Three names come up more than any others when the conversation turns to GLP-1 compounds: semaglutide, tirzepatide, and retatrutide. They tend to get talked about as three versions of the same thing. They are related, but the differences are real, and most of the confusion comes from one fact that rarely gets explained clearly.
This is a research overview of how the three compare, drawn from the clinical literature to date. It is not medical guidance, and the figures below are trial results, not promises.
The one difference that explains most of the others
All three belong to the incretin class, and all three act on the GLP-1 receptor. What separates them is how many receptors each one activates.
- Semaglutide is a single agonist. It targets the GLP-1 receptor only.
- Tirzepatide is a dual agonist. It targets GLP-1 and a second incretin receptor, GIP. The structural basis for that dual activity is set out in the published characterisation of tirzepatide.
- Retatrutide is a triple agonist. It targets GLP-1, GIP, and a third receptor, glucagon (GCGR), as described in a systematic review of the retatrutide trials.
Almost every other difference between them in the trial data traces back to that one-versus-two-versus-three receptor count.
What each receptor is thought to contribute
In preclinical and clinical research, the three receptors are associated with different effects.
- GLP-1 signalling amplifies glucose-dependent insulin release, slows gastric emptying, and reduces appetite. It is the shared foundation of all three compounds.
- GIP is a second incretin receptor. Adding it (tirzepatide) has been linked to improved insulin sensitivity and to effects on lipid handling that appear distinct from GLP-1 alone.
- Glucagon (GCGR) is retatrutide’s third target. Alongside its role in glucose, glucagon signalling is associated with increased energy expenditure and with a marked reduction in liver fat, which is why retatrutide is also being studied specifically in metabolic liver disease.
What the trials have reported
The pattern in the published data is that adding receptor targets has tended to track with larger average weight reductions, although the compounds were mostly studied in separate trials.
- Semaglutide reported roughly 15% average weight reduction in its obesity programme.
- Tirzepatide reported roughly 20 to 21%.
- Retatrutide reported roughly 24% at 48 weeks in Phase 2, and its Phase 3 TRIUMPH programme has since reported reductions of roughly 28%.
The most useful single data point is the one direct comparison. In SURMOUNT-5, a head-to-head trial, tirzepatide produced a mean weight reduction of 20.2% against 13.7% for semaglutide over 72 weeks, and improved several cardiometabolic measures more than semaglutide did. There is not yet an equivalent published head-to-head between retatrutide and the other two, so retatrutide’s higher figures come from its own trials rather than a direct contest.
Where each one stands on approval
This is the practical difference the receptor count does not capture, and it is the part most often missed.
| Compound | Receptors | Reported trial weight reduction | Approval status (2026) |
|---|---|---|---|
| Semaglutide | GLP-1 | ~15% | Approved for type 2 diabetes and weight management |
| Tirzepatide | GLP-1 + GIP | ~20 to 21% | Approved for type 2 diabetes and weight management |
| Retatrutide | GLP-1 + GIP + glucagon | ~24 to 28% | Investigational; Phase 3 ongoing; not approved |
Semaglutide and tirzepatide are approved medicines with years of post-approval use behind them. Retatrutide is not: its Phase 3 results are still reading out through 2026, and a regulatory filing is expected around late 2026 or 2027. Any figure quoted for retatrutide is a trial result for an investigational compound, not an approved-label claim.
How to read the comparison
A few things are easy to lose in the headline numbers.
- More receptors is not automatically “better” for every question. A larger average weight reduction is one outcome among several. Tolerability, the side-effect profile, and long-term data all matter, and the longest safety record of the three belongs to the single agonist.
- Cross-trial numbers are not a ranking. Apart from SURMOUNT-5, these figures come from separate trials with different populations and designs. They are directionally informative, not a leaderboard.
- The evidence is still moving. Retatrutide alone has several more Phase 3 readouts due, spanning obesity, diabetes, sleep apnoea, and liver and cardiovascular outcomes.
The short version
Semaglutide, tirzepatide, and retatrutide are one, two, and three-receptor agonists respectively. In the trials to date that ladder has tracked with progressively larger average weight reductions, and the one head-to-head trial put tirzepatide ahead of semaglutide. The largest reductions reported so far belong to retatrutide, but it is also the one compound of the three that is still investigational and not approved. This is a research summary; the approved medicines are prescribed and supervised, and retatrutide remains in trials.