GLP-1 receptor agonists are the most consequential peptide medicines of the last decade. Understanding how they work makes the whole category easier to read, including the newer compounds still in trials.
The hormone they copy
GLP-1 (glucagon-like peptide-1) is released by cells in your gut after you eat. It does several things at once: prompts the pancreas to release insulin when blood sugar is high, suppresses glucagon, slows how quickly the stomach empties, and acts on appetite centres in the brain.
Natural GLP-1 is broken down within minutes. The engineering problem was making a version that survives long enough to be useful. Semaglutide solves this with chemical modifications that let it bind to albumin in the blood, giving it a half-life of about a week.
One receptor, two, or three
The category has expanded by adding receptors rather than refining a single target.
| Compound | Receptors | Status |
|---|---|---|
| Semaglutide | GLP-1 | FDA-approved |
| Tirzepatide | GIP + GLP-1 | FDA-approved |
| Cagrilintide (with semaglutide) | Amylin + GLP-1 | Investigational |
| Retatrutide | GIP + GLP-1 + glucagon | Investigational |
Adding receptors has generally produced more weight loss in trials, with gastrointestinal side effects rising alongside.
The glucagon receptor in retatrutide is the most interesting addition, because glucagon raises energy expenditure and mobilises liver fat. That is a different mechanism from simply eating less.
What the trials have shown
- Semaglutide: around 15% average weight loss over 68 weeks in its main obesity trial, plus reduced heart attack and stroke risk in people with established cardiovascular disease.
- Tirzepatide: approximately 20% average weight loss at the highest dose over 72 weeks.
- Retatrutide: up to 28.3% at 80 weeks on 12 mg in the phase 3 TRIUMPH-1 trial, the largest figure reported for any obesity drug so far.
People with type 2 diabetes consistently lose less weight on these drugs than people without it, across every compound in the class.
The side effect pattern is predictable
Because these drugs slow gastric emptying, nausea, vomiting, diarrhoea and constipation dominate the adverse event tables. They cluster during dose escalation, which is why every approved product starts low and steps up over months.
Retatrutide added a signal not prominent with the others: dysesthesia, an abnormal skin sensation, in up to 12.5% of participants on higher doses.
Approved products in this class carry a boxed warning about thyroid C-cell tumours observed in rodents, and are contraindicated for anyone with a personal or family history of medullary thyroid cancer or MEN 2 syndrome.
Why the investigational ones are not the same thing
Retatrutide and cagrilintide are not approved anywhere. Material sold online under those names is not the trial drug; it is made by unregulated manufacturers, and the trial dosing schedules were designed around pharmaceutical-grade material given under medical supervision.