Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist
Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose -dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide ago...
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creator | Bossart, Martin Wagner, Michael Elvert, Ralf Evers, Andreas Hu, Thomas Kloeckener, Tim Lorenz, Katrin Moessinger, Christine Eriksson, Olof Velikyan, Irina Pierrou, Stefan Johansson, Lars Dietert, Gabriele Dietz-Baum, Yasmin Kissner, Thomas Nowotny, Irene Einig, Christine Jan, Christelle Rharbaoui, Faiza Gassenhuber, Johann Prochnow, Hans-Peter Agueusop, Inoncent Porksen, Niels Smith, William B. Nitsche, Almut Konkar, Anish |
description | Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose -dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism. |
doi_str_mv | 10.1016/j.cmet.2021.12.005 |
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title | Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist |
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