Semaglutide, Tirzepatide and Retatrutide Compared

A family built by adding receptors

Glucagon-like peptide-1 (GLP-1) is a gut hormone that intestinal L-cells release after a meal. As a drug candidate it fails, because the enzyme dipeptidyl peptidase-4 (DPP-4) halves the circulating amount within about two minutes. Semaglutide and tirzepatide carry a non-natural residue at the point where the enzyme would cut, and all three carry a fatty acid chain that binds serum albumin, a carrier protein the kidney does not filter. Half-lives of five to seven days follow, and with them the weekly interval used in the trials.

The difference lies in the receptors each one switches on. Semaglutide is a modified GLP-1(7-37) backbone of 31 residues and acts on the GLP-1 receptor alone. Tirzepatide has 39 amino acids, is built on the sequence of GIP, the second incretin hormone, and was engineered until it fitted the GLP-1 receptor too. Retatrutide (LY3437943) has both of those activities and adds the glucagon receptor. Published weight reductions rise in the same order. How much of that rise the extra receptors explain is less certain than the percentages suggest.

Semaglutide, tirzepatide and retatrutide in one table

Each weight figure is the mean for the highest dose in the named trial, in adults with overweight or obesity, and each trial had a placebo arm that lost between 2.1% and 3.1%. The active arms were read at 48, 68 and 72 weeks, a first sign that the three percentages do not sit on one scale.

What each receptor contributes

The GLP-1 receptor is the engine all three share, and its effects are spread over several tissues. Beta cells in the pancreas release more insulin, but only while glucose is raised. Alpha cells release less glucagon, and the stomach empties more slowly. Body weight responds mostly to a central effect: receptors in the hypothalamus and in the area postrema of the brainstem, which lies outside the blood-brain barrier, reduce hunger, and weight follows appetite down.

GIP was an unlikely second target. In type 2 diabetes it loses much of its insulin-releasing effect, in fat tissue it favours storage, and mice lost weight when the GIP receptor was blocked, so agonism and antagonism seemed to lead to the same place. The explanation with most support puts the useful signal in the brain: GIP receptors in appetite-regulating regions lower food intake and, in animal models, seem to soften the nausea that GLP-1 agonism provokes. The matter is not settled. In receptor assays tirzepatide matches native GIP at the GIP receptor and is weaker than GLP-1 itself at the GLP-1 receptor, a profile pharmacologists call imbalanced agonism.

Glucagon looks like the wrong hormone to add, since it tells the liver to release glucose. It also raises resting energy expenditure and makes the liver burn more fatty acids. In retatrutide the glucagon arm is kept modest on purpose, and the GLP-1 arm offsets its effect on blood glucose. GLP-1 and GIP mainly cut energy intake; glucagon is meant to raise energy output. Because no published trial separates the three activities in people, the share of the weight effect that belongs to glucagon is unknown. The guide to peptide combinations contrasts this one-molecule approach with mixing peptides in a vial.

Which trial produced which figure

Five studies supply nearly every number quoted for these compounds, and they did not ask the same question.

STEP 1 and SURMOUNT-1 are large randomised trials of the kind that supports a marketing authorisation. SELECT is a cardiovascular outcome trial and counted events, not kilograms; it is the only hard-outcome result any of the three holds. SURMOUNT-5 is the single head-to-head study among them. The retatrutide study is a phase 2 dose-finding trial: smaller, shorter and built to choose a dose, not to prove a benefit.

Why subtraction across trials misleads

Taking 14.9 from 24.2 looks like arithmetic. The answer has no clear meaning, for four reasons.

• Length. The trials ran for 48, 68 and 72 weeks. The retatrutide weight curve had not flattened at week 48, so its figure may understate what a longer study would show.
• Population. Starting weight, age, sex balance and diabetes status differ. With type 2 diabetes, the same incretin compound reliably produces a smaller weight reduction than without it.
• Background programme. The lifestyle support that ran alongside the drug was not the same from trial to trial.
• Statistics. The rule for handling participants who stopped treatment can shift a headline figure by several points without any change in the drug.

SURMOUNT-5 removed all four problems for one pair by randomising one pool of participants to tirzepatide or semaglutide. On weight, that settles the order of those two. Nothing comparable exists for retatrutide. Until the phase 3 TRIUMPH programme reports, its position relative to the other two rests on one dose-finding study.

Adverse events and the slow climb in dose

A shared GLP-1 arm gives the three a shared adverse-event pattern. Nausea, vomiting, diarrhoea and constipation lead every trial report; they are dose related and cluster in the weeks when the dose is rising. Gallbladder events are more frequent than on placebo. Pancreatitis is uncommon but appears as a warning on the labels. Thyroid C-cell tumours in rats and mice are a class finding of unproven relevance to humans, and the medicines remain contraindicated where there is a family history of medullary thyroid carcinoma or MEN2.

Retatrutide adds one finding: a rise in heart rate, seen across doses in phase 2, with glucagon receptor activity as the suspected cause. What it means over years is unknown; the whole safety record comes from a few hundred participants followed for months.

Dose escalation exists because of the gut effects. The Wegovy label steps from 0.25 mg through 0.5, 1.0 and 1.7 mg to 2.4 mg, one step every four weeks. The tirzepatide label starts at 2.5 mg, which is not a therapeutic dose, and rises by 2.5 mg every four weeks until 5, 10 or 15 mg is reached. The retatrutide trial used a staged increase as well; no approved label exists for that compound. These are the schedules of supervised trials and licensed products, recorded here as study designs. They are not guidance for anyone.

Status in the Netherlands, Belgium and Luxembourg

Marketing authorisations for these medicines are granted centrally, after assessment by the European Medicines Agency, and apply in the Netherlands, Belgium and Luxembourg alike. Semaglutide is authorised under three names: Wegovy for weight management, and Ozempic and Rybelsus (an oral tablet) for type 2 diabetes. Tirzepatide is authorised as Mounjaro, both for type 2 diabetes and for weight management. All are prescription-only and dispensed through pharmacies.

Retatrutide holds no authorisation in the EU or anywhere else. It is still in phase 3, so people can lawfully receive it only as participants in an approved clinical trial.

EU medicines law allows a medicinal product onto the market only with an authorisation. Research peptides hold none, and they are not sold for human use. What national law says about possession and personal import varies from one member state to the next, and universities and institutes add rules of their own, so check what applies to you; the Benelux buying guide covers the general frame. The WADA Prohibited List does not at present name any of the three individually. The list is reissued every year, so athletes should read the version in force.

What a research vial is, and what it is not

Semaglutide and tirzepatide are authorised medicines. A vial of research-grade semaglutide or tirzepatide is not one of those medicines, even when the molecule inside is identical. Behind the pharmacy product stand an assessed dossier, a licensed manufacturer, a qualified person who releases each batch, a patient leaflet and a pharmacovigilance system. The research vial comes with a certificate of analysis (CoA). That document is useful, but it is a different kind of assurance. A 10 mg vial of lyophilised powder is also bulk laboratory material, not a measured dose. The primer on research peptides sets out the distinction.

The shop names are GLP-3 RT (Retatrutide) 10 mg, Trizzy (Tirzepatide) 10 mg and Sema (Semaglutide) 10 mg. King Peptides supplies a lot-specific CoA with HPLC and mass spectrometry for every lot, and its lab reports page lists HPLC purity of 99% or higher for these three products. On the CoA, the mass identifies the compound: 4113.6 Da for semaglutide, 4813.5 Da for tirzepatide, 4731.3 Da for retatrutide. Tirzepatide and retatrutide are less than 100 Da apart, too close for a low-resolution mass spectrum to tell one from the other, so the lot number on the CoA must match the vial. The CoA guide walks through both checks.

Orders leave the Netherlands in a tracked parcel. Delivery usually takes 1–2 business days inside the country and 3–5 business days to other EU countries, which covers Belgium and Luxembourg, with no customs clearance inside the EU. Lyophilised material is stored at −20 °C; the storage and reconstitution protocol has the details.

Quick answers

Is tirzepatide more effective than semaglutide? On body weight, yes, and this is the one comparison with a direct test behind it: 20.2% against 13.7% at 72 weeks in SURMOUNT-5.

Has retatrutide been tested against either of the other two? No. Its −24.2% comes from a 48-week phase 2 trial against placebo, so any ranking above tirzepatide is a cross-trial comparison.

Do the rules differ between the Netherlands, Belgium and Luxembourg? The list of authorised medicines does not, because the authorisations are EU-wide. National rules on possession and personal import, and the rules of your own institution, can differ and need checking locally.

What does GLP-3 RT on the shop label mean? It is the supplier’s product name for retatrutide. No hormone called GLP-3 exists. The identity check is the mass on the CoA, 4731.3 Da, read together with a lot number that matches the vial.