Semaglutide vs Tirzepatide vs Retatrutide
Three GLP-1 class compounds. Different receptor targets, different dose ranges, different trial data. Here's the full picture.
At a Glance
Quick Comparison Table
| Parameter | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Receptor targets | GLP-1 | GLP-1 + GIP | GLP-1 + GIP + Glucagon |
| Drug class | Single agonist | Dual agonist | Triple agonist |
| Developer | Novo Nordisk | Eli Lilly | Eli Lilly |
| FDA approval status | Approved (Ozempic, Wegovy) | Approved (Mounjaro, Zepbound) | Not approved (Phase 3) |
| Starting dose | 0.25 mg | 2.5 mg | 2 mg |
| Maximum studied dose | 2.4 mg | 15 mg | 12 mg |
| Injection frequency | Once weekly | Once weekly | Once weekly |
| Phase trial weight reduction | ~15% at 68 weeks (2.4 mg) | ~22.5% at 72 weeks (15 mg) | ~24% at 48 weeks (12 mg) |
| Titration duration to max dose | 16+ weeks | 20+ weeks | 20+ weeks |
| Prescription availability | Yes | Yes | No — research only |
| Compounded versions available | Yes (pharmacy) | Yes (pharmacy) | Research grade only |
Why the Receptor Targets Matter
Mechanism Differences
All three compounds act on the GLP-1 receptor, which drives the core effects — slowed gastric emptying, reduced appetite signaling, and glucose-dependent insulin secretion. The differences come from what else each compound targets.
Semaglutide
Acts on a single receptor. The most clinically studied of the three with the largest body of human safety and efficacy data. FDA-approved for type 2 diabetes (Ozempic) and weight management (Wegovy). The reference point against which newer compounds are compared.
Tirzepatide
Adds GIP receptor agonism to GLP-1. GIP receptor activation is proposed to enhance insulin sensitivity and may improve tolerability compared to GLP-1 alone. Phase 3 SURMOUNT trials showed greater mean weight reduction than semaglutide at comparable timepoints. FDA-approved as Mounjaro and Zepbound.
Retatrutide
Adds glucagon receptor agonism to the GLP-1 + GIP combination. Glucagon receptor activation is proposed to increase energy expenditure — influencing both energy intake and output simultaneously. Not FDA-approved. Phase 2 data showed the highest mean weight reduction of the three at comparable timepoints, though direct head-to-head trial data does not yet exist.
Side-by-Side Titration
Titration Schedule Comparison
All three require gradual dose titration to manage gastrointestinal side effects. The timelines and dose increments differ significantly.
| Week | Dose |
|---|---|
| Weeks 1–4 | 0.25 mg |
| Weeks 5–8 | 0.5 mg |
| Weeks 9–12 | 1.0 mg |
| Weeks 13–16 | 1.7 mg |
| Weeks 17+ | 2.4 mg |
| Week | Dose |
|---|---|
| Weeks 1–4 | 2.5 mg |
| Weeks 5–8 | 5.0 mg |
| Weeks 9–12 | 7.5 mg |
| Weeks 13–16 | 10.0 mg |
| Weeks 17–20 | 12.5 mg |
| Weeks 21+ | 15.0 mg |
| Week | Dose |
|---|---|
| Weeks 1–4 | 2 mg |
| Weeks 5–8 | 4 mg |
| Weeks 9–12 | 6 mg |
| Weeks 13–16 | 8 mg |
| Weeks 17–20 | 10 mg |
| Weeks 21+ | 12 mg |
All three compounds share the same core titration principle — advance only when the current dose is well tolerated. Nausea, vomiting, or severe appetite suppression are signals to hold rather than advance.
Reconstitution at a Glance
Reconstitution Comparison
Research-grade versions of all three compounds are supplied as lyophilized powder and require reconstitution with bacteriostatic water. The recommended concentrations differ due to their different dose ranges.
| Compound | Recommended concentration | Reason |
|---|---|---|
| Semaglutide | 1.0–2.5 mg/mL | Low dose range (0.25–2.4 mg) requires lower concentration for measurable draw volumes |
| Tirzepatide | 5.0–10.0 mg/mL | Higher dose range (2.5–15 mg) requires higher concentration to keep volumes under 1 mL |
| Retatrutide | 5.0–10.0 mg/mL | Similar dose range to tirzepatide — same concentration logic applies |
Calculate your exact syringe draw for any compound
Open the Calculator →How to Think About the Choice
Which Should You Research?
This is not a medical recommendation. The following reflects considerations commonly discussed in the research community.
Largest human safety dataset
Semaglutide has the most extensive clinical trial data and longest real-world use history of the three. For researchers prioritizing established human data, semaglutide is the reference compound.
Strongest Phase 3 efficacy data
Tirzepatide's SURMOUNT program produced the largest body of Phase 3 weight management trial data currently available among approved compounds, with mean weight reductions exceeding semaglutide in head-to-head comparisons.
Highest Phase 2 weight reduction
Retatrutide produced the highest mean weight reduction figures in Phase 2 data of any compound in this class. Phase 3 data is pending. It is not FDA-approved and has no prescription pathway.
Prescription vs research only
Semaglutide and tirzepatide are available by prescription through licensed healthcare providers and as compounded versions through licensed pharmacies. Retatrutide is available only as a research chemical with no prescription pathway.
Do not combine these compounds
Semaglutide, tirzepatide, and retatrutide all act on the GLP-1 receptor. Combining any two of these compounds introduces unpredictable receptor competition and is not supported by any research protocol. Use only one GLP-1 class compound at a time.
Full Guides for Each Compound
Individual Compound Pages
Semaglutide Guide
Titration schedule, reconstitution tables, syringe draw reference
Read guide →Tirzepatide Guide
Titration schedule, reconstitution tables, syringe draw reference
Read guide →Retatrutide Guide
Titration schedule, reconstitution tables, syringe draw reference + full protocol PDF
Read guide →