What Is Semaglutide?

Semaglutide is a peptide medicine, which means it is built from amino acids, the same building blocks as proteins. It belongs to the GLP-1 receptor agonists, a group of drugs that switch on the same receptor as the body's own glucagon-like peptide-1. Other members include exenatide, liraglutide and dulaglutide.

What GLP-1 Does in the Body

Cells in the lower gut release GLP-1 when food arrives. The hormone reaches the pancreas, the stomach and the brain and has several effects that work together after a meal:

• It tells the pancreas to release more insulin, but only when blood sugar is high, which keeps the risk of low blood sugar small.
• It lowers glucagon, a hormone that makes the liver release sugar.
• It makes the stomach empty more slowly, so sugar from a meal enters the blood more gradually.
• It acts on areas of the brain that control hunger and fullness.

Why Appetite Changes

Much of the weight loss seen with semaglutide comes from eating less. In a 2017 study in Diabetes, Obesity and Metabolism, people with obesity who took semaglutide for 12 weeks ate about 24% fewer calories over a day of meals where they could eat as much as they liked. They also reported less hunger, fewer cravings and more control over eating, and they chose fatty foods less often. The drug reaches areas of the brain involved in appetite, which is thought to explain these effects.

Three Small Changes, One Long-Acting Drug

Semaglutide is based on the natural hormone, and its chain of 31 amino acids matches human GLP-1 at 94% of positions. Novo Nordisk's chemists made three changes to it, described in the Journal of Medicinal Chemistry in 2015:

• At position 8 the natural alanine is replaced by aminoisobutyric acid (Aib). This stops the enzyme DPP-4 from cutting the hormone apart, which is what normally ends GLP-1's action within minutes.
• At position 34 lysine is swapped for arginine, leaving only one lysine for the next change.
• The lysine at position 26 carries a linker and an 18-carbon fatty diacid. This chain grips albumin, the main protein in blood, so the drug circulates slowly instead of being filtered out.

Compared with liraglutide, its daily predecessor, semaglutide binds the GLP-1 receptor about three times less tightly but holds on to albumin much more strongly. In practice the stronger albumin binding matters more, and it is the reason for weekly dosing.

A Tablet as Well as an Injection

Peptides are normally destroyed in the stomach, so almost all of them have to be injected. Rybelsus gets round this with an absorption enhancer called SNAC. SNAC briefly raises the pH around the tablet and helps semaglutide pass through the stomach wall. Even so, only a small fraction of each dose is absorbed. For that reason the tablet has to be swallowed on an empty stomach with a little water, at least 30 minutes before food or other medicines.

How Long It Stays in the Body

In people, semaglutide has a half-life of about one week. After a fixed weekly dose, blood levels settle after four to five weeks. Treatment starts at a low dose that is raised every four weeks, which gives the digestive system time to adjust. Ozempic is used at 0.5, 1 or 2 mg a week, and Wegovy's usual maintenance dose is 2.4 mg a week.

In Short

• Semaglutide is a modified copy of the gut hormone GLP-1, not a new kind of hormone.
• Protection from DPP-4 and strong albumin binding make one dose last about a week.
• It lowers blood sugar after meals and reduces appetite through the brain.
• It is sold as an injection and, thanks to an absorption enhancer, as a tablet.