Liraglutide (revision 15)
Old revision·22:43, 12 Feb 2025·LotTraceLuka
| LiraglutideClinical data | |
|---|---|
| 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% |
| Compound infobox · conventions | |
Liraglutide is an acylated analogue of Glucagon-like peptide-1 and was the first GLP-1 receptor agonist to use 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.[1]
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.[2]
It has been largely superseded in practice by weekly agents with larger effect sizes, but it remains clinically and historically important: the design that produced it is the direct ancestor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, and the difference between the two is a compact illustration of what a change of acyl chain and spacer is worth.[3]
Chemistry
[edit]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 DPP-4 cleaves.[1]
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.[3]
The comparison with 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
[edit]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.[2]
The 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.[2]
See also
References
- ^ a b Knudsen LB, Lau J. "The discovery and development of liraglutide and semaglutide." Frontiers in Endocrinology 10:155 (2019). PMID 31031702.
- ^ a b c 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.
- ^ a b 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.