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3 Evolution of GLP-1-based therapeutics 3.1 First-generation GLP-1RAs The development of GLP-1 receptor agonists stemmed from the significant finding that natural GLP-1 had an exceptionally short half-life of about 1.5 to 5 min, due to its rapid degradation by the enzyme DPP-4 (Campbell and Drucker 2013) (Fig