Source of Semaglutide

{{Infobox compound | name = Semaglutide | subtitle = Clinical data | image = peptide-chain.svg | caption = A 31-residue backbone with Aib at position 8 and a C-18 diacid on Lys26 through a γ-Glu-2×OEG spacer. | INN = semaglutide | Class = [[GLP-1 receptor agonist]] | Routes = Subcutaneous weekly; oral daily | First approval = 2017 (type 2 diabetes) <!-- Identifiers --> | CAS Number = 910463-68-2 | Molecular formula = {{math|C_{187}H_{291}N_{45}O_{59}}} | Molar mass = 4,113.58 g·mol⁻¹ <!-- Pharmacokinetics --> | Half-life = ≈165 h (7 days) | Bioavailability, SC = ≈89% | Albumin binding = >99% | Time to steady state = 4–5 weeks <!-- Engineering --> | Position 8 = α-aminoisobutyric acid (DPP-4 resistance) | Position 26 = C-18 diacid via γ-Glu-2×OEG | Position 34 = Lys→Arg (single acylation site) }} {{hatnote|For the oral formulation and its absorption enhancer, see [[Oral semaglutide]]. For the drug class, see [[GLP-1 receptor agonist]].}} {{medical|talk=Scope of the research-material section}} '''Semaglutide''' is an acylated analogue of [[Glucagon-like peptide-1]] and a [[GLP-1 receptor agonist]]. Three engineering changes to the native 31-residue sequence give it a circulating half-life of about seven days: α-aminoisobutyric acid at position 8 confers resistance to [[Dipeptidyl peptidase-4]], a C-18 fatty diacid attached at Lys26 confers [[Albumin binding half-life extension|albumin binding]], and an arginine substitution at position 34 leaves a single site available for acylation.{{r|lau2015}} It is approved for type 2 diabetes, for chronic weight management, and — following the [[SELECT trial|SELECT]] trial — for reduction of major adverse cardiovascular events in people with established cardiovascular disease and overweight or obesity but without diabetes. An oral formulation using the absorption enhancer SNAC is approved for type 2 diabetes.{{r|lincoff2023}} In the [[STEP trial programme|STEP 1]] trial, weekly semaglutide 2.4 mg produced a mean body-weight change of −14.9% against −2.4% for placebo at 68 weeks.{{r|wilding2021}} Semaglutide is also among the most heavily copied peptides in the research-chemical market, and material sold that way is not the approved medicine: it is not manufactured under a marketing authorisation and carries no regulatory assurance of identity, purity, sterility or fill mass. See [[Research use only]]. == Chemistry and engineering == The native GLP-1(7–37) backbone was modified at three positions. The alanine at position 8 — the second residue of the mature hormone and the site of [[Dipeptidyl peptidase-4|DPP-4]] cleavage — was replaced with α-aminoisobutyric acid, a non-proteinogenic residue whose gem-dimethyl substitution prevents the protease from engaging the peptide.{{r|lau2015}} Lys34 was substituted with arginine so that Lys26 is the only lysine available for acylation, which removes a difficult di-acylated impurity from the synthesis rather than requiring it to be separated by [[Preparative HPLC purification|preparative chromatography]]. The acyl group itself is octadecanedioic acid — a C-18 ''diacid'' rather than the C-16 monoacid used in [[Liraglutide|liraglutide]] — attached through a γ-glutamate and two oligoethylene glycol units. The spacer does real work. It holds the peptide far enough from the albumin surface that the receptor-binding N-terminus remains accessible while the fatty acid is buried in the albumin binding site, so the albumin-bound fraction is a genuine reservoir rather than a sequestered pool. The terminal carboxylate of the diacid raises albumin affinity substantially over a monoacid.{{r|knudsen2019}} == Pharmacokinetics == Subcutaneous bioavailability is approximately 89% and is not materially affected by injection site. The terminal half-life of about 165 hours supports weekly dosing, with steady state reached after four to five weeks — which is why titration steps are held for four weeks and why a dose change is not fully expressed for a month.{{r|lau2015}} Elimination is by proteolysis and β-oxidation of the fatty-acid chain rather than by a single organ pathway, and neither renal nor hepatic impairment requires dose adjustment in the studied ranges. There is no clinically significant cytochrome-mediated interaction, though delayed [[Gastric emptying|gastric emptying]] can alter the absorption rate of concomitant oral drugs. The oral formulation is a different pharmacokinetic proposition entirely. Bioavailability is roughly 0.4–1%, achieved by co-formulation with the absorption enhancer sodium N-(8-(2-hydroxybenzoyl)amino)caprylate, and it is critically dependent on dosing in the fasting state with no more than 120 mL of water and a subsequent 30-minute fast. Deviation from those conditions changes exposure severalfold.{{r|knudsen2019}} == Clinical evidence == | Trial | Population | Dose | Primary result | |---|---|---|---| | SUSTAIN 6 | T2D, high CV risk | 0.5/1.0 mg weekly | MACE HR 0.74 (95% CI 0.58–0.95) | | STEP 1 | Obesity, no diabetes | 2.4 mg weekly | −14.9% vs −2.4% weight at 68 wk | | STEP 2 | Obesity with T2D | 2.4 mg weekly | −9.6% vs −3.4% weight at 68 wk | | SELECT | CVD, overweight, no T2D | 2.4 mg weekly | MACE HR 0.80 (95% CI 0.72–0.90) | | FLOW | T2D with CKD | 1.0 mg weekly | Kidney outcome HR 0.76 | The [[STEP trial programme|STEP]] programme established the obesity indication and the [[SUSTAIN trial programme|SUSTAIN]] programme the glycaemic one; [[SELECT trial|SELECT]] and [[FLOW trial|FLOW]] added the outcome indications.{{r|wilding2021,lincoff2023}} Results are means from trials that included intensive behavioural support and a structured escalation schedule. Individual response is widely distributed: in STEP 1 roughly a third of participants on active treatment lost 20% or more of body weight, and roughly one in seven lost less than 5%. The determinants of that spread are not established.{{r|wilding2021}} == Adverse effects == Gastrointestinal events predominate — nausea in roughly 40% of participants at the 2.4 mg dose, vomiting in about 24%, diarrhoea in about 30% — concentrated during escalation and declining with time at a stable dose. They accounted for most of the 7% discontinuation rate in STEP 1.{{r|wilding2021}} Cholelithiasis and cholecystitis occur more often than on placebo, a finding consistent across rapid weight loss by other means and probably not specific to the drug. Acute pancreatitis is rare and its causal relationship remains debated. The label carries a contraindication in personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, derived from rodent C-cell tumour findings whose human relevance is unestablished.{{r|lincoff2023}} Delayed gastric emptying has prompted revised preoperative fasting guidance; see [[Aspiration risk under anaesthesia]]. A fuller account of class-wide effects is at [[Adverse effects of GLP-1 receptor agonists]]. == Material sold outside licensed supply == Semaglutide is offered by a large number of research-chemical suppliers, generally as a lyophilised powder in 2 mg, 5 mg or 10 mg nominal fills. Such material is not the approved medicine and this wiki does not represent it as suitable for human use. Documentation quality varies widely. A [[Certificate of analysis|certificate]] reporting only an [[Area percent purity|area percent]] figure does not establish how much semaglutide a vial contains: without a [[Peptide content|peptide content]] determination and a water figure by [[Karl Fischer titration|Karl Fischer titration]], the mass of active substance cannot be calculated, and a nominal 5 mg vial may contain considerably less.{{r|usp1503}} [[Underfilling|Underfilling]] is documented in independently tested material. Acylated peptides are also analytically demanding. Their hydrophobicity requires a different gradient and often an elevated column temperature from that used for unmodified peptides, and a certificate that does not name its column and gradient cannot be assessed for adequacy. Community-submitted independent reports are collated at [[Third-party testing]]; they are self-selected and are not a survey.{{r|reports}} == References == {{reflist}} <ref name="lau2015">Lau J, Bloch P, Schäffer L, et al. "Discovery of the once-weekly glucagon-like peptide-1 analog semaglutide." ''Journal of Medicinal Chemistry'' 58(18):7370–7380 (2015). DOI:10.1021/acs.jmedchem.5b00726. PMID 26308095.</ref> <ref name="knudsen2019">Knudsen LB, Lau J. "The discovery and development of liraglutide and semaglutide." ''Frontiers in Endocrinology'' 10:155 (2019). PMID 31031702.</ref> <ref name="wilding2021">Wilding JPH, Batterham RL, Calanna S, et al. "Once-weekly semaglutide in adults with overweight or obesity." ''New England Journal of Medicine'' 384(11):989–1002 (2021). DOI:10.1056/NEJMoa2032183. PMID 33567185.</ref> <ref name="lincoff2023">Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. "Semaglutide and cardiovascular outcomes in obesity without diabetes." ''New England Journal of Medicine'' 389(24):2221–2232 (2023). PMID 37952131.</ref> <ref name="usp1503">United States Pharmacopeia, General Chapter <1503>, ''Quality Attributes of Synthetic Peptide Drug Substances''.</ref> <ref name="reports">PeptidePedia Wiki community test-report tally, 2024–2026 (self-reported; see [[Project:Sourcing_guidelines]]).</ref> == Further reading == * Mahapatra MK, Karuppasamy M, Sahoo BM. "Semaglutide, a glucagon like peptide-1 receptor agonist with cardiovascular benefits." ''Reviews in Endocrine and Metabolic Disorders'' 23(3):521–539 (2022). == External links == * [https://clinicaltrials.gov/study/NCT03548935 STEP 1 — NCT03548935] — Registry record for the pivotal obesity trial. * [https://clinicaltrials.gov/study/NCT03574597 SELECT — NCT03574597] — Registry record for the cardiovascular outcome trial. == See also == * [[GLP-1 receptor agonist]] * [[Tirzepatide]] * [[Liraglutide]] * [[Oral semaglutide]] * [[STEP trial programme]] * [[SELECT trial]] * [[Albumin binding half-life extension]] {{DEFAULTSORT:Semaglutide}} [[Category:GLP-1 receptor agonists]] [[Category:Peptide drugs]] [[Category:Pharmacokinetics]] [[Category:Articles describing unapproved compounds]]