Elucidating the Benefit of Pump-Delivered Subcutaneous GLP-1R Agonist—Exploratory Study in the DIO Mouse

Introduction and Objective: Recent advances in GLP-1R agonist (GLP-1Ra) therapies have transformed diabetes and obesity management. Yet, gastrointestinal side effects and rigid weekly dosing regimens hinder patient adherence, leading to suboptimal outcomes in a real-world setting. We evaluated pump-delivered GLP-1Ra as an alternate treatment approach. Methods: We conducted a 28d study of continuous pump-delivered subcutaneous (SC) short-acting GLP-1Ra (exenatide) in diet-induced obese (DIO) mice (n=60; post-21-week high-fat diet, 60% kcal). We included two control arms: daily SC dosing of vehicle (VEH) or semaglutide (SEMA, 20 nM/kg/day) and three exenatide arms: low basal (LOB, 50 µg/kg/day), low basal + bolus (LBB, basal 30 + bolus 20 µg/kg/day), and high basal + bolus (HBB, basal 50 + bolus 20 µg/kg/day). Basal dosing continued throughout, while bolus and control treatments were given daily at the feeding cycle start. Body weight and food intake were monitored daily, with an oral glucose tolerance test (OGTT) on day 27. Standard t-test analyses were performed. Results: SEMA reduced food intake during initiation (0-5d) to 42% of VEH (p<0.01; SEMA 0.86±0.13, VEH 2.04±0.17 g/day), with intermediate reductions in exenatide arms (LOB 1.32±0.20, LBB 1.50±0.21, HBB 1.21±0.19 g/day). By day 28, SEMA (24.5±1.4%) and HBB (17.3±1.9%) achieved the greatest body weight reductions (p<0.01 vs VEH 4.7±1.2%; LOB 13.9±1.7%, LBB 13.7±1.3%). HBB and LBB attenuated plasma glucose excursion during OGTT (p<0.05; at 60min HBB 167±7, LBB 169±8, VEH 196±8 mg/dl). Conclusion: Pump-delivered GLP-1Ra exhibits favorable body weight and glycemic effects in DIO mice, with a less abrupt initial suppression of food intake than SEMA. Bolus GLP-1Ra also reduced post-caloric challenge glycemic excursion. GLP-1Ra delivered by a basal-bolus pump may represent an alternative for patients seeking GLP-1Ra clinical benefit with greater dosing flexibility. Further clinical evaluation is warranted. Disclosure: L. Thisted: None. M. Feigh: None. D.G. Maggs: None. Funding: Modular Medical