Semaglutide vs Tirzepatide vs Retatrutide
Three generations of GLP-1 drugs. What actually separates them?
Reviewed by the amino101 editorial team. , first published .
These three are the same idea taken further each time. Semaglutide hits one receptor, GLP-1. Tirzepatide hits two, adding GIP. Retatrutide hits three, adding glucagon. Each added receptor bought more weight loss in trials: roughly 15 percent of body weight for semaglutide, 20 percent for tirzepatide, and about 24 percent for retatrutide at 48 weeks in phase 2. The trade-off runs the other way on evidence. Semaglutide has been approved and used by millions for years, tirzepatide is approved with a few years of real-world data, and retatrutide is still in phase 3 with no approved product anywhere.
| Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
| Typical dosage | 0.25 mg (starting dose) | 2.5 mg (starting dose) | 1 to 2 mg (starting dose) |
| Frequency | once weekly | once weekly | once weekly |
| Route | Subcutaneous, Oral | Subcutaneous | Subcutaneous |
| Half-life | About 7 days (roughly 165 hours) | About 5 days (roughly 117 hours) | About 6 days (phase 1 estimate) |
| Cycle | ongoing, step up every 4 weeks through 0.5, 1.0, 1.7 and 2.4 mg | ongoing, increase by 2.5 mg every 4 weeks as tolerated | ongoing in trials, escalated every 4 weeks toward 4, 8 or 12 mg |
| Research level | Extensively studied | Extensively studied | Extensively studied |
| Human trials | Approved drug | Approved drug | Randomized trials |
| Status | FDA approved as Ozempic, Wegovy and Rybelsus. Compounded and grey-market vials are not approved products. | FDA approved as Mounjaro and Zepbound. Grey-market vials are not the approved product. | Investigational, in Phase 3 trials. Not FDA approved anywhere. |
| Effects timeline | appetite drops within 1 to 2 weeks, steady weight loss from about week 4 once past 0.5 mg, plateau around 12 to 18 months | appetite drops within the first 1 to 2 weeks, weight loss builds from about week 4, plateau around 12 to 18 months | appetite drop within 1 to 2 weeks, resting heart rate rise in the first month, weight loss builds from about week 4 and was still going at 48 weeks in phase 2 |
Key differences
Semaglutide vs Tirzepatide vs Retatrutide dosage
Dosage patterns reported in research and community protocols, by goal. Taken from each compound page. Not a prescription.
| Goal | Dosage | Frequency |
|---|---|---|
| Weeks 1 to 4, tolerance | 0.25 mg | once weekly |
| Weeks 5 to 8 | 0.5 mg | once weekly |
| Weeks 9 to 12 | 1.0 mg | once weekly |
| Weeks 13 to 16 | 1.7 mg | once weekly |
| Week 17 onward, maintenance | 2.4 mg, or the lowest step that works | once weekly |
| Goal | Dosage | Frequency |
|---|---|---|
| Weeks 1 to 4, tolerance | 2.5 mg | once weekly |
| Weeks 5 to 8 | 5 mg | once weekly |
| Weeks 9 to 12 | 7.5 mg | once weekly |
| Weeks 13 to 16 | 10 mg | once weekly |
| Week 17 onward, if still needed | 12.5 to 15 mg | once weekly |
| Goal | Dosage | Frequency |
|---|---|---|
| Weeks 1 to 4, tolerance | 1 to 2 mg | once weekly |
| Weeks 5 to 8 | 2 to 4 mg | once weekly |
| Weeks 9 to 12 | 4 to 8 mg | once weekly |
| Week 13 onward, if still needed | 8 to 12 mg | once weekly |
| Low-dose hold (common community pattern) | 4 mg | once weekly |
Convert any of these to syringe units in the dosage calculator.
Side effects compared
- ▲Nausea, especially the first few days after each dose increase
- ▲Constipation or diarrhea
- ▲Burping, reflux and early fullness
- ▲Fatigue and low energy from eating less
- ▲Injection site redness or itching
- ▲Nausea and reduced appetite, worst right after each dose increase
- ▲Diarrhea or constipation
- ▲Burping, reflux and indigestion
- ▲Fatigue during the first weeks of each step
- ▲Injection site reactions
- ▲Nausea, vomiting and diarrhea, rougher than semaglutide in the early weeks
- ▲Resting heart rate up by several beats per minute for the first months
- ▲Skin tingling or heightened skin sensitivity (dysesthesia)
- ▲Constipation and reflux
- ▲Injection site reactions
Which should you choose?
Semaglutide is the right pick if cost per mg matters most, if you want the longest safety record in the class, or if you have cardiovascular disease, since the SELECT trial showed a 20 percent reduction in major cardiac events. It is also the one paired with cagrilintide in the CagriSema program. Expect more nausea than the other two during titration.
Tirzepatide is the pick for most people who want the strongest approved option. It beat semaglutide head to head in SURMOUNT-5, roughly 20 versus 14 percent at 72 weeks, the GIP component appears to blunt nausea, and it has a sleep apnea indication. The tirzepatide dosage chart covers the 2.5 mg step schedule.
Retatrutide is only for people who accept an unapproved compound from an unverified supply. The 2026 TRIUMPH-1 topline figure, about 28 percent at 80 weeks on 12 mg, is the largest number reported for any single drug, but it is sponsor reported and pending full publication, and Lilly does not plan to file for approval until early 2027. The heart rate increase is the extra safety signal. See the retatrutide phase 3 results before deciding.
If you want the most evidence behind what you are injecting, tirzepatide is the current sweet spot: approved, stronger than semaglutide, gentler on the stomach. Semaglutide still makes sense if cost matters most or you respond well to it. Retatrutide gives the biggest number on paper, but you are buying an unapproved compound from a market where purity varies vial to vial, and the glucagon component brings a heart rate signal that the other two do not have. Whichever you pick, the titration schedule is not optional. Nearly every bad experience with these drugs comes from starting too high or stepping up too fast.
Stacking: These are not stacked with each other. People sometimes pair one of them with cagrilintide, which is a different mechanism.
Semaglutide is a once-weekly GLP-1 receptor agonist that cuts appetite and slows digestion, producing average weight loss around 15 percent in trials. It is the molecule behind the Ozempic and Wegovy brand names.
Tirzepatide is a once-weekly peptide that activates both the GIP and GLP-1 receptors, producing average weight loss of about 20 percent at the top dose in trials. It is sold as Mounjaro for diabetes and Zepbound for weight management and sleep apnea.
Retatrutide is a once-weekly peptide that activates GLP-1, GIP and glucagon receptors together. Phase 2 data showed about 24 percent weight loss at 48 weeks, the largest figure reported for any single compound, but it is still years from approval.
Semaglutide vs Tirzepatide vs Retatrutide: frequently asked
Which is strongest, semaglutide, tirzepatide or retatrutide?
By trial weight loss: retatrutide (about 24 percent at 48 weeks in phase 2, about 28 percent at 80 weeks in TRIUMPH-1 topline), then tirzepatide (about 20 percent at 72 weeks), then semaglutide (about 15 percent at 68 weeks). Those are averages from different trials with different durations, so treat the ranking as approximate. Only semaglutide and tirzepatide are approved.
Is retatrutide approved by the FDA?
No. As of October 2026 it is in phase 3. Lilly reported positive TRIUMPH results in 2026 and said it plans to file in the first quarter of 2027, which puts any approval at late 2027 or later. Everything sold as retatrutide today is grey market.
Can you switch from semaglutide to tirzepatide?
People do, and SURMOUNT-5 showed tirzepatide produced more weight loss than semaglutide in a direct comparison. There is no official conversion table; the usual approach is to drop to a low or starting tirzepatide dose rather than match milligrams, because the two are not interchangeable mg for mg. Nausea can return during the switch.
Which GLP-1 has the least nausea?
Tirzepatide is generally reported as gentler than semaglutide at equivalent effect, which is attributed to the GIP component. Retatrutide was similar to tirzepatide in phase 2 but adds a heart rate increase from glucagon. Across all three, escalating too fast is the main cause of nausea, not the molecule.
Do you lose muscle on these drugs?
Some. Reviews estimate 30 to 40 percent of weight lost may be fat free mass, and the STEP 1 DEXA substudy of semaglutide put lean mass at roughly 39 percent of weight lost. Resistance training and protein are the proven counters. See GLP-1 muscle loss for what is and is not known.
What are the starting doses for each?
Semaglutide starts at 0.25 mg weekly, tirzepatide at 2.5 mg weekly, and retatrutide trials started at 1 or 2 mg weekly. Each step is held at least 4 weeks. Dose charts for all three are at semaglutide, tirzepatide and retatrutide.
Related reading
Weight loss beyond semaglutide alone
Weight loss while limiting muscle loss
The triple agonist beats the dual agonist on paper. Is it worth waiting for, or buying early?
The two approved GLP-1 drugs went head to head. What does the result mean for you?
First generation versus third. How big is the gap, and what do you give up to close it?
Dosage
Sources
- Once-weekly semaglutide in adults with overweight or obesity (STEP 1). New England Journal of Medicine, 2021
- Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). New England Journal of Medicine, 2022
- Tirzepatide versus semaglutide for weight loss in adults with obesity without diabetes (SURMOUNT-5). New England Journal of Medicine, 2025
- Triple-hormone-receptor agonist retatrutide for obesity, a phase 2 trial. New England Journal of Medicine, 2023