Semaglutide vs tirzepatide vs retatrutide — what actually differs mechanistically?

These three get compared constantly on outcome numbers. What is the mechanistic difference underneath, and does it explain the ordering?

It does, fairly neatly, which is unusual and satisfying.

Semaglutide — GLP-1 receptor agonist. One receptor.

Tirzepatide — GLP-1 and GIP. Two.

Retatrutide — GLP-1, GIP and glucagon. Three, which is where "triple G" comes from.

And the trial results order the same way. That is a genuinely tidy dose-response-like relationship across three separate development programmes, and it is one of the better pieces of evidence that the mechanism is doing the work rather than the effect being trial artefact.

The glucagon addition is the conceptually interesting one, because glucagon raises blood sugar — which sounds like the opposite of what you want. It is in there for energy expenditure rather than intake, which is a different lever from the appetite side. Adding it without breaking glycaemic control is the hard part and is most of why it took longest.

Two of those three are approved and prescribable. Only the third is not. Which reverses the usual pattern on this site, where the interesting compound is the unapproved one.

And it is worth noticing that this whole class is what an actual peptide success story looks like. Approved, prescribable, manufactured under inspection, with phase 3 evidence and known adverse effect profiles.

The contrast with the evidence: none end of the index is not a coincidence. Compounds that work well enough to get through trials get prescribed. Nobody is selling semaglutide in an unlabelled vial because they had to — they are doing it because of price and access, which is a different problem with different answers.

That last paragraph deserves its own thread. The reason something is on the grey market matters enormously and gets flattened into one word, "unapproved", covering two completely different situations.

Very clear, thank you. One receptor, two, three, and the results line up.