2551-P: Survodutide Improves Stroke Outcome in Obese/Type 2 Diabetic Mice

Introduction and Objective: Obesity and type 2 diabetes (T2D) are closely linked comorbidities that elevate stroke risk and worsen stroke outcomes. Thus, the continuously expanding obesity/T2D prevalence results in a large population in need of therapies to reduce stroke-related disability. Glucagon-like peptide receptor (GLP-1R) agonists improve stroke outcome in obese/T2D animal models through weight loss. However, whether new, more efficacious dual glucagon/GLP-1R agonists can potentiate this effect is unknown. We addressed this question experimentally using survodutide, a long-acting dual glucagon/GLP-1R agonist, currently in phase 3 trials for obesity and metabolic dysfunction-associated steatohepatitis (MASH). Methods: Obesity/T2D (body weight > 50 grams, fasting glucose > 7 mmol/L, insulin resistance) was induced in C57bl6/j mice by 6 months of high fat diet. Then, mice received daily 15 nmol/kg s.c. survodutide or vehicle for 4 weeks followed by middle cerebral artery occlusion to induce stroke. A pair-fed group with caloric intake matched to survodutide was included to distinguish improved stroke outcome mediated by GLP-1R-driven anorexia from that driven by glucagon-induced effects. Stroke outcome was evaluated via weekly motor/sensory tests for 4 weeks and via measuring infarct volume. Data were analyzed by two-tailed t-test or one-way ANOVA followed by Tukey’s post-hoc test. Results: Survodutide induced ≈30% weight loss, resolved hyperglycemia (4.5-6 mmol/L) and improved insulin sensitivity (p<0.0001 vs. vehicle and vs. pair-fed). Survodutide significantly improved stroke outcome via food-intake independent effects by enhancing paretic forepaw grip strength (p<0.0001 vs. vehicle, p = 0.003 vs. pair-fed) and lateralized sensorimotor integration (p=0.0014 vs. vehicle, p = 0.0015 vs. pair-fed), without affecting stroke volume. Conclusion: We showed that survodutide-mediated weight loss markedly improves stroke outcome in obese/T2D mice, suggesting that it can add secondary cardiovascular benefit when used to treat people living with obesity and MASH. Disclosure E. Vercalsteren: None. T. Klein: Employee; Current; Boehringer Ingelheim International GmbH. C. Patrone: None. V. Darsalia: Research Support; Current; Boehringer Ingelheim International GmbH. Funding Boehringer Ingelheim