• Ralf Elvert, Andreas W Herling, Martin Bossart, Tilo Weiss, Baohong Zhang, Pierre Wenski, Jörn Wandschneider, Sabrina Kleutsch, Uwe Butty, Aimo Kannt, Michael Wagner, Torsten Haack, Andreas Evers, Angela Dudda, Martin Lorenz, Stefanie Keil, and Philip J Larsen.
• Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany.
• Diabetes Obes Metab. 2018 Aug 1; 20 (8): 1836-1851.

AimWe performed acute and chronic studies in healthy and diet-induced obese animals using mouse-specific or monkey-specific dual GLP-1R/GCGR agonists to investigate their effects on food intake, body weight, blood glucose control and insulin secretion. The selective GLP-1R agonist liraglutide was used as comparator.MethodsThe mouse-specific dual agonist and liraglutide were tested in lean wild type, GLP-1R knockout and diet-induced obese mice at different doses. A chronic study was performed in DIO mice to investigate the effect on body weight, food consumption and total energy expenditure (TEE) in obese and diabetic monkeys with a focus on body weight and energy intake.ResultsThe mouse-specific dual agonist and liraglutide similarly affected glycaemic control. A higher loss in body weight was measured in dual agonist-treated obese mice. The dual agonist significantly enhanced plasma glucose excursion in overnight fed GLP-1R-/- mice, probably reflecting a potent GCGR agonist activity. It increased TEE and enhanced fat and carbohydrate oxidation, while liraglutide produced no effect on TEE. In obese and diabetic monkeys, treatment with the monkey-specific dual agonist reduced total energy intake to 60%-70% of baseline TEI during chronic treatment. A decrease in body weight and significant improvement in glucose tolerance was observed.ConclusionsIn DIO mice and non-human primates, dual agonists elicited robust glycaemic control, similar to the marketed GLP-1R agonist, while eliciting greater effects on body weight. Results from DIO mice suggest that the increase in TEE is caused not only by increased fat oxidation but also by an increase in carbohydrate oxidation.© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

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