Read this first
This is plain-language harm-reduction information, not medical advice. Peptides discussed here are research compounds; most are not approved for human use. People will use them either way — we would rather they have the facts.
The three differ mainly in which gut-hormone receptors they act on. Semaglutide targets GLP-1 only, tirzepatide targets GLP-1 and GIP, and retatrutide targets GLP-1, GIP and glucagon. Semaglutide and tirzepatide are licensed medicines in many countries; retatrutide is an investigational drug from Eli Lilly and is not licensed anywhere, so anything sold as retatrutide is unlicensed.
This is general information, not medical advice. Licensed GLP-1 medicines are prescribed after a clinical assessment for good reason. If you are considering weight-loss medication, speak to a GP or pharmacist first.
The three at a glance
- Semaglutide: a GLP-1 receptor agonist. Licensed, with brand names such as Ozempic and Wegovy (injections) and Rybelsus (tablet).
- Tirzepatide: a dual GIP and GLP-1 receptor agonist. Licensed, with brand names such as Mounjaro and Zepbound.
- Retatrutide: a triple agonist acting on GLP-1, GIP and glucagon receptors. Investigational, being developed by Eli Lilly. Not licensed.
What the receptors do
GLP-1
GLP-1 is a gut hormone released after eating. Activating its receptor slows stomach emptying, increases feelings of fullness, reduces appetite and helps the pancreas release insulin when blood sugar is high. This is the shared foundation for all three drugs.
GIP
GIP is another gut hormone that affects insulin release. Its role in weight and appetite is more complicated and still being studied. Tirzepatide and retatrutide both activate it, which is the main mechanistic difference from semaglutide.
Glucagon
Glucagon normally raises blood sugar, but it is also linked to increased energy expenditure and effects on liver fat. Adding glucagon activity is retatrutide's distinguishing feature. It is also why people watch it closely: a different mechanism can mean different benefits and different risks.
Licensing status
This is the part that matters most for safety.
- Semaglutide: licensed and prescribed for type 2 diabetes and, in specific products, for weight management. Years of large clinical trials and post-marketing data exist.
- Tirzepatide: licensed for type 2 diabetes and weight management in specific products, also with large trial programmes behind it.
- Retatrutide: in clinical development. It has been studied in trials run by its manufacturer, but it has no marketing authorisation. There is no approved dose, no approved product and no regulated supply chain.
The "research chemical" versions of semaglutide and tirzepatide sold online are a separate category from the licensed pens: they are not the licensed product, are not made under the same controls, and may differ in purity, dose and sterility.
What about the results?
All three have been studied for weight reduction, and the general pattern from the published trials is that dual and triple agonists have been reported to produce larger average weight loss than GLP-1 alone. We deliberately do not quote percentages here, because figures depend on the dose, trial population, duration and how the result is analysed. Check the original trial publications rather than relying on a summary, including this one.
An important caveat for retatrutide: its data come from ongoing or early-to-mid-stage development programmes. Findings can change as trials finish, and a drug being effective in a trial does not tell you how a random vial of powder behaves.
Side effects
These classes share a recognisable side effect profile, dominated by the digestive system:
- Nausea, vomiting, diarrhoea and constipation, especially when starting or increasing the dose
- Reduced appetite (the intended effect, but it can go too far)
- Reflux, bloating and stomach discomfort
- Fatigue and dizziness, particularly if eating very little
- Injection-site reactions
Rarer but more serious concerns that licensed labels discuss include pancreatitis, gallbladder problems and dehydration affecting the kidneys. Muscle loss alongside fat loss is also a recognised concern with rapid weight reduction. Retatrutide's side effect picture is still being built; the glucagon component is one reason heart rate and other cardiovascular effects are watched.
Your pharmacist or the product information leaflet for licensed medicines is the reliable source here. For unlicensed products there is no leaflet, which is itself a risk.
The unlicensed market
Interest in retatrutide in particular has created a market for unlicensed supply. The risks stack up: no approved dose to start from, no way to be sure what is in the vial, no clinical supervision, and a drug whose long-term safety is unknown. Read how to spot fake or under-dosed peptides before assuming a vial contains what the label says, and see the safer use guide for the basics of handling.
Other related compounds are in the pipeline or on the grey market too, such as cagrilintide (an amylin analogue), CagriSema (cagrilintide with semaglutide) and mazdutide (a GLP-1/glucagon dual agonist). Each has its own status and evidence base, so do not assume they behave like the three above.
Which is "best"?
That is not a question this site can answer, and it is not the right question for most people. The better questions are: is there a licensed route available to me, what are my health conditions and other medicines, and who is monitoring me? The most thoroughly studied option is not always the strongest on paper, but it is the one where the dose, purity and safety data actually exist.
Bottom line
Semaglutide acts on GLP-1; tirzepatide adds GIP; retatrutide adds glucagon on top. The first two are licensed medicines with substantial evidence; retatrutide is investigational and unlicensed. More receptors have generally meant stronger effects in trials, but not necessarily a better risk profile, and unlicensed supply adds uncertainty on top. If you are considering any of them, a clinician is the right first stop.
Common questions
What is the difference between semaglutide, tirzepatide and retatrutide?
Semaglutide activates the GLP-1 receptor only, tirzepatide activates GLP-1 and GIP receptors, and retatrutide activates GLP-1, GIP and glucagon receptors. Semaglutide and tirzepatide are licensed medicines, while retatrutide is investigational.
Is retatrutide approved?
No. Retatrutide is an investigational drug being developed by Eli Lilly and has no marketing authorisation, so any product sold as retatrutide is unlicensed.
Is tirzepatide stronger than semaglutide?
Trials have generally reported larger average weight loss with tirzepatide than semaglutide, but results depend on dose and population. Check the original trial publications for exact figures.
Are research-chemical semaglutide and tirzepatide the same as Ozempic or Mounjaro?
No. Licensed pens are made under regulated controls with a defined dose and purity, whereas research-chemical powders are unlicensed and their contents can vary.