118-OR: The Apelin Receptor Agonist Azelaprag Increases Weight Loss in Diet-Induced Obese Mice on Incretin Agonists and Restores Body Composition and Muscle Function to That of Lean Controls

Introduction & Objective: Incretin receptor agonists have emerged as leading treatments for obesity. Despite the efficacy of these drugs, they can negatively impact body composition, raising interest in complementary mechanisms. In a Phase 1b trial, our oral apelin receptor agonist azelaprag preserved muscle mass, quality, and protein synthesis during bed rest and shifted the plasma proteome into a state associated with endurance exercise, including higher basal metabolic rate and VO2 max. Accordingly, we tested whether azelaprag could improve body composition and muscle function in mice on incretin agonist therapy.

Methods: High fat diet-induced obese (DIO) mice were treated for 20 days with incretin agonists, with or without azelaprag. Food and water intake, serum glucose and protein levels, body composition (via EchoMRI), and grid hang latency were measured.

Results: DIO mice on tirzepatide (10 nmol/kg) lost 16% of body weight, while mice on tirzepatide+azelaprag (1.1 g/L) lost 39%, bringing body weight in range of lean controls. Combined treatment also improved body composition: DIO/tirzepatide mice had lean mass 60% of body weight, vs. 69% for DIO/tirzepatide+azelaprag and 70% for lean controls. Grid hang assays showed that azelaprag fully restored muscle function to that of lean controls (latency, 79 sec): DIO/tirzepatide, 38 sec; DIO/tirzepatide+azelaprag, 86 sec. Similar results were obtained with semaglutide.

Conclusion: Addition of azelaprag to incretin regimens increased weight loss while restoring body composition and muscle function relative to monotherapy. In the clinic, combination therapy has the potential to amplify healthy weight loss, enabling next-generation oral incretin drugs to achieve efficacy comparable to current injectables with improved tolerability.