Source of Exenatide

{{Infobox compound | name = Exenatide | subtitle = Clinical data | INN = exenatide | Class = [[GLP-1 receptor agonist]] | Origin = Synthetic exendin-4 | First approval = 2005 <!-- Properties --> | Residues = 39 | Molar mass = 4,186.6 g·mol⁻¹ | Half-life, immediate release = ≈2.4 h | Half-life, extended release = ≈2 weeks apparent }} '''Exenatide''' is a synthetic version of exendin-4, a 39-residue peptide isolated from the venom of the Gila monster, ''Heloderma suspectum''. It shares approximately 53% sequence identity with human [[Glucagon-like peptide-1]] and is a full agonist at the [[GLP-1 receptor]]. Approved in 2005, it was the first [[GLP-1 receptor agonist]] to reach the market.{{r|nielsen2004}} Its therapeutic relevance rests on an accident of sequence: exendin-4 carries glycine rather than alanine at position 2, so [[Dipeptidyl peptidase-4|DPP-4]] does not cleave it. No engineering was required to obtain protease resistance — the peptide is naturally resistant, and this is why a venom peptide became a diabetes drug.{{r|nielsen2004}} Two formulations were marketed: a twice-daily immediate-release product, and a once-weekly extended-release product in which the peptide is encapsulated in poly(lactide-co-glycolide) microspheres. Both have been largely displaced by later agents with greater efficacy and simpler pharmacokinetics.{{r|drucker2018}} == Origin and sequence == Exendin-4 was identified in Gila monster venom in the early 1990s and shown to bind the mammalian GLP-1 receptor with high affinity despite substantial sequence divergence. The peptide is not a lizard GLP-1 orthologue; lizards have their own GLP-1, and exendin-4 is a separate gene product expressed in the salivary gland.{{r|nielsen2004}} The C-terminal nine residues, absent from human GLP-1, form a tryptophan-cage motif that stabilises the helix and contributes to receptor affinity. This "Trp-cage" extension is the reason exendin-4 binds more tightly than native GLP-1 and is a frequently cited example of a natural product outperforming the endogenous ligand at its own receptor. Glycine at position 2 provides the DPP-4 resistance. The resulting half-life of about 2.4 hours is still short — renal clearance dominates once proteolysis is removed — which is why the immediate-release product required twice-daily injection. As a 39-residue synthetic peptide, exenatide is characterised by the ordinary battery for a synthetic peptide drug substance — chromatographic purity, [[Peptide content|peptide content]], water, counterion and related substances — rather than by the protein methods needed for a fusion construct.{{r|usp1503}} == The extended-release formulation == The weekly product suspends exenatide in biodegradable poly(lactide-co-glycolide) microspheres, which release peptide as the polymer hydrolyses. This is a formulation solution to a pharmacokinetic problem rather than a molecular one, and it behaves differently from a long-half-life molecule.{{r|drucker2018}} Concentrations rise slowly over six to seven weeks to a plateau, so the full effect of starting treatment is not seen for around two months, and concentrations decay over a comparable period after stopping. Neither the onset nor the offset can be accelerated. A distinctive injection-site nodule occurs in a substantial minority of recipients, attributable to the polymer matrix rather than to the peptide. The suspension also requires reconstitution and vigorous mixing immediately before injection, a preparation burden that later single-solution products removed. == Clinical position == Exenatide reduces glycated haemoglobin by roughly 0.8–1.5 percentage points depending on formulation and background therapy, with modest weight reduction. The EXSCEL cardiovascular outcome trial of the extended-release product reported a hazard ratio of 0.91 (95% CI 0.83–1.00) for the primary composite, narrowly failing conventional significance for superiority while establishing non-inferiority.{{r|holman2017}} That result is worth noting whenever a cardiovascular benefit is described as a class effect: within the same class, [[LEADER trial|LEADER]] and [[SELECT trial|SELECT]] were positive, EXSCEL was neutral, and the outcome trial of lixisenatide was neutral. Whether the differences reflect molecule, dose, population or duration is unresolved.{{r|holman2017}} Exenatide retains some use where a short-acting agent is specifically wanted, since its effect on [[Gastric emptying|gastric emptying]] does not attenuate in the way that a continuously present long-acting agonist's does. == References == {{reflist}} <ref name="nielsen2004">Nielsen LL, Young AA, Parkes DG. "Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes." ''Regulatory Peptides'' 117(2):77–88 (2004). PMID 14700743.</ref> <ref name="drucker2018">Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." ''Cell Metabolism'' 27(4):740–756 (2018). PMID 29617641.</ref> <ref name="holman2017">Holman RR, Bethel MA, Mentz RJ, et al. "Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes." ''New England Journal of Medicine'' 377(13):1228–1239 (2017). DOI:10.1056/NEJMoa1612917. PMID 28910237.</ref> <ref name="usp1503">United States Pharmacopeia, General Chapter <1503>, ''Quality Attributes of Synthetic Peptide Drug Substances''.</ref> == See also == * [[GLP-1 receptor agonist]] * [[Lixisenatide]] * [[Liraglutide]] * [[Dipeptidyl peptidase-4]] * [[Gastric emptying]] {{DEFAULTSORT:Exenatide}} [[Category:GLP-1 receptor agonists]] [[Category:Peptide drugs]] [[Category:Pharmacokinetics]]