Dual agonism of glucagon-like peptide-1 receptor and glucagon receptor (GLP-1 R/GCGR) was shown to reduce body weight. Species-specific dual GLP-1 R/GCGR agonist peptides (SSDA), structurally based on exendin-4 and carrying a fatty acid side-chain for half-life extension, or the selective GLP-1 R agonist liraglutide (lira) were administered to diet-induced obese (DIO) mice twice daily for 32 days, and to DIO and diabetic cynomolgus monkeys once daily for 43 days. Potencies of the SSDA and lira on mouse and monkey GLP-1 receptors were in the single-digit picomolar range. Body weight change was greater with SSDA than with lira in mice (-21.1 ± 2.1% vs. -12.9 ± 1.4%) and monkeys (-8.2 ± 1.2%; p<0.001 vs. -5.1 ± 1.1%; p<0.001; Figure). Indirect calorimetry in mice showed increased total energy expenditure (TEE) in those treated with SSDA, caused not only by increased fat oxidation but also by increased oxidation of carbohydrates. Lira significantly increased TEE, but significantly less than SSDA. These data support the mechanistic view that weight loss with SSDA does not result exclusively from reduced food intake but also from increased energy expenditure induced by GCGR activity. In murine and primate models, dual GLP-1 R/GCGR agonism with SSDA led to greater body weight loss than GLP-1 R alone. This represents a novel dual mechanism of action with potential for the treatment of obesity.

R. Elvert: Employee; Self; Sanofi. M. Bossart: Employee; Self; Sanofi. B. Zhang: None. A. Kannt: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. M. Wagner: Employee; Self; Sanofi. T. Haack: Employee; Self; Sanofi-Aventis Deutschland GmbH. A. Evers: Employee; Self; Sanofi. A. Dudda: Employee; Self; Sanofi. M. Lorenz: None. S. Keil: Employee; Self; Sanofi. P.J. Larsen: Employee; Self; Sanofi.

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