Research review
Semaglutide vs tirzepatide vs retatrutide: what the trials show
In their main obesity trials, semaglutide 2.4 mg produced about 15% average weight loss, tirzepatide 15 mg about 21%, and retatrutide 12 mg about 28% according to 2026 topline results. Each step adds a receptor target. Only one direct head-to-head trial exists so far, comparing tirzepatide with semaglutide.
Key points
- Semaglutide targets one receptor (GLP-1), tirzepatide two (GIP, GLP-1), retatrutide three (GIP, GLP-1, glucagon).
- Trials differ in length, population and analysis method, so numbers from different trials are not directly comparable.
- SURMOUNT-5 is the only completed head-to-head obesity trial: tirzepatide 20.2% vs semaglutide 13.7% at 72 weeks.
- Retatrutide phase 3 data were company-reported topline results at our last review, not yet peer-reviewed publications.
Headline results
| Drug | Trial | Population | Length | Mean weight change (highest dose) | Placebo |
|---|---|---|---|---|---|
| Semaglutide 2.4 mg | STEP 1 | Obesity, no diabetes | 68 weeks | −14.9% | −2.4% |
| Tirzepatide 15 mg | SURMOUNT-1 | Obesity, no diabetes | 72 weeks | −20.9% | −3.1% |
| Retatrutide 12 mg | Phase 2 | Obesity, no diabetes | 48 weeks | −24.2% | −2.1% |
| Retatrutide 12 mg | TRIUMPH-1 (topline) | Obesity, no diabetes | 80 weeks | −28.3% | not reported in topline summary |
| CagriSema | REDEFINE 1 | Obesity, no diabetes | 68 weeks | −20.4% | −3.0% |
| Orforglipron (oral) | ATTAIN | Obesity, no diabetes | 72 weeks | −12.4% (adherent) | −0.9% |
Figures are from the primary publications or, for TRIUMPH-1 and ATTAIN, from company and press summaries of the results. See each profile for references.
Why the numbers are not a ranking
Trials use two main ways of counting. The treatment-regimen estimand includes everyone randomized, whether or not they kept taking the drug. The efficacy estimand (or “on-treatment”) counts only those who stayed on treatment, and gives larger numbers. Companies sometimes headline one and journals the other. Trial length also matters: weight loss on these drugs continues for more than a year, so an 80-week result is not comparable with a 48-week one.
The one head-to-head trial
SURMOUNT-5 randomized 751 adults with obesity to tirzepatide or semaglutide at their maximum tolerated doses for 72 weeks. Tirzepatide produced 20.2% mean weight loss and semaglutide 13.7%. This is the strongest evidence that adding GIP agonism increases weight loss.
What the extra receptors do
GLP-1 agonism reduces appetite and slows stomach emptying. GIP agonism appears to add appetite suppression and improve fat tissue insulin sensitivity, and may reduce nausea from GLP-1 signalling. Glucagon agonism, added in retatrutide, increases energy expenditure and fat burning in the liver; in phase 2, liver fat fell by more than 80% in many participants.
Side effects across the class
All of these drugs mainly cause gastrointestinal effects: nausea, diarrhoea, vomiting and constipation, concentrated during dose increases. In TRIUMPH-1, discontinuation for adverse events reached 11.3% at the highest retatrutide dose. Glucagon-containing agonists also raise resting heart rate. See side effects reported in trials.
Related profiles
- GLP-1 receptor agonist Semaglutide Semaglutide is a long-acting GLP-1 receptor agonist approved for type 2 diabetes, chronic weight management and cardiovascular risk reduction. Approved medicine
- GIP and GLP-1 receptor agonist Tirzepatide Tirzepatide activates both the GIP and GLP-1 receptors. Approved medicine
- GIP, GLP-1 and glucagon receptor agonist Retatrutide Retatrutide is an investigational triple agonist of the GIP, GLP-1 and glucagon receptors. Human RCTs
- Long-acting amylin analog Cagrilintide Cagrilintide is a long-acting amylin analog that acts on both amylin and calcitonin receptors. Human RCTs
Questions
Which GLP-1 drug causes the most weight loss?
In published and reported trials, retatrutide has produced the largest average weight loss, followed by tirzepatide and then semaglutide. Only tirzepatide and semaglutide have been compared directly.
Is retatrutide available?
Not as an approved medicine. Lilly has said it plans to file with the FDA in 2027.
References
- Wilding JPH, Batterham RL, Calanna S, et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine.
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. (2022). Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine.
- Jastreboff AM, Kaplan LM, Frías JP, et al. (2023). Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine.
- Aronne LJ, Horn DB, le Roux CW, et al. (2025). Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. New England Journal of Medicine.