Semaglutide (revision 24)

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, and an arginine substitution at position 34 leaves a single site available for acylation.^[1]

It is approved for type 2 diabetes, for chronic weight management, and — following the 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.^[2]

In the 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.^[3] 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.

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 DPP-4 cleavage — was replaced with α-aminoisobutyric acid, a non-proteinogenic residue whose gem-dimethyl substitution prevents the protease from engaging the peptide.^[1]

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 chromatography. The acyl group itself is octadecanedioic acid — a C-18 diacid rather than the C-16 monoacid used in 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.^[4]

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.^[1]

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 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.^[4]

The STEP programme established the obesity indication and the SUSTAIN programme the glycaemic one; SELECT and FLOW added the outcome indications.^[3][2]

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.^[3]

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.^[3]

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.^[2]

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.

• GLP-1 receptor agonist
• Tirzepatide
• Liraglutide
• Oral semaglutide
• STEP trial programme
• SELECT trial
• Albumin binding half-life extension

• 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).