Semaglutide vs Tirzepatide vs Retatrutide

One receptor, two, or three

The incretin peptides are a family built by addition. Semaglutide activates the GLP-1 receptor. Tirzepatide activates the GLP-1 receptor and the GIP receptor. Retatrutide activates both of those and the glucagon receptor as well. Each generation kept what worked and added another signalling arm, and the published weight reductions increase along the same line.

That neat progression is the reason this comparison needs care. The three compounds were tested at different times, in different trial designs, against different comparators, and only one direct head-to-head trial exists among them. The ordering is probably real. The size of the gaps between them is far less certain than a table of percentages suggests.

The three peptides side by side

Every weight figure in that table comes from the highest dose tested in the trial named beside it, measured against placebo, in adults with obesity or overweight. The placebo arms lost between 2.1% and 3.1% in all three trials, a useful reminder that the studies at least agree about their control groups.

How the mechanisms differ

All three share one engine. GLP-1 receptor agonism produces glucose-dependent insulin release, suppression of glucagon, slower gastric emptying and, most importantly for weight, an appetite signal in the hypothalamus and brainstem. Everything else is an addition to that.

The GIP arm in tirzepatide is the odd one. GIP is the other incretin hormone, its insulin-releasing effect is blunted in type 2 diabetes, and in fat tissue it favours storage. Blocking the GIP receptor also produces weight loss in mice, which left the field with a paradox it has not fully resolved. The working explanation is that the useful GIP signal sits in the brain, where it reduces food intake and appears to dampen the nausea that GLP-1 agonism causes, rather than in adipose tissue.

The glucagon arm in retatrutide is a different proposition again. Glucagon raises blood glucose, so adding it to a metabolic peptide looks self-defeating until you account for the rest of its physiology: it increases resting energy expenditure and drives fat oxidation in the liver. The GLP-1 arm is there to hold the glucose effect in check. Where GLP-1 and GIP work mainly by reducing energy intake, the glucagon arm is an attempt to raise energy output, which is why the liver rather than the stomach is the tissue to watch.

What the trials actually measured

The three trial programmes did not ask identical questions, and the differences matter more than the headline percentages.

• STEP 1 (semaglutide, 68 weeks). Weight change on 2.4 mg weekly against placebo, with lifestyle counselling in both arms. A large randomised trial in adults without diabetes.
• SELECT (semaglutide, more than three years). Not weight but cardiovascular events, in people with established cardiovascular disease and without diabetes: a 20% relative reduction. This is the only hard-outcome result any of the three holds.
• SURMOUNT-1 (tirzepatide, 72 weeks). Weight change at 5, 10 and 15 mg weekly against placebo, in adults without diabetes. A clear dose response across the range tested.
• SURMOUNT-5 (tirzepatide vs semaglutide, 72 weeks). The only direct comparison among these three peptides: 20.2% against 13.7%.
• Retatrutide phase 2 (48 weeks). A dose-finding study of 1, 4, 8 and 12 mg weekly. Smaller and shorter than the others, designed to choose a dose rather than to prove a benefit.

Two of these are pivotal trials supporting a marketing authorisation. One is a cardiovascular outcome trial. One is a dose-finding study. Treating their outputs as four points on the same scale is the most common mistake in this comparison.

Why cross-trial comparison is rough

Subtracting one trial's percentage from another's feels like arithmetic. It is closer to guesswork, for reasons that apply to all three programmes.

Duration differs: 48, 68 and 72 weeks. Since weight loss in these trials had not plateaued at the point of measurement, a shorter trial understates what a longer one would show, and the retatrutide figure is the one measured earliest. Populations differ in starting weight, sex balance, age and whether participants had diabetes, which reliably changes the result: incretin trials in people with type 2 diabetes produce smaller weight reductions than the same drug in people without it. The lifestyle programmes running alongside differ, and so do the rules for handling participants who stopped the drug, a statistical choice that can move a headline number by several points on its own.

This is why SURMOUNT-5 matters out of proportion to its size. Randomising the same participants to tirzepatide or semaglutide removes all of those confounders at once. Nothing equivalent exists for retatrutide, against either of the others, and until phase 3 reports there is no honest way to say how much of its phase 2 advantage would survive a direct test.

Side effects and the logic of dose escalation

All three share a side effect profile, because it follows from the shared GLP-1 arm. Nausea, vomiting, diarrhoea and constipation are the most frequent adverse events in every trial, they are dose related, and they are strongest while the dose is being increased. Gallbladder problems appear more often than on placebo across the class, which is expected with rapid weight loss. Pancreatitis is uncommon and carries a labelled warning. Rodent thyroid C-cell tumours are a class finding of unproven human relevance that regulators still act on.

Retatrutide adds one finding the other two do not share in the same way: an increase in heart rate, most plausibly from glucagon receptor activity. It was consistent across doses in phase 2, and its long-term significance is unknown.

This is where the escalation schedules come from. Every trial started well below the target dose and stepped up every four weeks: 0.25 mg to 2.4 mg for semaglutide, 2.5 mg upwards in 2.5 mg steps for tirzepatide, and a similar staged increase in the retatrutide trial. Tolerance to the gastrointestinal effects develops over roughly a month while the appetite effect persists, so a slow climb reaches the same place with fewer dropouts. Faster escalation produces more nausea, not faster results. These schedules describe supervised clinical trials and approved labels; they are study designs, not instructions for anyone.

Regulatory status in Europe

Semaglutide and tirzepatide are authorised medicines in the European Union, assessed by the European Medicines Agency: Ozempic and Rybelsus for type 2 diabetes, Wegovy for weight management, Mounjaro for both indications. All are prescription-only and supplied through pharmacies. Retatrutide is authorised nowhere in the world. It remains an investigational compound in the phase 3 TRIUMPH programme, which means no prescriber anywhere can supply it outside a trial.

Under EU law a medicinal product needs a marketing authorisation before it can be placed on the market. Research peptides hold no such authorisation and are not sold for human use. Rules on possession and personal import differ between member states, and none of the three is currently named individually on the WADA Prohibited List, which is reissued every year.

Research material is not the medicine

This is the distinction that matters most on a page full of clinical trial results. A vial of research peptide and a pharmacy box of an authorised medicine can contain the same molecule and still be entirely different things. The medicine has a regulatory dossier, a manufacturing licence, a patient leaflet, batch release by a qualified person and a pharmacovigilance system behind it. The research vial has a certificate of analysis. That certificate is genuinely useful, and it is not the same kind of guarantee.

King Peptides sells the three as Sema (Semaglutide) 10 mg, Trizzy (Tirzepatide) 10 mg and GLP-3 RT (Retatrutide) 10 mg, as research material only. On the certificate, check HPLC purity of 99% or better and a mass matching the compound: 4113.6, 4813.5 and 4731.3 Da respectively. Tirzepatide and retatrutide differ by under 100 Da, so a low-resolution mass trace will not separate them and the lot number on the document has to match the vial. Our guide to reading a certificate of analysis sets out both checks in detail. Individual profiles for semaglutide, tirzepatide and retatrutide cover each compound's evidence, dosing schedules and sourcing in full.

Frequently asked questions

Which of the three produces the most weight loss? On published figures, retatrutide at −24.2% over 48 weeks, then tirzepatide at −20.9% over 72 weeks, then semaglutide at −14.9% over 68 weeks. Only the tirzepatide and semaglutide comparison has been tested directly, in SURMOUNT-5, where tirzepatide won 20.2% to 13.7%.

Does adding receptors mean worse side effects? Not proportionally. The gastrointestinal profile is similar across all three, and the GIP arm may actually reduce nausea. The finding specific to the triple agonist is the heart rate increase.

Can I get retatrutide on prescription in Europe? No. It has no marketing authorisation in the EU or anywhere else, so no prescriber can supply it outside a clinical trial.

Why do the shop names differ from the medicine names? Because the products are not those medicines. Ozempic, Wegovy and Mounjaro are brand names belonging to authorised products; a supplier selling research material uses its own names and sells for laboratory use only.

Do the three look different on a certificate of analysis? By mass, yes, provided the analysis has the resolution to show it and the lot number matches the vial in hand. HPLC purity tells you how much of the material is one compound; the mass tells you which compound it is.