PT  - JOURNAL ARTICLE
AU  - Gilroy, C. A.
AU  - Capozzi, M. E.
AU  - Varanko, A. K.
AU  - Tong, J.
AU  - D'Alessio, D. A.
AU  - Campbell, J. E.
AU  - Chilkoti, A.
TI  - Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia
AID  - 10.1126/sciadv.aaz9890
DP  - 2020 Aug 01
TA  - Science Advances
PG  - eaaz9890
VI  - 6
IP  - 35
4099  - http://advances.sciencemag.org/content/6/35/eaaz9890.short
4100  - http://advances.sciencemag.org/content/6/35/eaaz9890.full
SO  - Sci Adv2020 Aug 01; 6
AB  - 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.