Liraglutide: difference between revisions
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| 11 | 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}} | 11 | 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}} |
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| + | 13 | It has been largely superseded in practice by weekly agents with larger effect sizes, but it remains clinically and historically important: the design that produced it is the direct ancestor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}} | |
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| 13 | == Chemistry == | 15 | == Chemistry == |
| 14 | 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}} | 16 | 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}} |
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| 16 | 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}} | 18 | 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}} |
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| + | 20 | 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. | |
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| 18 | == References == | 22 | == References == |