Glucagon-like Peptide-1 (GLP-1)-Based Therapeutics: Current Status and Future Opportunities Beyond Type 2 Diabetes

Glucagon-like peptide-1 (GLP-1) is secreted by intestinal L-cells following food intake, and plays an important role in glucose homeostasis due to its stimulation of glucose-dependent insulin secretion. Further, GLP-1 is also associated with protective effects on pancreatic β-cells and the cardiovascular system, reduced appetite, and weight loss, making GLP-1 derivatives an exciting treatment for type 2 diabetes and obesity. Despite these benefits, wild-type GLP-1 exhibits a short circulation time, due to its poor metabolic stability and rapid renal clearance, and needs to be administered by injection, making it a poor therapeutic agent. Many strategies have been employed to improve the circulation time of GLP-1 (e.g. mutations, unnatural amino acids, depot formulations, use of exendin-4 sequences and fusions with high molecular weight proteins or polymers), with its therapeutic utility further improved by adding agonist activity for gastric inhibitory peptide and glucagon receptors. This minireview focuses on strategies that have been used to improve the pharmacokinetics of GLP-1 and provides an overview of GLP-1 based therapeutics in the pipeline