tissue and hypothalamic signaling.
SURPASS-2 head-to-head trial
SURPASS-2 (Frias JP et al., NEJM 2021, PMID 34170647) compared tirzepatide and semaglutide 1 mg in 1,879 adults with T2D over 40 weeks:
| Arm | HbA1c reduction | Weight change |
|---|---|---|
| Tirzepatide 5 mg | -2.01% | -7.6 kg |
| Tirzepatide 10 mg | -2.24% | -9.3 kg |
| Tirzepatide 15 mg | -2.30% | -11.2 kg |
| Semaglutide 1 mg | -1.86% | -5.7 kg |
Note: SURPASS-2 used semaglutide 1 mg (T2D dose), not 2.4 mg (obesity dose). Comparing tirz 15 mg in obesity to sema 2.4 mg in obesity (separate trials) narrows the gap.
Obesity trial results
In separate dedicated obesity populations:
| Drug · Trial | Mean WL at 68-72wk | ≥10% WL |
|---|---|---|
| Semaglutide · STEP-1 (n=1,961) | -14.9% | 69.1% |
| Tirzepatide · SURMOUNT-1 (n=2,539, 15 mg) | -20.9% | 90.0% |
Cardiovascular outcomes
Semaglutide: SELECT (Lincoff AM et al., NEJM 2023, PMID 37952131) showed 20% MACE reduction in 17,604 adults with BMI ≥27 + established CVD. Led to Wegovy CV indication (March 2024).
Tirzepatide: No published CV outcome trial as of May 2026. SURPASS-CVOT enrolling, readout 2027.
For patients with established CVD, semaglutide has the relevant evidence base today.
FDA-approved indications
| Indication | Semaglutide | Tirzepatide |
|---|---|---|
| T2D | Ozempic (2017), Rybelsus oral (2019) | Mounjaro (2022) |
| Chronic weight management | Wegovy (2021) | Zepbound (2023) |
| CV risk reduction (obesity + CVD) | Wegovy (Mar 2024) | Not yet |
| OSA in obesity | Not approved | Zepbound (Dec 2024) |
Compounded pricing (May 2026)
| Provider | Sema (12-mo plan) | Tirz (12-mo plan) |
|---|---|---|
| NexLife | $145/mo flat through 2.4 mg | $186/mo flat through 15 mg |
| Mochi Health | ~$178/mo | ~$208/mo |
| Henry Meds | ~$279/mo | ~$369-449/mo |
| Eden Health | ~$189-249/mo | ~$229-349/mo |
How to choose
- Tirzepatide if: max weight loss is the primary goal, no CV concerns, can tolerate higher GI burden at 15 mg
- Semaglutide if: established CVD or CV risk factors; want the deeper outcomes evidence base
- Either if: T2D (both approved); OSA-only with obesity → tirzepatide (only OSA-approved)
- Sema first if: budget-constrained or had prior GI intolerance to incretins