Semaglutide

Native glucagon-like peptide-1 is an incretin hormone released from intestinal L-cells after a meal. It is also almost useless as a drug: dipeptidyl peptidase-4 cleaves it within about two minutes of release.

Semaglutide addresses that with three specific changes to the GLP-1(7-37) backbone:

• Aib at position 8. α-aminoisobutyric acid replaces alanine at the DPP-4 cleavage site. The non-standard residue is not recognised by the enzyme, which removes the primary degradation route.

• Arg at position 34. Lysine is replaced by arginine, leaving exactly one lysine in the molecule so that the acylation below attaches at one defined position rather than several.

• A C18 diacid at Lys26, attached through a γ-glutamic acid and two short PEG spacers. The fatty diacid binds non-covalently to serum albumin, which both shields the peptide from renal clearance and creates a circulating depot.

Together these extend the half-life from roughly two minutes to about a week — an increase of around five thousand-fold, achieved by three deliberate structural decisions.

The GLP-1 receptor is a class B G protein-coupled receptor expressed on pancreatic beta cells, and in the hypothalamus, area postrema, gastrointestinal tract, heart and kidney. That distribution is why a single receptor agonist has effects reported across so many organ systems in the literature.

• Glucose-dependent insulin secretion. Signalling potentiates insulin release only when glucose is elevated, which is the pharmacological basis of the class.

• Glucagon suppression, also glucose-dependent.

• Gastric emptying, slowed — one of the more consistently measured peripheral effects.

• Central appetite signalling, via hypothalamic and hindbrain receptor populations.

Semaglutide has an unusually large and well-indexed body of randomised data, organised into named programmes:

• SUSTAIN — type 2 diabetes, the original registration programme.

• PIONEER — the oral formulation, co-administered with the absorption enhancer SNAC.

• STEP — obesity, the programme behind the weight-management indication.

• SELECT — cardiovascular outcomes in overweight and obese patients without diabetes.

• FLOW — chronic kidney disease in type 2 diabetes.

• ESSENCE — MASH, addressing hepatic endpoints.

For a research context this volume matters less for its conclusions than for its comparability: newer incretins are almost always trialled against semaglutide, so it functions as the field's common reference point.

Supplied as a lyophilised powder. Acylated peptides of this type are typically reconstituted in bacteriostatic water and are sensitive to agitation — vigorous shaking promotes aggregation at the air-liquid interface, which is a documented failure mode for albumin-binding peptides rather than a general caution. Store reconstituted material refrigerated and protected from light.

Tirzepatide adds GIP receptor agonism to the same mechanism, Retatrutide adds glucagon on top of that, and CagriSema pairs semaglutide with an amylin analogue. The progression from one receptor to three is the organising story of this category.