Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia.

Journal Article (Journal Article)

There is great interest in identifying a glucagon-like peptide-1 (GLP-1)-based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due to its thermogenic and insulin-sensitizing effects. Here, we describe the development of a biologic that fuses GLP-1 to FGF21 with an elastin-like polypeptide linker that acts as a sustained release module with zero-order drug release. We show that once-weekly dual-agonist treatment of diabetic mice results in potent weight-reducing effects and enhanced glycemic control that are not observed with either agonist alone. Furthermore, the dual-agonist formulation has superior efficacy compared to a GLP-1/FGF21 mixture, demonstrating the utility of combining two structurally distinct peptides into one multifunctional molecule. We anticipate that these results will spur further investigation into GLP-1/FGF21 multiagonism for the treatment of metabolic disease.

Full Text

Duke Authors

Cited Authors

  • Gilroy, CA; Capozzi, ME; Varanko, AK; Tong, J; D'Alessio, DA; Campbell, JE; Chilkoti, A

Published Date

  • August 2020

Published In

Volume / Issue

  • 6 / 35

Start / End Page

  • eaaz9890 -

PubMed ID

  • 32923621

Pubmed Central ID

  • PMC7449677

Electronic International Standard Serial Number (EISSN)

  • 2375-2548

Digital Object Identifier (DOI)

  • 10.1126/sciadv.aaz9890

Language

  • eng

Conference Location

  • United States