At a glance
| Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
| Hormones targeted | GLP-1 | GIP + GLP-1 | GIP + GLP-1 + glucagon |
| Average weight loss in key trial | 14.9% (68 weeks) | 20.9% (72 weeks) | 28.3% (80 weeks, phase 3) |
| Taken | Once weekly | Once weekly | Once weekly |
| Starting dose | 0.25 mg | 2.5 mg | 2 mg |
| Maintenance dose | 2.4 mg | Up to 15 mg | Up to 12 mg |
| Common compounded strength | 2.5 mg/mL + B6 | 15 mg/mL + B6 | 15 mg/mL + B6 |
| FDA status | Brand versions approved | Brand versions approved | Investigational |
How they differ
All three reduce appetite and slow digestion through the GLP-1 pathway. The difference is what else they act on. Tirzepatide adds GIP, and retatrutide adds both GIP and glucagon. In trials, each added pathway was linked to greater average weight loss.
Head-to-head results
In SURMOUNT-5, the first large trial to compare them directly, tirzepatide led to an average weight loss of 20.2% compared with 13.7% for semaglutide over 72 weeks. Retatrutide hasn't been compared head to head yet.
Side effects
Side effects are similar across all three: mostly nausea, diarrhea, constipation, and reduced appetite, especially after dose increases. Retatrutide also raised heart rate in earlier trials, and more people stopped treatment at the highest dose. See the side-effect guide.
How to choose
- Semaglutide has the longest track record and proven heart benefits. It's often a good place to start.
- Tirzepatide produced more weight loss on average, and it may suit people who want stronger appetite control or who didn't reach their goals on semaglutide.
- Retatrutide is investigational. It's an option only under close prescriber supervision, with less long-term data.
Your health history, other medications, side effects, and goals all matter. Your prescriber will help you decide.
Switching between them
Doses aren't interchangeable. 1 mg of semaglutide is not the same as 1 mg of tirzepatide. If you switch, your prescriber will choose a new starting dose and schedule, usually beginning lower and stepping up again.
Sources
- Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). New England Journal of Medicine, 2021.
- Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). New England Journal of Medicine, 2022.
- Aronne LJ, et al. Tirzepatide as compared with semaglutide for the treatment of obesity (SURMOUNT-5). New England Journal of Medicine, 2025.
- Eli Lilly and Company. Topline results from the TRIUMPH-1, TRIUMPH-2, TRIUMPH-3, and TRIUMPH-4 phase 3 trials of retatrutide. Press releases, December 2025 to July 2026.
- Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. New England Journal of Medicine, 2023.
