As of: November 7, 2026 · Sources: New England Journal of Medicine, ClinicalTrials.gov
Semaglutide, Tirzepatide, and Retatrutide belong to the group of incretin-based drugs. The most important difference is the number of hormone receptors they activate: Semaglutide acts on one, Tirzepatide on two, and Retatrutide on three receptors. In their large phase 3 trials, body weight decreased by an average of 14.9%, 20.9%, and 25.0%, respectively, at the highest doses [1][2][3]. Semaglutide and Tirzepatide are approved as drugs, while Retatrutide is not yet.
An overview of the three active ingredients
| Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
| Manufacturer | Novo Nordisk | Eli Lilly | Eli Lilly |
| Receptors | GLP-1 | GLP-1, GIP | GLP-1, GIP, Glucagon |
| Operating principle | Mono-agonist | Dual-agonist | Triple agonist |
| Key study | STEP 1 (2021) [1] | SURMOUNT-1 (2022) [2] | TRIUMPH-1 (2026) [3] |
| Participants | 1961 | 2539 | 2339 |
| Study duration | 68 weeks | 72 weeks | 80 weeks |
| Average weight change (highest dose) | -14.9% (2.4 mg) | -20.9% (15 mg) | -25.0% (12 mg) |
| Placebo | -2.4% | -3.1% | -3.9% |
| Status | approved | approved | not approved yet |
| Trade names | Ozempic®, Wegovy®, Rybelsus® | Mounjaro®, Zepbound® | – |
All values are taken from the main analysis of all participants. The studies are not directly comparable because they differ in duration, dosage, and participant composition.
How do the mechanisms of action differ?
- Semaglutide: It mimics the gut hormone GLP-1. It promotes glucose-dependent insulin release, slows gastric emptying, and increases the feeling of satiety.
- Tirzepatide: It also activates the GIP receptor, which also increases glucose-dependent insulin secretion.
- Retatrutide: It also activates the glucagon receptor. This third signaling pathway increases energy consumption and promotes fat breakdown in the liver.
Which active ingredient leads to the greatest weight loss?
In the respective phase 3 trials, Retatrutide showed the greatest weight loss, followed by Tirzepatide and Semaglutide. Since these trials were conducted independently, a direct comparison of the figures is only possible to a limited extent.
Direct comparison: Tirzepatide vs. Semaglutide
In the SURMOUNT-5 study, 751 adults with obesity without diabetes received either Tirzepatide or Semaglutide at the highest tolerated dose for 72 weeks [4]. Body weight decreased by 20.2% with Tirzepatide and by 13.7% with Semaglutide. Waist circumference decreased by 18.4 cm and 13.0 cm, respectively.
Are there any direct comparisons with Retatrutide?
Direct comparative studies are already underway: TRIUMPH-5 compares Retatrutide with Tirzepatide in obese adults, and another study compares Retatrutide with Semaglutide in type 2 diabetes [6][7]. Results of these studies have not yet been published.
What side effects were observed?
For all three active substances, gastrointestinal disturbances such as nausea and diarrhea were the most common side effects [1][2][3]. They were mostly mild to moderate.
- Semaglutide: In the STEP 1 study, 4.5% of participants discontinued treatment due to gastrointestinal problems, compared to 0.8% in the placebo group [1].
- Tirzepatide: In the SURMOUNT-1 study, 4.3% to 7.1% of patients discontinued treatment due to side effects, depending on the dose, compared to 2.6% in the placebo group [2].
- Retatrutide: Gastrointestinal disturbances occurred in a dose-dependent manner [3]. In the phase 2 study, heart rate also temporarily increased [8].
What data is available beyond body weight?
- Semaglutide: In the SELECT study of 17,604 adults with cardiovascular disease, Semaglutide reduced the risk of cardiovascular death, heart attack or stroke by 20% [5].
- Tirzepatide: In direct comparison with Semaglutide, waist circumference decreased more [4].
- Retatrutide: In TRIUMPH-1, participants with knee osteoarthritis experienced a reduction in pain, and participants with sleep apnea experienced a reduction in breathing pauses per hour [3].
More about the individual active ingredients
- Effects, studies and storage of Semaglutide in detail.
- Effects, studies and storage of Tirzepatide in detail.
- Effects, studies and storage of Retatrutide in detail.
Reta24 offers all three active ingredients as research peptides. Each batch is tested by HPLC for a purity of at least 98.9%.
- View all dosages and prices of Semaglutide.
- View all dosages and prices of Tirzepatide.
- View all dosages and prices of Retatrutide.
Sources
- Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med 2021;384:989–1002. doi:10.1056/NEJMoa2032183
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med 2022;387:205–216. doi:10.1056/NEJMoa2206038
- Jastreboff AM, Kaplan LM, Davies MJ, et al. Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity. N Engl J Med 2026;395:1781–1793. doi:10.1056/NEJMoa2604169
- Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med 2025;393:26–36. doi:10.1056/NEJMoa2416394
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med 2023;389:2221–2232. doi:10.1056/NEJMoa2307563
- TRIUMPH-5: A Study of Retatrutide (LY3437943) Compared to Tirzepatide (LY3298176) in Adults Who Have Obesity. ClinicalTrials.gov NCT06662383
- Effect of Retatrutide Compared With Semaglutide in Adult Participants With Type 2 Diabetes. ClinicalTrials.gov NCT06260722
- Jastreboff AM, Kaplan LM, Frías JP, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med 2023;389:514–526. doi:10.1056/NEJMoa2301972
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