How the GLP-1 class works: one receptor, then two, then three

Every entry on this site describes a drug that imitates a gut hormone. This guide is the physiology they share, written once so the entries can get on with their specifics.

The incretin effect

Glucose swallowed produces more insulin than the same glucose infused into a vein. The difference is the incretin effect, and it is carried by two hormones released from the gut lining after a meal: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The Bydureon BCise label puts it in one sentence: incretins such as GLP-1 enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions after their release from the gut.

"Glucose-dependent" is the property that makes the class safe on its own. GLP-1 receptor activation raises insulin only when glucose is high; as glucose falls, the signal fades. That is why the labels report low rates of hypoglycemia unless the drug is combined with insulin or a sulfonylurea, which force insulin out regardless.

What GLP-1 receptor activation does

The labels list the same four effects, in slightly different words, for every agent:

1. More insulin when glucose is high. GLP-1 receptors on the beta cell are coupled to adenylyl cyclase; the Trulicity label describes the rise in intracellular cyclic AMP that follows.
2. Less glucagon. Alpha-cell glucagon secretion falls, so the liver releases less glucose.
3. Slower gastric emptying. Food leaves the stomach more slowly, blunting the post-meal glucose spike. This is also the source of the nausea, fullness and reflux in every adverse-reaction table on this site, and of the warnings about oral drug absorption and about aspiration under anaesthesia.
4. Less appetite. The Foundayo label states that GLP-1 receptors are present in brain regions that regulate appetite and caloric intake. The weight indications rest on this effect, which is why the weight doses (semaglutide 2.4 mg, tirzepatide 15 mg) are higher than the diabetes doses that were enough for the pancreas.

Why the hormone itself is useless as a drug

Native GLP-1 is cleaved by the enzyme dipeptidyl peptidase-4 within minutes of release. Every approved agent is an answer to that problem, and there have been four answers:

• A foreign sequence that DPP-4 ignores. Exenatide (from the Gila monster) and lixisenatide are exendin-4 based; they resist the enzyme but are cleared by the kidney within hours, hence twice-daily and once-daily dosing.
• A fatty acid that hitches to albumin. Liraglutide (daily), semaglutide (weekly) and tirzepatide (weekly, with a C20 fatty diacid per its label) carry a lipid side chain that binds circulating albumin, which slows clearance and shields the peptide. Semaglutide adds an amino-acid substitution at the DPP-4 cleavage site.
• Fusion to a large protein. Dulaglutide is fused to an antibody Fc fragment; albiglutide was fused to albumin itself. Both are too large for rapid renal clearance and last a week.
• A drug that is not a peptide at all. Orforglipron is a small molecule that binds the receptor; it is not a substrate for DPP-4 or any protease and is cleared by the liver's CYP3A4 system, which is why its label has interaction rules that no peptide label has.

Getting a peptide through the stomach

Oral semaglutide is the one peptide taken by mouth. It is co-formulated with an absorption enhancer (salcaprozate sodium, SNAC) and depends on the tablet dissolving in an almost empty stomach, which is why the label requires it to be taken with no more than 4 ounces of water followed by a 30-minute wait. The daily oral dose (up to 25 mg for Wegovy tablets) is roughly ten times the weekly injected dose (2.4 mg) because so little is absorbed. Orforglipron, being a small molecule, needs none of that.

Adding receptors

The second generation activates more than one receptor with one injection.

• GIP plus GLP-1 (tirzepatide). The Mounjaro label describes a single peptide that selectively binds and activates both the GIP and GLP-1 receptors. GIP on its own is a weak drug; in combination the weight and HbA1c results exceeded the GLP-1 comparator in SURPASS-2. Why GIP helps is still argued over, and the Science site goes into the competing explanations.
• Glucagon plus GLP-1 (survodutide, mazdutide). Glucagon raises glucose, which sounds like the wrong target, but it also raises energy expenditure and liver fat oxidation; paired with GLP-1 the glucose effect is offset. Both agents are also being studied in fatty liver disease for that reason.
• GIP plus GLP-1 plus glucagon (retatrutide). All three. The phase 2 trial reported minus 24.2% at 48 weeks at the top dose.
• Amylin plus GLP-1 (CagriSema). Amylin is a beta-cell hormone co-secreted with insulin that slows gastric emptying and reduces intake through a separate central pathway. CagriSema pairs a long-acting amylin analogue with semaglutide as two peptides given together rather than one engineered molecule.

What is shared regardless of receptor

Read the adverse-reaction tables across the entries and the same rows appear on every one: nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia. Read the warnings and the same list appears: pancreatitis, gallbladder disease, kidney injury from dehydration, hypoglycemia with insulin or sulfonylureas, retinopathy complications in diabetes, aspiration under anaesthesia. Every long-acting peptide, and orforglipron by class inheritance, carries the thyroid C-cell boxed warning. The receptor additions change the size of the weight effect and, so far, not the shape of the safety profile.

Where next

The glossary defines the terms used above. The agent comparison table puts receptor profile, dosing and results side by side for any four agents.