“Let's Stay Together”; GIP and GLP-1 dual agonism in the treatment of metabolic disease

Richard D. DiMarchi

In this issue of Molecular Metabolism, Coskun and co-authors report the discovery and biological assessment of a novel peptide of sustained duration of action that displays agonism at the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptors. This work presents the characterization of LY3298176 in preclinical studies through early phase clinical evaluation in Type 2 Diabetes Mellitus (T2D). These results represent the foundation upon which the more advanced 26-week clinical study recently reported in Lancet is based. The peptide is structurally derived from the N-terminal fragment of native GIP with alterations that mirror similar changes in previously reported peptides that lead to balanced full agonism at both incretin receptors and pharmacokinetics suitable for once weekly clinical administration. These include an identical substitution at the second position to prevent DPP4 proteolysis and lipidation as observed in semaglutide but with a slightly longer fatty acid. The peptide is C-terminally extended with a Cex-sequence derived from exendin and a mid-sequence non-native amino acid substitution three residues prior to what has been previously reported to result in dual and triple agonism.