Liraglutide (revision 6)

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It has been largely superseded in practice by weekly agents with larger effect sizes, but it remains clinically and historically important: the design that produced it is the direct ancestor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]

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.