Pharmacodynamics
Studies to date suggest liraglutide improves control of blood glucose.
It reduces meal-related hyperglycemia (for 12 hours after administration) by increasing insulin secretion, delaying gastric emptying, and suppressing prandial glucagon secretion.
Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1) agonist, with a 97% amino acid sequence identity to endogenous human GLP-1(7-37). GLP-1(7-37) represents less than 20% of total circulating endogenous GLP-1. Like GLP-1(7-37), liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. Liraglutide increases intracellular cyclic AMP (cAMP), leading to insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Liraglutide also decreases glucagon secretion in a glucose-dependent manner. The mechanism of blood glucose lowering also involves a delay in gastric emptying. GLP-1(7-37) has a half-life of 1.5–2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once daily administration, is a result of self-association that delays absorption, plasma protein binding and stability against metabolic degradation by DPP-IV and NEP.
Liraglutide may have advantages over current therapies:
- It acts in a glucose-dependent manner, meaning it will stimulate insulin secretion only when blood glucose levels are higher than normal. Consequently, it shows negligible risk of hypoglycemia.
- It has the potential for inhibiting apoptosis and stimulating regeneration of beta cells (seen in animal studies).
- It decreases appetite and maintains body weight, as shown in a head-to-head study versus glimepiride.
- It lowers blood triglyceride levels.
- It has only mild and transient side effects, mainly gastrointestinal.
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