Semaglutide and tirzepatide: one receptor, then two

Semaglutide is a GLP-1 receptor agonist. Tirzepatide is a dual agonist at the GIP receptor and the GLP-1 receptor. Both are long peptides with a fatty-acid chain hung on them so albumin carries them and DPP-4, the enzyme that destroys native GLP-1 in about two minutes, cannot end the experiment before it starts. Semaglutide is the molecule in Ozempic and in Wegovy. Tirzepatide is the molecule in Mounjaro and in Zepbound. Retatrutide, the one this catalogue's research page is about, adds a third receptor, the glucagon receptor, and is a different structure, LY3437943. Three drugs, three receptor counts. The internet's habit of calling all of them 'GLP-1' keeps the least interesting fact and throws away the pharmacology.

In short. Semaglutide hits the GLP-1 receptor. Tirzepatide hits GLP-1 and GIP. Retatrutide hits those two plus glucagon. A fat tail on the chain is why they last days rather than minutes.

GLP-1, from the L cells of the gut, slows the stomach, raises insulin when glucose is high, lowers glucagon, and tells the brainstem and the hypothalamus that a meal has happened. That last signal is why appetite falls and why nausea is not an accident. You are occupying a receptor whose job includes making you decline the next plate. GIP, from the K cells, is the other incretin. For years it looked like the duller sibling. Tirzepatide's trials say the combination is not a copy of GLP-1 at a higher dose. The weight loss is larger, and the tolerability is not simply 'more GLP-1'. Glucagon, the third voice on retatrutide, adds energy expenditure and hepatic fat handling to the same conversation. Same family of ideas. Not the same molecule.

In short. GLP-1 slows the stomach and cuts appetite, which is also why people feel sick. GIP is the extra receptor on tirzepatide. Glucagon is the extra one on retatrutide. More receptors, different drug.

STEP-1, Wilding and colleagues, New England Journal of Medicine, 2021: adults with obesity, without diabetes, semaglutide 2.4 milligrams weekly. Mean weight loss about 14.9 percent at 68 weeks, against about 2.4 percent on placebo, both with a lifestyle programme. SURMOUNT-1, Jastreboff and colleagues, New England Journal of Medicine, 2022: tirzepatide at 5, 10 or 15 milligrams weekly. At 15 milligrams, mean loss about 20.9 percent at 72 weeks. Those are trial populations, titrated slowly because the nausea is dose-shaped, and they are not a promise to a person who was not in the trial. They are the reason the drugs exist as medicines. Retatrutide's phase 2, also Jastreboff, 2023, printed about 24 percent at the top dose over 48 weeks. Larger still, shorter trial, not yet the medicine the other two already are.

In short. In the big obesity trials, weekly semaglutide averaged about 15 percent weight loss in just over a year. Tirzepatide at the top dose averaged about 21 percent. Retatrutide's phase 2 was higher and is not the same kind of approval.

A share of the weight is lean tissue. Any large energy deficit takes muscle unless the person is eating enough protein and loading the fibres. The drug does not know the difference between a fat cell and a biceps. It knows appetite, gastric emptying and, for tirzepatide, a second incretin receptor. People who lose twenty kilograms without a stimulus for muscle keep less muscle than people who lift and eat protein while the same kilograms leave. That is ordinary physiology from the protein and fibre essays, arriving here because the deficit is unusually effective. Stopping the drug is the other plain finding. Appetite returns because the receptor is no longer occupied. The weight returns in the extension studies unless something else in the life has changed. Occupancy was doing the work.

In short. A lot of the lost weight can be muscle if you do not eat protein and train. Stop the drug and appetite comes back, and in the extension studies a lot of the weight comes back with it.

MOTS-c, AOD-9604, growth hormone and a stimulant reach different proteins, and none of them occupies the GLP-1 receptor. MOTS-c is a mitochondrial peptide read from 12S rRNA. AOD-9604 is a fragment of growth hormone and does not bind GLP-1R. Growth hormone binds the growth-hormone receptor, JAK2 phosphorylates the tail, STAT5 writes IGF-1, and fat distribution can change without ever printing a STEP trial. A stimulant raises catecholamines at adrenergic receptors and does not slow gastric emptying through a gut-hormone receptor. The side-effect list of semaglutide and tirzepatide is the receptor list: nausea, vomiting, constipation or diarrhoea, a risk of gallbladder disease because the stomach is slow and the weight loss is fast, and a boxed warning carried over from the rodent C-cell finding that human calcitonin monitoring has not turned into a clinical epidemic. Diabetic retinopathy can worsen short-term if glucose falls very fast.

In short. These are not fat-loss peptides from a different family. The nausea, the gallbladder risk and the rebound are GLP-1 pharmacology. A fragment of growth hormone does not do this job.