Semaglutide — pharmacology
Molecular targets, mechanism of action, pharmacokinetics and interactions as characterised in humans.
§2Pharmacology
§2.1Molecular targets
Table 2. Molecular targets recorded for Semaglutide, with the character of the interaction and the potency where the Institute holds it.
| Target | Interaction | Note |
|---|---|---|
| GLP-1 receptor (GLP1R) | Full agonist | EC₅₀ ≈ 0.1 nM; affinity approximately three-fold lower than native GLP-1 owing to albumin binding |
| Albumin (non-receptor) | Reversible binding via C18 diacid | Drives the extended half-life; >99 % bound in plasma |
| Neuraminidase-resistant DPP-4 cleavage site | Not a target — structurally protected | Aib8 substitution prevents N-terminal degradation |
§2.2Mechanism of action
Semaglutide is a full agonist at the glucagon-like peptide-1 receptor, a class B G protein-coupled receptor signalling principally through Gαs and adenylyl cyclase. In pancreatic beta cells the resulting rise in cyclic AMP potentiates glucose-dependent insulin secretion; in alpha cells it suppresses glucagon release at euglycaemia and above. Peripheral effects include delayed gastric emptying. Central effects, mediated through GLP-1 receptor populations in the area postrema, nucleus tractus solitarius, arcuate nucleus and other hypothalamic sites accessible to circulating peptide, reduce appetite and energy intake; the weight effect is attributed principally to this central action rather than to gastric emptying, which shows partial tachyphylaxis with continued dosing.[1,2]
§2.3Pharmacokinetics
- Terminal half-life
- ≈165 h (approximately 7 days)
- Time to maximum concentration
- 1–3 days after subcutaneous injection
- Volume of distribution
- ≈12.5 L
- Plasma protein binding
- >99 % (albumin)
- Clearance
- ≈0.05 L/h
- Bioavailability
- ≈89 % absolute bioavailability (subcutaneous)
Proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty-acid side chain. Approximately 3 % of the dose is excreted as intact peptide in urine. Steady state is reached after 4–5 weeks of weekly dosing.
§2.4Interactions
- Delayed gastric emptying may alter the rate, though generally not the extent, of absorption of concomitant oral medicines
- Insulin secretagogues and insulin require dose reduction to limit hypoglycaemia
- No clinically relevant cytochrome P450 interaction has been identified; semaglutide is not a substrate, inducer or inhibitor of the major isoforms
References cited on this page
References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.
- Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF. Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine 2021;384(11):989–1002. doi:10.1056/NEJMoa2032183 · PMID 33567185
- Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, Rosenstock J, Shimomura I, Viljoen A, Wadden TA, Lingvay I. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. The Lancet 2021;397(10278):971–984. doi:10.1016/S0140-6736(21)00213-0 · PMID 33667417
Identifiers are reproduced only where the Institute holds them. Where a digital object identifier or PubMed identifier is not shown, the Institute has recorded the journal and year and has not constructed an identifier.