How retatrutide works: GLP-1, GIP and glucagon explained

Retatrutide is one molecule that copies three of the body's own hormones: GLP-1, GIP and glucagon. The first two are the same targets as the weight-loss injections already licensed in the UK. The third is new, and it is where most of the extra effect, and most of the extra questions, come from.

Three hormones, one molecule

After you eat, your gut and pancreas release hormones. Some of them tell your brain you have had enough, some slow your stomach down, and some help move sugar out of your blood. Each hormone works by locking on to a receptor, a protein on the surface of a cell that responds to that hormone and nothing else.

A drug that locks on to the same receptor and switches it on is called an agonist. Semaglutide (Wegovy) is an agonist at one receptor. Tirzepatide (Mounjaro) is an agonist at two. Retatrutide is designed to be an agonist at three.^[1] The what is retatrutide page covers who makes it and where it is in testing; this page is about what the three switches do.

GLP-1: fullness, a slower stomach and insulin

GLP-1 is released by the gut after a meal. It does three things that matter here.^[2]

• In the brain, it signals fullness. People on GLP-1 medicines usually eat less without trying to, and many describe constant thoughts about food going quiet.
• In the stomach, it slows gastric emptying, so food stays in the stomach longer. That adds to the feeling of fullness. It is also the main reason for nausea, bloating and reflux, especially after big or fatty meals.
• In the pancreas, it boosts insulin release when blood sugar is high, which is why the same family of drugs is used for type 2 diabetes.

The stomach effect is the one most people notice first, and it is worst in the weeks after each dose increase. See nausea, vomiting and gut effects.

GIP: the second signal

GIP is another gut hormone released after eating. Like GLP-1, it is an incretin, meaning it increases insulin release after meals. Adding it to GLP-1 appears to increase the appetite effect, and it may take the edge off some of the nausea that GLP-1 alone causes. Tirzepatide already uses this combination, which is one reason it produced more weight loss in trials than semaglutide did.

Glucagon: the new part

Glucagon is a hormone from the pancreas that normally does the opposite of insulin: it tells the liver to release stored sugar into the blood. That sounds like an odd thing to want in a drug for obesity and diabetes. The idea behind retatrutide is that, with the GLP-1 and GIP arms boosting insulin at the same time, the blood-sugar-raising effect is held in check, while two other effects of glucagon come through.^[2]

It appears to raise energy expenditure

Energy expenditure is the number of calories your body burns. Appetite drugs work only on the "calories in" side. Glucagon receptor activation appears to nudge the "calories out" side as well. This is the leading explanation for why retatrutide produced more weight loss in trials than drugs that act on appetite alone: 24.2% at the highest dose after 48 weeks in Phase 2, against 2.1% on placebo.^[2] The exact size of the energy-burning effect in people has not been published, so treat "burns more" as a well-supported explanation rather than a measured number.

It reduces liver fat

Glucagon acts directly on the liver, and the liver is where the effect is easiest to measure. In a sub-study of the Phase 2 trial, 98 people with MASLD (fatty liver disease linked to metabolic health) had liver fat measured by MRI. After 24 weeks, liver fat had fallen by 82.4% in the highest-dose group and by 42.9% in the lowest, compared with a 0.3% rise on placebo. Liver fat returned to a normal level in 86% of the highest-dose group and none of the placebo group.^[3] More on this in other indications.

The trade-off: heart rate

Every drug in this class raises resting heart rate a little. With retatrutide the rise was larger and dose-dependent in Phase 2, peaked at around week 24, and had come down by weeks 36 to 48.^[2] The paper's summary does not give a beats-per-minute figure; a fair description is a few to about ten beats per minute at higher doses. The Phase 3 announcements have not reported heart-rate figures at all.^[4] Abnormal heart rhythms were recorded in 2% to 11% of people on retatrutide in Phase 2 against 2% on placebo, mostly mild.^[2] The glucagon arm is the likely reason. What that means for people with existing heart conditions is not yet known, because the trials excluded them. See heart rate and rhythm.

What this does not mean

• It is not a magic switch. Trial participants also got diet and activity advice, regular check-ups, and doses that were stepped up slowly under supervision. Even the placebo groups lost 2% to 4% of their body weight.^[4] The drug adds to those things; it does not replace them. The weight-loss section covers the parts that work with or without any medicine.
• Effects vary. An average of 25% weight loss in TRIUMPH-1 means some people lost far more and some far less. About one in nine on the highest dose stopped because of side effects.^[4] How to read a trial explains why averages hide the spread.
• It describes the trial product only. Every figure above comes from pharmaceutical-grade retatrutide made by Lilly and given inside a trial. A vial sold online has unknown identity, strength and sterility, so nothing on this page can be assumed to apply to it. See what is actually in the vials.