Source of Liraglutide

{{Infobox compound | name = Liraglutide | subtitle = Clinical data | image = peptide-chain.svg | INN = liraglutide | Class = [[GLP-1 receptor agonist]] | Route = Subcutaneous, daily | First approval = 2009 (type 2 diabetes) <!-- Identifiers --> | CAS Number = 204656-20-2 | Molar mass = 3,751.20 g·mol⁻¹ | Residues = 31 <!-- Pharmacokinetics --> | Half-life = ≈13 h | Bioavailability, SC = ≈55% | Albumin binding = >98% }} '''Liraglutide''' is an acylated analogue of [[Glucagon-like peptide-1]] and was the first [[GLP-1 receptor agonist]] to use [[Albumin binding half-life extension|albumin binding]] for half-life extension. A C-16 palmitic acid is attached to Lys26 through a γ-glutamate spacer, and Lys34 is substituted with arginine so that acylation occurs at a single site.{{r|knudsen2019}} The resulting half-life of about thirteen hours supports once-daily subcutaneous dosing. Liraglutide was approved for type 2 diabetes in 2009 and, at a higher dose, for weight management in 2014; the LEADER trial subsequently established cardiovascular benefit in type 2 diabetes with high cardiovascular risk.{{r|marso2016}} It has been largely superseded in practice by weekly agents with larger effect sizes, but it remains clinically and historically important: the design that produced it is the direct ancestor of [[Semaglutide|semaglutide]], and the difference between the two is a compact illustration of what a change of acyl chain and spacer is worth.{{r|lau2015}} == Chemistry == Liraglutide differs from native GLP-1(7–37) in two respects: Lys34 is replaced by arginine, and a palmitoyl group is attached to Lys26 through a γ-glutamate linker. The peptide backbone otherwise retains the native sequence, including the alanine at position 8 that [[Dipeptidyl peptidase-4|DPP-4]] cleaves.{{r|knudsen2019}} That last point is important and is often misstated. Liraglutide is not DPP-4 resistant by substitution; its resistance is conferred indirectly, because the albumin-bound fraction is sterically inaccessible to the protease and only the small free fraction is exposed. The molecule also self-associates into heptamers in the pharmaceutical formulation, which slows absorption from the subcutaneous depot and contributes as much to the duration of action as albumin binding does.{{r|lau2015}} The comparison with [[Semaglutide|semaglutide]] is instructive: substituting the C-16 monoacid for a C-18 diacid, lengthening the spacer with two OEG units, and adding Aib at position 8 together take the half-life from about thirteen hours to about 165 hours. == Clinical evidence == In type 2 diabetes, liraglutide 1.8 mg daily reduces glycated haemoglobin by roughly 1.1–1.5 percentage points. At 3.0 mg daily for weight management, mean weight loss in the pivotal trial was about 8% against about 2.6% for placebo at 56 weeks — substantially less than the weekly agents that followed.{{r|marso2016}} The [[LEADER trial|LEADER]] trial randomised 9,340 people with type 2 diabetes and high cardiovascular risk and reported a hazard ratio of 0.87 (95% CI 0.78–0.97) for the primary composite cardiovascular outcome, with a reduction in cardiovascular death. It was among the first trials to establish that an incretin therapy could reduce cardiovascular events rather than merely not increase them.{{r|marso2016}} Liraglutide is also approved for use in adolescents with type 2 diabetes and, in some jurisdictions, for adolescent obesity — a broader paediatric position than most agents in the class hold, reflecting its longer regulatory history. == Practical differences from weekly agents == Daily dosing changes the practical profile in ways that are not captured by efficacy figures. Steady state is reached in two to three days rather than four to five weeks, so a dose change is expressed almost immediately and titration can proceed weekly rather than monthly. A missed dose matters less: the next scheduled dose simply resumes the schedule, whereas a missed weekly dose leaves a longer gap. See [[Missed dose]]. Conversely, the peak-to-trough ratio within a dosing interval is higher than for a weekly agent, and daily injection is a larger practical burden. Discontinuation rates in head-to-head comparisons have favoured weekly agents.{{r|knudsen2019}} For anyone examining a [[Certificate of analysis|certificate]] on liraglutide, the analytical caution is the same as for other acylated peptides: hydrophobicity requires a strong organic gradient, and the self-associated forms mean that size-based methods can report an apparent high-molecular-weight species that is a reversible oligomer rather than an aggregate. See [[Peptide aggregation]].{{r|usp1503}} == References == {{reflist}} <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="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). PMID 26308095.</ref> <ref name="marso2016">Marso SP, Daniels GH, Brown-Frandsen K, et al. "Liraglutide and cardiovascular outcomes in type 2 diabetes." ''New England Journal of Medicine'' 375(4):311–322 (2016). DOI:10.1056/NEJMoa1603827. PMID 27295427.</ref> <ref name="usp1503">United States Pharmacopeia, General Chapter <1503>, ''Quality Attributes of Synthetic Peptide Drug Substances''.</ref> == External links == * [https://clinicaltrials.gov/study/NCT01179048 LEADER — NCT01179048] — Registry record for the cardiovascular outcome trial. == See also == * [[GLP-1 receptor agonist]] * [[Semaglutide]] * [[Albumin binding half-life extension]] * [[LEADER trial]] * [[Dulaglutide]] {{DEFAULTSORT:Liraglutide}} [[Category:GLP-1 receptor agonists]] [[Category:Peptide drugs]] [[Category:Pharmacokinetics]]