• Brian Finan, Tao Ma, Nickki Ottaway, Timo D Müller, Kirk M Habegger, Kristy M Heppner, Henriette Kirchner, Jenna Holland, Jazzminn Hembree, Christine Raver, Sarah H Lockie, David L Smiley, Vasily Gelfanov, Bin Yang, Susanna Hofmann, Dennis Bruemmer, Daniel J Drucker, Paul T Pfluger, Diego Perez-Tilve, Jaswant Gidda, Louis Vignati, Lianshan Zhang, Jonathan B Hauptman, Michele Lau, Mathieu Brecheisen, Sabine Uhles, William Riboulet, Emmanuelle Hainaut, Elena Sebokova, Karin Conde-Knape, Anish Konkar, Richard D DiMarchi, and Matthias H Tschöp.
• Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg 85764, Germany.
• Sci Transl Med. 2013 Oct 30;5(209):209ra151.

AbstractWe report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.

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