GLP-1 and GLP-1 receptor agonists, explained

GLP-1 lasts a few minutes and acts on four organs at once. What changes when a long-acting agonist keeps the same receptor occupied for a week? The natural hormone, the receptor and the studies in people, animals and cells, explained separately.

GLP-1: how a gut hormone steers appetite, the stomach and the pancreas

GLP-1 is a hormone the gut releases the moment food arrives. It does four things at once: it raises insulin release for as long as blood glucose is high, it suppresses glucagon, it slows gastric emptying, and it dampens appetite through the brain. The body's own hormone lasts a few minutes. A receptor agonist such as semaglutide activates the same receptor but stays in the blood for a week. That difference in duration, rather than a different mechanism, accounts for most of what the clinical trials have shown.

The body's own hormone

GLP-1 stands for glucagon-like peptide-1. The name comes from biochemistry: the peptide is cut from the same precursor protein as glucagon, called proglucagon. In the pancreas that protein yields glucagon; in the L-cells of the small and large intestine it yields GLP-1. Two hormones from one gene, with opposite effects on blood glucose.

Release follows the meal. Within minutes of eating, GLP-1 rises in the blood in proportion to the carbohydrate and fat reaching the gut. Bloom's group in London showed in 1987 what a meal-level infusion does in seven volunteers: insulin rose, glucose and glucagon fell, and during a glucose load GLP-1 amplified insulin release so strongly that a reactive hypoglycaemia followed (Kreymann 1987). That established GLP-1 as an incretin: a gut hormone that enlarges the insulin response to glucose taken by mouth.

The work on the pancreas depends on glucose. GLP-1 raises insulin release only when blood glucose is elevated; at normal or low values little happens. The same dependence applies to the suppression of glucagon. This is why the hormone on its own rarely causes hypoglycaemia, a property the reviews by Holst (2007) and Drucker (2018) place at the centre of its physiology.

Then the stomach. In eight poorly controlled patients with type 2 diabetes, Willms and colleagues in Bad Lauterberg, with Nauck as senior author, infused GLP-1 at 1.2 pmol per kg per minute around a liquid test meal. In the control condition the stomach had emptied within 120 minutes; with GLP-1 the gastric volume stayed constant for the whole period, and plasma glucose fell to normal fasting values within three to four hours (Willms 1996). Slower emptying means glucose enters the blood more gradually. It is a second route to a flatter glucose curve, independent of insulin.

And appetite. Flint and colleagues in Copenhagen gave twenty healthy young men of normal weight a GLP-1 infusion at 50 pmol per kg per hour around a breakfast of fixed energy content. The men reported more satiety and fullness, and at a lunch where they could eat freely they took in 12 percent less energy than with saline (Flint 1998). The appetite effect is measurable with the natural hormone too, though in an acute infusion in people without excess weight.

All of these effects are brief. The enzyme DPP-4 cuts GLP-1 into an inactive form within one to two minutes of release. Of the hormone the gut secretes, only a small fraction reaches the pancreas intact. That the physiology is this fleeting is exactly the problem pharmacology had to solve.

What a receptor agonist does differently

The GLP-1 receptor is a G-protein-coupled receptor that mainly raises cAMP inside the cell after binding. An agonist is a molecule that activates that receptor. The clinically studied compounds are peptides that resemble the body's GLP-1 but differ in two respects: they are protected against DPP-4, and they bind to albumin, the transport protein in blood, so that the kidneys clear them far more slowly.

Liraglutide carries a sixteen-carbon fatty acid for that purpose and has a half-life of about a day. In semaglutide the chain is a longer diacid, the DPP-4-sensitive position is replaced by a non-natural amino acid, and the half-life extends to about a week (Lau 2015). The mechanism at the receptor is the same as for the hormone; what changes is that the receptor is no longer activated for a few minutes after a meal but around the clock.

Where the agonist acts is known mostly from animals. Secher and colleagues followed fluorescently labelled liraglutide in mice and rats. The drug reached the circumventricular organs, brain regions with a permeable blood-brain barrier, and bound to neurons in the arcuate nucleus of the hypothalamus. Weight loss in rats proved independent of GLP-1 receptors in the vagus nerve, the area postrema and the paraventricular nucleus, and brain uptake vanished in animals lacking the receptor (Secher 2014). For semaglutide, Gabery's group described a comparable distribution in rodent brain in 2020 (Gabery 2020). Whether this maps one-to-one onto people cannot be measured with the same techniques; the human evidence for the appetite effect comes from reported satiety and the weight trajectories in the trials.

What the studies show

In people

The trials with long-acting agonists are large and long, which makes their results easy to read.

In the SCALE trial, 3731 adults with obesity, or overweight plus a risk factor, and without diabetes received 56 weeks of daily liraglutide 3.0 mg or placebo, both alongside lifestyle counselling. The liraglutide group lost a mean of 8.4 kg, the placebo group 2.8 kg. At least 5 percent weight loss was reached by 63.2 percent of the liraglutide group against 27.1 percent on placebo. Serious events occurred in 6.2 percent against 5.0 percent (Pi-Sunyer 2015).

STEP 1 did the same with semaglutide: 1961 adults without diabetes, 68 weeks, 2.4 mg subcutaneously once a week or placebo. Weight fell by 14.9 percent against 2.4 percent, a difference of 12.4 percentage points with a confidence interval of 11.5 to 13.4. In kilograms: 15.3 against 2.6. Of the semaglutide group, 86.4 percent reached at least 5 percent loss and 50.5 percent at least 15 percent; on placebo the figures were 31.5 and 4.9 percent. Nausea and diarrhoea were the most commonly reported adverse events; 59 participants (4.5 percent) stopped because of gastrointestinal complaints, against 5 (0.8 percent) on placebo (Wilding 2021).

The STEP 1 extension shows what happens when the agonist stops. There, 327 participants were followed for a year after discontinuation. Those who had received semaglutide had lost 17.3 percent in 68 weeks and regained 11.6 percentage points of it in the following year, leaving a net loss of 5.6 percent at 120 weeks. The cardiometabolic improvements largely returned towards baseline (Wilding 2022). The investigators read this as evidence that obesity is chronic; at minimum it shows the effect is tied to the presence of the agonist.

The cardiovascular outcomes are the strongest evidence that the receptor does more than weight and glucose. LEADER randomised 9340 patients with type 2 diabetes at high cardiovascular risk to liraglutide or placebo, with a median follow-up of 3.8 years. The composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred in 608 of 4668 patients (13.0 percent) on liraglutide and 694 of 4672 (14.9 percent) on placebo, a hazard ratio of 0.87 with an interval of 0.78 to 0.97 (Marso 2016). SELECT asked the same question in 17,604 people with established cardiovascular disease and overweight but no diabetes: 569 of 8803 (6.5 percent) on semaglutide against 701 of 8801 (8.0 percent) on placebo after a mean of 39.8 months, hazard ratio 0.80 (0.72 to 0.90). Discontinuation for adverse events in that trial ran at 16.6 percent against 8.2 percent (Lincoff 2023).

In type 2 diabetes the evidence came earlier. Nauck showed in 1993, in ten patients with an HbA1c of 11.6 percent, that an intravenous GLP-1 infusion normalised fasting hyperglycaemia, something the natural hormone can do once its concentration is kept high enough (Nauck 1993).

In animals

The animal studies explain the route, not the size of the effect. The hypothalamus studies above show where the agonist binds and which nuclei are required. The same rodent models are also the source of the best-known safety signal. In rats and mice exposed to liraglutide or exenatide for their whole lives, C-cell tumours of the thyroid developed. Madsen and colleagues showed that 13 weeks of continuous exposure in ordinary mice raised calcitonin and produced C-cell hyperplasia, and that this was absent in mice without the GLP-1 receptor (Madsen 2012). The effect therefore runs through the receptor. Human C-cells carry that receptor far more sparsely, and no comparable signal appeared in the large trials above; the product labels carry the warning nonetheless.

In cells

The cell work concerns the receptor itself. In cell lines expressing the receptor, both GLP-1 and the agonists activate the cAMP pathway and also recruit β-arrestin, a protein that pulls the receptor inside and dampens the signal. Different agonists weigh those two routes differently; Willard and colleagues showed in 2020 that tirzepatide favours the cAMP route over β-arrestin at the GLP-1 receptor (Willard 2020), a property that returns in part 3 of this series. How much that distinction matters for the clinical outcome has not been measured directly in people.

Adverse events and limitations

The adverse events the trials report are consistent: nausea, vomiting, diarrhoea and constipation, mostly mild to moderate, mostly during dose escalation, and easing with time. In STEP 1, 4.5 percent stopped for that reason; in SELECT, 16.6 percent stopped for any adverse event. Discontinuation rises as the population gets older and sicker. Pancreatitis and gallbladder disease are tracked in the trials; in LEADER the incidence of pancreatitis on liraglutide was not higher than on placebo (Marso 2016).

The limitations lie in what the trials do not measure. The slowing of gastric emptying was measured during short infusions; Willms and colleagues wrote in 1996 that for long-term use this inhibition would have to fade, for instance through tachyphylaxis. How much of the long-term weight effect still runs through the stomach rather than almost entirely through the brain cannot be separated in people. The ratio of fat to muscle lost has been measured only in substudies of the large trials. And the STEP 1 extension makes plain that the evidence base is almost entirely on-treatment: little is known about the years after stopping.

What remains open is where the cardiovascular benefit comes from. Weight, blood pressure, lipids and inflammatory markers all improve in the trials, and receptors also sit on the heart, the vessel wall and immune cells. Which share of the 20 percent risk reduction in SELECT belongs to which route cannot be determined with the current trial designs. That is the kind of question for which mechanistic studies in people are missing, because they are expensive and serve no registration purpose.

A longer-acting agonist, then, does not change what the receptor does. It changes how long and how fully the receptor is occupied, and with that a meal signal of a few minutes grows into an effect on weight and heart that is measured in years. Part 2 of this series turns to the other incretin hormone, GIP, whose role is far less settled.

Registered nurse with eleven years in psychiatry and founder of Peptalis. Writes the platform's knowledge layer: compound profiles, evidence reviews and the quality methodology. Works from primary literature (PubChem for chemistry, PubMed for studies) and states where evidence is absent.

Sources checked via PubMed · 16 references

• The body's own hormone
• What a receptor agonist does differently
• What the studies show
• Adverse events and limitations

• Wilding et al. 2021 ↗
• Lincoff et al. 2023 ↗
• Marso et al. 2016 ↗
• Flint et al. 1998 ↗
• Secher et al. 2014 ↗

• DEEP DIVEThe GLP class: from one receptor to three

Compounds in this article

• Semaglutide · Not in catalogue · Research profile
• Liraglutide · Not in catalogue · Research profile

For laboratory research use only. Not for human use.

SCIENTIFIC REFERENCES

These references are provided for informational and research purposes only. They do not constitute medical advice.

1. 01Human studyGlucagon-like peptide-1 7-36: a physiological incretin in man.Kreymann B, et al. Lancet. 1987.View on PubMed →DOI →
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