Journal
SCIENCE ADVANCES
Volume 6, Issue 35, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aaz9890
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Funding
- Duke MEDx, a Duke University program
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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.
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