"GLP-1 drugs" has become shorthand for a whole class, but the class is actually three generations of increasingly multi-targeted peptides. Each generation adds a receptor. Each generation produces more weight loss in clinical trials. This is the quick comparison.
Receptor targets β the core difference
| GLP-1 | GIP | Glucagon | |
|---|---|---|---|
| Semaglutide | β full agonist | β | β |
| Tirzepatide | β full agonist | β full agonist | β |
| Retatrutide | β full agonist | β full agonist | β full agonist |
What each receptor contributes:
- GLP-1 β appetite suppression, delayed gastric emptying, glucose-dependent insulin secretion.
- GIP β enhanced insulin secretion, modulation of adipose metabolism.
- Glucagon β increased energy expenditure, hepatic lipid oxidation.
Semaglutide and tirzepatide reduce energy intake. Retatrutide is the first in the class that also measurably increases energy expenditure.
Clinical weight-loss outcomes
| Agent | Trial | Top dose | Duration | Mean % weight loss |
|---|---|---|---|---|
| Semaglutide | STEP-1 | 2.4 mg weekly | 68 weeks | β14.9% |
| Tirzepatide | SURMOUNT-1 | 15 mg weekly | 72 weeks | β20.9% |
| Retatrutide | Phase 2 (Jastreboff 2023) | 12 mg weekly | 48 weeks | β24.2% |
Retatrutide achieves more weight loss in less time. The curve at 48 weeks also hadn't visibly plateaued β a suggestive but unconfirmed hint of further loss with longer treatment. Phase 3 trials (TRIUMPH) are in progress.
Pharmacokinetics
| Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
| Half-life | ~7 days | ~5 days | ~6 days |
| Cadence | Once weekly SC | Once weekly SC | Once weekly SC |
| Steady-state | ~5 weeks | ~4 weeks | ~4β5 weeks |
| Escalation | 4β8 weeks per step | 4 weeks per step | 4 weeks per step |
Side-effect profile β broadly similar
All three agents share a dose-dependent GI side-effect profile: nausea, diarrhea, constipation, and occasional vomiting, concentrated in the first 4β8 weeks of each dose step. Across the class, these effects attenuate with continued dosing at a stable level.
Retatrutide additionally reports a modest resting heart-rate increase (3β6 bpm) at higher doses, attributed to glucagon-driven metabolic-rate elevation. Pancreatitis risk remains an ongoing class-level concern but trial rates have not been meaningfully different from placebo.
Regulatory status
- Semaglutide β FDA-approved for T2DM (Ozempic) and weight management (Wegovy). Widely prescribed.
- Tirzepatide β FDA-approved for T2DM (Mounjaro) and weight management (Zepbound). Widely prescribed.
- Retatrutide β not FDA-approved. In Phase 3 trials. Research-use only at this time.
Reconstitution and calculator
All three are dosed once weekly in mg, which means the calculator math is identical β only the target dose changes:
| Agent | Vial | BAC water | Top dose β IU (U-100) |
|---|---|---|---|
| Semaglutide | 5 mg | 2 ml | 2.4 mg β 96 IU |
| Tirzepatide | 10 mg | 2 ml | 15 mg β entire vial weekly (multi-vial protocols) |
| Retatrutide | 10 mg | 2 ml | 12 mg β 240 IU (multi-vial or higher dilution) |
For every peptide in the class:
Open Reconstitution CalculatorWhich would a researcher choose?
Framed as research selection criteria, not medical advice:
- Broadest clinical evidence: semaglutide. Longest time on market, largest patient populations, most post-marketing data.
- Approved and strongest outcomes: tirzepatide. FDA-approved with ~21% weight loss.
- Highest magnitude, earliest-stage: retatrutide. Largest weight-loss numbers on record, but limited long-term safety data and not approved.
For the full retatrutide breakdown see our Retatrutide complete guide. For reconstitution technique see how to reconstitute peptides.
Research use only. All peptides referenced are supplied by Capital Peptides as laboratory reagents. Not for human consumption, diagnostic, or therapeutic use.