Semaglutide vs Tirzepatide vs Retatrutide
Robert
Founder, F*CK Getting Old — independent researcher, not a medical professional.
Last reviewed · 5 cited sources
These three drugs are built on the same foundation — mimicking GLP-1, a gut hormone that slows stomach emptying and reduces appetite — but each generation adds another hormone target. Semaglutide acts on GLP-1 alone, tirzepatide adds GIP, and retatrutide adds glucagon on top of both. In the trials so far, each additional target has produced more average weight loss.
At a glance
| Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
| Receptor targets | GLP-1 | GLP-1 + GIP | GLP-1 + GIP + glucagon |
| Brand names | Wegovy, Ozempic | Zepbound, Mounjaro | None (not approved) |
| Key obesity trial (top dose) | STEP 1: −14.9% at 68 weeks | SURMOUNT-1: −20.9% at 72 weeks | Phase 3: −25.0% at 80 weeks |
| Typical reference dose | 0.25–2.4 mg, Weekly | 2.5–15 mg, Weekly | 1–12 mg, Weekly |
| Regulatory status | FDA Approved | FDA Approved | Investigational |
| Research volume | 4.5/5 | 4.5/5 | 4.0/5 |
| Human / animal studies | 30 / 40 | 20 / 25 | 5 / 20 |
Research volume reflects how much research exists, not effectiveness. Doses are commonly reported reference protocols, not recommendations.
What the trials show
In STEP 1, adults with overweight or obesity on semaglutide 2.4 mg weekly lost an average of 14.9% of body weight over 68 weeks, versus 2.4% on placebo. In SURMOUNT-1, tirzepatide produced average losses of 15.0%, 19.5%, and 20.9% at the 5, 10, and 15 mg doses over 72 weeks. Retatrutide’s phase 2 trial reported 24.2% at 48 weeks on the 12 mg dose, and its phase 3 trial reported 23.7% (9 mg) and 25.0% (12 mg) at 80 weeks versus 3.9% on placebo.
Cross-trial comparisons are imperfect because the populations, durations, and dose schedules differ. The one direct head-to-head trial, SURMOUNT-5, randomized 751 adults without diabetes to tirzepatide or semaglutide at their maximum tolerated doses: average weight loss at 72 weeks was 20.2% with tirzepatide versus 13.7% with semaglutide, and waist circumference fell 18.4 cm versus 13.0 cm.
Side effects
All three share the same main side effects: nausea, diarrhea, constipation, vomiting, and reduced appetite, most common while the dose is being increased. Slow dose escalation is the main tool for managing them. Gallbladder problems and, rarely, pancreatitis have been reported with the class. Rapid weight loss of any kind also includes some lean mass, which is why resistance training and adequate protein matter more, not less, for men over 40 using these drugs.
Approved drugs vs. research and compounded versions
Semaglutide and tirzepatide are FDA-approved, manufactured products with years of safety monitoring. Compounded or “research” versions sold online are not the same product — purity, dose accuracy, and sterility are not verified to the same standard. Retatrutide is not FDA approved; anything sold as retatrutide today is not a regulated pharmaceutical.
Frequently asked questions
Is tirzepatide better than semaglutide for weight loss?
In the head-to-head SURMOUNT-5 trial, tirzepatide produced more average weight loss (20.2% vs 13.7% at 72 weeks). Individual responses vary, and tolerability, cost, and access also matter.
Is retatrutide FDA approved?
No. Retatrutide has completed phase 3 trials but was not FDA approved as of this writing. Products sold as retatrutide online are not regulated drugs.
Do these drugs cause muscle loss?
Part of the weight lost on any of these drugs is lean mass, as with other forms of rapid weight loss. Resistance training and a higher protein intake help preserve muscle.
What is the difference between GLP-1, GIP, and glucagon?
All three are hormones involved in appetite, blood sugar, and energy use. GLP-1 reduces appetite and slows digestion, GIP appears to enhance some of those effects and improve tolerability, and glucagon increases energy expenditure and fat burning in the liver.
Sources
- Wilding JPH et al. (2021). Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med. PMID 33567185.
- Jastreboff AM et al. (2022). Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. PMID 35658024.
- Aronne LJ et al. (2025). Tirzepatide as compared with semaglutide for the treatment of obesity (SURMOUNT-5). N Engl J Med. PMID 40353578.
- Jastreboff AM et al. (2023). Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. PMID 37366315.
- Jastreboff AM et al. (2026). Retatrutide, a triple hormone receptor agonist, for treatment of obesity. N Engl J Med. PMID 42814954.
For informational and research purposes only — not medical advice. Talk to a licensed clinician before starting, stopping, or combining any of these compounds. See our Terms.