Important Note This article is for educational purposes only. None of the medicines discussed here should be used without proper medical supervision. Retatrutide is still investigational and not approved in the UK. This content does not constitute medical advice.
In recent years, several peptide-based medicines that target incretin hormones have been developed or are under investigation for weight management. The most discussed ones are semaglutide, tirzepatide, and the newer investigational compound retatrutide.
While they share some similarities, there are important differences in how they work, the results seen in clinical trials, and their current regulatory status. This page provides a straightforward, evidence-based comparison of the three.
How They Differ in Mechanism
These medicines work by mimicking or influencing natural hormones involved in appetite and metabolism, but they target different receptors:
| Medicine | Type | Receptors Targeted | How It Works (Simplified) |
|---|---|---|---|
| Semaglutide | GLP-1 agonist | GLP-1 only | Primarily reduces appetite and slows digestion |
| Tirzepatide | Dual agonist | GLP-1 + GIP | Targets two pathways for potentially stronger effects |
| Retatrutide | Triple agonist | GLP-1 + GIP + Glucagon | Targets three pathways, including energy expenditure |
The key difference with retatrutide is the addition of glucagon receptor activity, which researchers believe may further increase energy use in the body. This is still being actively studied.
Reported Weight Loss in Clinical Trials
Here’s a summary of weight loss results reported from major trials (note that these come from separate studies with different designs and participant groups):
| Medicine | Highest Reported Average Weight Loss | Trial Duration | Status in UK (July 2026) | Notes |
|---|---|---|---|---|
| Semaglutide | ~15–20% | 68–72 weeks | Approved (Wegovy) | Well-established GLP-1 medicine |
| Tirzepatide | ~20–22% | 72 weeks | Approved (Mounjaro) | Dual agonist with stronger results than semaglutide in head-to-head data |
| Retatrutide | ~24–28.7% | 68 weeks | Investigational only | Triple agonist; still in Phase 3 trials |
Retatrutide has shown the highest average weight loss in its Phase 3 data so far. However, it is important to remember that these are not direct head-to-head comparisons, and individual results can vary considerably. Long-term data for retatrutide is still being collected.
Side Effects and Tolerability
All three medicines are associated with gastrointestinal side effects, particularly during dose escalation. Common effects include nausea, vomiting, diarrhoea, and constipation.
Some analyses of available data suggest that retatrutide may be associated with a higher rate of these side effects compared to tirzepatide, though this needs further confirmation from ongoing studies. Tirzepatide and semaglutide have more established safety profiles because they are already approved and in wider use.
Current Availability in the United Kingdom
| Medicine | Approved in UK? | Available on NHS? | Notes |
|---|---|---|---|
| Semaglutide | Yes | Yes (with criteria) | Available as Wegovy for weight management |
| Tirzepatide | Yes | Yes (with criteria) | Available as Mounjaro |
| Retatrutide | No | No | Still in clinical trials; not available outside research |
As of July 2026, only semaglutide and tirzepatide are approved and available for clinical use in the UK. Retatrutide remains investigational.
Which One Is “Best”?
There isn’t a simple answer to this question. The “best” option depends on individual circumstances, medical history, and how someone responds to treatment. What we can say based on current research is:
- Semaglutide has the longest track record among the three and is well understood.
- Tirzepatide has generally shown stronger weight loss results than semaglutide in studies.
- Retatrutide has shown the highest average weight loss in its trials so far, but it is still under investigation and not yet available for clinical use.
All three continue to be studied, and researchers are still learning about their long-term effects, optimal use, and safety profiles.For more information, see our main guide on Semaglutide and our comparison article Semaglutide vs Tirzepatide.
Summary
| Aspect | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Receptors targeted | GLP-1 | GLP-1 + GIP | GLP-1 + GIP + Glucagon |
| Reported weight loss | 15–20% | 20–22% | 24–28.7% (Phase 3) |
| Current UK status | Approved | Approved | Investigational |
| Availability | Available | Available | Not available |
| Stage of development | Widely used | Widely used | Phase 3 trials |
References
- ClinicalTrials.gov – STEP Programme (Semaglutide), SURMOUNT Programme (Tirzepatide), and TRIUMPH Programme (Retatrutide).
- Jastreboff, A.M. et al. (2022). Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine.
- Wilding, J.P.H. et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine.
- Frias, J.P. et al. (various years). Head-to-head studies comparing semaglutide and tirzepatide. The Lancet and related publications.
- Medicines and Healthcare products Regulatory Agency (MHRA) – Guidance on investigational medicines.
Last Updated: July 2026