Emerging opportunities for the treatment of metabolic diseases: Glucagon-like peptide-1 based multi-agonists

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…These medicines include exenatide (Byetta; AstraZeneca, Cambridge, UK), lixisenatide (Lyxumia; Sanofi, Paris, France), liraglutide (Victoza; Novo Nordisk, Copenhagen, Denmark), dulaglutide (Trulicity; Eli Lilly & Co., Indianapolis, IN), and albiglutide (Tanzeum; GlaskoSmithKline, Middlesex, UK). Semaglutide (Novo Nordisk, Copenhagen, Denmark) is a late-stage, longacting structural refinement related to liraglutide that when coformulated with suitable absorption enhancers is reported to be active in oral application (Gotfredsen et al, 2014;Finan et al, 2015a;Kapitza et al, 2015;Ahren et al, 2017;Blundell et al, 2017).…”

“…2). Lixisenatide when compared with exenatide demonstrates a slightly enhanced potency to activate the GLP-1 receptor and a near doubling in half-life of 4 hours (Finan et al, 2015a). Unlike the first two GLP-1 analogs, Liraglutide (Novo Nordisk, Copenhagen, Denmark) is an analog based upon the native GLP-1 sequence, but with the exception that the lysine at residue 28 is replaced with arginine (Fig.…”

Renaissance of leptin for obesity therapy

“…GLP-1 receptor/glucagon receptor co-agonism Recent progress in biotechnology has helped facilitate the generation of a series of single-molecule compounds that combine and integrate different modes of pharmacological action [58]. In 2009, this strategy was used to show that a molecule with balanced action at the glucagon receptor and the GLP-1 receptor (GLP-1R), synergistically orchestrates distinct biological pathways to exhibit a coordinated effect on energy metabolism in rodents [59].…”

“…Importantly, and in contrast to treatment with exendin-4 and FGF21 [15], the GLP-1R/glucagon receptor co-agonist restored leptin responsiveness in DIO mice chronically exposed to a high-fat, high sucrose diet. While it remains to be uncovered how exactly the dual agonist activating glucagon-and GLP-1 receptors alleviates leptin unresponsiveness, the antiobesity properties of concerted GLP-1R and glucagon receptor co-agonism translates to humans [61,62], and several pharmaceutical companies are now pursuing GLP/glucagon co-agonism for the treatment of obesity [58].…”

Endocrine control of energy homeostasis

“…In this regard, Khandekar et al review the potentials of the anorexigenic factor, pancreatic polypeptide, as a target for the treatment of obesity, as well as the mechanisms involved in its effects (Khandekar et al, 2015). During the last years, several reports have demonstrated that glucagon-like peptide-1 based multiagonists are promising tools to treat obesity and type 2 diabetes, and the roles of these newly designed molecules is summarized by Finan et al (Finan et al, 2015).…”