Semaglutide (revision 10)

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.