GLP-1: the hormone it copies
GLP-1 stands for glucagon-like peptide-1. It is a hormone your intestine releases after a meal. The Wegovy® label describes GLP-1 as a physiological regulator of appetite and calorie intake, and notes that GLP-1 receptors are found in several areas of the brain involved in appetite [1].
Natural GLP-1 does not last. The Saxenda® label, which describes the same native hormone, gives it a half-life of 1.5 to 2 minutes, because the enzymes DPP-4 and neutral endopeptidase break it down [6]. A medicine that copies it has to survive far longer to be useful, and that is where semaglutide differs from the hormone.
What semaglutide is
According to its prescribing information, semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1, which selectively binds to and activates the same receptor the natural hormone uses [1][2]. In other words, it is a peptide built to look almost exactly like the natural hormone, with a few deliberate changes.
The labels list those changes. The amino acid at position 8 is altered to protect it from DPP-4. At position 26 a hydrophilic spacer carries an 18-carbon fatty di-acid, which lets semaglutide bind to albumin, the most common protein in blood. A small change at position 34 makes sure only one fatty chain attaches. The peptide backbone itself is produced by yeast fermentation [1][2].
Where the appetite effect comes from
The Wegovy® label says semaglutide decreases calorie intake and that the effect is likely mediated by affecting appetite. Animal studies described in the label show that semaglutide reached and activated nerve cells in brain regions that regulate food intake [1].
The same section says semaglutide lowers body weight with greater loss of fat mass than lean mass [1]. The label does not promise any amount of weight loss for an individual; results in its clinical studies are reported as group averages, and people in those studies also followed a reduced-calorie diet with more physical activity.
The semaglutide labels describe less food going in; they do not describe the medicine raising how many calories the body burns. For comparison, the label of the related medicine liraglutide states outright that it does not increase 24-hour energy expenditure [1][6].
Insulin and glucagon, only when sugar is high
Semaglutide stimulates insulin release and reduces glucagon release in a glucose-dependent way. The Ozempic® label explains what that means: when blood sugar is high, insulin secretion goes up and glucagon secretion goes down [2]. In a test in which blood sugar was deliberately pushed low, semaglutide did not change the rise in glucagon that the body uses to recover, compared with placebo [2].
After 12 weeks on 1 mg in people with type 2 diabetes, the label reports fasting glucose 29 mg/dL (22%) lower and two-hour after-meal glucose 74 mg/dL (36%) lower than at the start, relative to placebo [2].
The labels still warn that combining semaglutide with insulin or with medicines that make the pancreas release insulin, such as sulfonylureas, can raise the risk of low blood sugar, including severe episodes [1][2]. Your prescriber may adjust those other medicines.
The stomach: a delay early after meals
Both labels say semaglutide delays gastric emptying, meaning food leaves the stomach more slowly. The Ozempic® label places this in the early period after a meal and calls it a minor delay; it also reports that a separate study found no apparent effect on the rate of gastric emptying with 2.4 mg, without explaining the difference [2].
Slower emptying is part of why stomach-related effects such as nausea are common, especially while the dose is being raised, and it is the reason for the labels’ warning about food entering the lungs during anaesthesia or deep sedation [1][2].
It can also change how other medicines taken by mouth are absorbed. In the label’s studies, levels of metformin, warfarin, digoxin, atorvastatin and an oral contraceptive did not change in a clinically relevant way, but levothyroxine exposure rose by 33% when taken with semaglutide tablets, and the labels ask for closer monitoring of medicines with a narrow safety margin [1][2].
Getting the molecule in: injection or tablet
A large peptide is normally destroyed in the gut, so the injection and the tablet take very different routes to the same receptor. The table uses the same three headings for each route [1][2][3].
- Water and waiting matter: in the label’s studies, more semaglutide was absorbed with a small volume of water than with a full glass, and more again when people waited longer before eating [1][3].
- That is the reason behind the instructions to take the tablet on an empty stomach with a little water and to wait at least 30 minutes before food, drinks or other oral medicines [3].
- Because so little is absorbed, tablet milligrams are much larger numbers and cannot be read as injection milligrams; the table below gives each route’s figures [1][3].
| Route | Share of the dose reaching the blood | Time to highest level | What the label notes |
|---|---|---|---|
| Under the skin (Ozempic®, Wegovy®) | 89% [1][2] | 1 to 3 days [1][2] | Similar levels whether injected in the abdomen, thigh or upper arm [1][2] |
| Rybelsus® tablet | About 0.4% to 1% [3] | About 1 hour [3] | Co-formulated with SNAC; absorbed mainly in the stomach [3] |
| Ozempic® and Wegovy® tablets | About 1% to 2% [1][3] | About 1 hour [1][3] | Co-formulated with SNAC; levels vary more between people than with the injection [1] |
Why it lasts a week
More than 99% of semaglutide in the blood is bound to albumin, which lowers how fast the kidneys clear it and shields it from being broken down [1][2]. The labels give an elimination half-life of about one week, and with weekly injections the level builds until it levels off after 4 to 5 weeks [2].
The body eventually breaks it down the way it handles proteins and fats: the peptide chain is cut apart and the fatty side chain is shortened step by step. About 3% leaves in the urine unchanged, and neither kidney nor liver impairment changed exposure in a clinically relevant way [1][2][5]. Semaglutide is still present for weeks after a last dose; the article on how long GLP-1 medicines stay in your system covers that timing in detail.
What the labels say is not yet known
- Heart: the Wegovy® label says the exact mechanism by which semaglutide lowers cardiovascular risk in adults has not been established [1].
- Kidneys: the Ozempic® label says the mechanism behind its kidney-related risk reduction has not been established [2].
- Liver: for MASH, the Wegovy® label calls the mechanism not fully understood and possibly involving several pathways, including weight loss [1].
- Thyroid: semaglutide caused thyroid C-cell tumours in rodents, and the labels say the relevance of this to people has not been determined [1][2].
- Antibodies: about 1% of people in the Ozempic® glycaemic trials developed antibodies to semaglutide, and whether they neutralise it is described as uncertain [2].
One molecule, several labels
Ozempic® (injection) is approved for type 2 diabetes, including lowering the risk of major cardiovascular events and of kidney decline in certain adults; Wegovy® (injection and tablets) for weight reduction and maintenance and for cardiovascular risk reduction, and as an injection for MASH; Rybelsus® and Ozempic® tablets for type 2 diabetes [1][2][3].
The mechanism is the same in each, but the labels differ in doses, ages and conditions. The one your prescriber chose is the one that applies to you.
Ozempic®, Wegovy®, Rybelsus® and Saxenda® are registered trademarks of Novo Nordisk A/S. PepLabo is not affiliated with or endorsed by Novo Nordisk.
When to get help
| Sign | Who to contact | How fast | Source |
|---|---|---|---|
| A new neck lump or swelling, a hoarse voice, difficulty swallowing or breathlessness | Your prescriber | Today | Ozempic® Medication Guide [2] |
| On insulin or a sulfonylurea: shakiness, sweating, confusion, blurred vision or a fast heartbeat | Treat it as your care plan says, then tell your prescriber | Today | Ozempic® Medication Guide [2] |
| Severe stomach trouble, or stomach trouble that persists | Your prescriber | Today | Ozempic® Medication Guide [2] |
| An upcoming operation or procedure with anaesthesia or deep sedation | Every clinician involved, before the procedure | At your next appointment | Section 5.10 [1][2] |
