GLP-1 and GIP: The Gut Hormones Behind the New Medicines

Semaglutide, tirzepatide and retatrutide are all built on hormones the gut releases after every meal. Understanding those hormones, and how short-lived they are, explains most of what makes the medicines behave the way they do, including their most common side effects.

An observation from 1964

Early in the twentieth century, physiologists proposed that the gut releases substances that prompt the pancreas to act. The clearest evidence came in 1964, when researchers showed that glucose swallowed by mouth triggers a much larger insulin response than the same glucose given directly into a vein. Something released by the gut in response to food was amplifying the pancreas. Those substances became known as incretins, and the amplification as the incretin effect.

Two incretin hormones account for it. They are glucose-dependent insulinotropic polypeptide, GIP, and glucagon-like peptide-1, GLP-1. GLP-1 is released from L-cells, including those in the jejunum, which explains why it rises so quickly after a meal. Many endocrine cells in the small intestine appear to make both.

What each hormone does

Both hormones increase insulin release when blood glucose is raised, and a review by the physiologist Jens Juul Holst concluded that they are about equally important to the incretin effect. Both are active even at fasting glucose levels. Beyond the pancreas their roles differ.

Holst's review makes a point that matters for understanding the medicines: GLP-1's signal through gut nerves to the brain, and its effect on how the gut moves, may be even more important physiologically than its direct action on the insulin-producing cells of the pancreas. A later review by the same author discusses how the medicines act in obesity, in particular the role of these sensory nerves and of GLP-1 receptors in the brain.

The half-life problem

In the body these hormones are short-lived: released after a meal, active briefly, then removed. The enzyme responsible is dipeptidyl peptidase-4, DPP-4, which cuts both GIP and GLP-1 near the start of the chain. For GLP-1 the effect is dramatic: about 90 percent is degraded before it reaches the general circulation. A hormone that disappears that quickly is not useful as an injected medicine, so the medicines in this family use one or more of three approaches to the same problem.

Exendin-4: an answer from a lizard

Exendin-4 was discovered in the venom of the Gila monster, Heloderma suspectum. It is a full agonist of the GLP-1 receptor, it is more resistant to DPP-4, and it lasts longer than the human hormone, which is why it was developed into a treatment for type 2 diabetes called exenatide. Its half-life was still short, though, and a review of its pharmacology notes that several modifications were made to improve it.

Liraglutide and semaglutide: fatty acids and albumin

Liraglutide, from Novo Nordisk, is a GLP-1 analogue with a fatty acid attached, which binds it to albumin in the blood; it lasts long enough for once-daily use. Semaglutide took the same idea further. Its designers aimed for stronger albumin binding and full stability against enzymatic breakdown, and the molecule they chose differs from human GLP-1 at two positions and carries its fatty acid on lysine 26. In people its half-life is approximately one week.

Tirzepatide: a GIP backbone

Tirzepatide starts from the sequence of GIP rather than GLP-1. It is a chain of 39 amino acids with aminoisobutyric acid at positions 2 and 13, and a 20-carbon fatty diacid attached through a linker to the lysine at position 20. About 99 percent of it circulates bound to albumin, and its half-life is about five days. Despite the GIP backbone, it activates both the GIP and GLP-1 receptors.

From one receptor to three

The first medicines in the class acted on the GLP-1 receptor alone. Tirzepatide added the GIP receptor, and retatrutide, still investigational, adds the glucagon receptor as a third. In a 2024 review, Holst describes the arrival of semaglutide and tirzepatide as a new era: normalised HbA1c levels, average reductions in body weight of around 15 to 25 percent in trials, and trial evidence linking the medicines to fewer cardiovascular events and fewer premature deaths.

The same review lists the questions that remain open, including how treatment should be maintained over the long term. The withdrawal trial SURMOUNT-4 gives one answer for tirzepatide: people switched to placebo regained 14.0 percent of body weight over the following year, while those who continued did not.

Safety: side effects that follow from the biology

Several of the best-known side effects make sense once the hormones are understood.

• Gastrointestinal effects. GLP-1 acts on how the stomach and intestine move. Nausea, vomiting, diarrhoea and constipation are the most common adverse events in the trials described on this blog, are usually mild to moderate, and are most frequent while the dose is being raised.
• Anaesthesia. The tirzepatide label warns about inhaling stomach contents during general anaesthesia or deep sedation, a warning that sits alongside the class's known effect on gut movement.
• Low blood glucose. Because the insulin effect depends on glucose being raised, low blood glucose is uncommon on its own, and the labels warn mainly about combining these medicines with insulin or with medicines that increase insulin release.
• Thyroid tumours in rodents. Medicines in this class caused thyroid C-cell tumours in rodents. Whether that applies to humans is unknown, which is why the labels carry a boxed warning and exclude people with medullary thyroid carcinoma in themselves or their family, or with multiple endocrine neoplasia syndrome type 2.
• Pancreas and gallbladder. Acute pancreatitis and gallbladder disease appear among the warnings on the labels.

What the biology does not tell you

Knowing how a hormone works does not tell you how a particular product behaves. The half-life, the exposure and the side effects described here were measured with specific molecules, made to specified quality, in controlled trials. A change to the molecule, such as the salt forms of semaglutide the FDA has warned about, or a product of unknown purity, is a different thing, and the numbers above do not apply to it.