The Discovery and Development of Liraglutide and Semaglutide

We describe one such approach, albumin binding, and explain how it was applied in the development of the human GLP-1 analog liraglutide once daily and, subsequently, semaglutide once weekly. The pharmacology of these two long-acting GLP-1 analogs, in terms of improving glycemic control, reducing body weight and decreasing cardiovascular (CV) risk, is also reviewed, together with some novel biology. In addition, we describe the importance of accurate target (GLP-1 receptor) tissue expression analysis. Now an established class of agents, GLP-1-based therapies represent a significant advance in the treatment of T2D. All currently available GLP-1 receptor agonists (GLP-1RAs) are, however, injectable. Ongoing efforts to advance this class of agents include, therefore, attempts to develop an oral formulation. In the final section of this article, we describe an oral formulation of semaglutide that is currently in phase 3 clinical development for the treatment of T2D, as well as summarizing other therapeutic applications—beyond T2D—of liraglutide and semaglutide. Albumin Binding as a Concept for Creating Long-Acting GLP-1 Analogs Human serum albumin (HSA) is among the most stable and abundant of plasma proteins. It comprises three homologous domains assembled into a heart-shaped protein. Approximately 10–15 g is produced by the liver daily, which—owing to its long half-life of several weeks—results in an HSA plasma concentration of 35 ...
Source: Frontiers in Endocrinology - Category: Endocrinology Source Type: research