Abstract Body (Do not enter title and authors here): Background: Heart failure with preserved ejection fraction (HFpEF) is a complex, multisystem disorder characterized by diastolic dysfunction and exercise intolerance. Despite its increasing prevalence and associated morbidity and mortality, current treatments primarily manage symptoms without significantly improving mortality. HFpEF is strongly linked to cardiometabolic risk factors, including obesity, hypertension, and diabetes. Semaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist approved for obesity and diabetes, has shown promising effects in HFpEF patients, but it is unclear whether these benefits are solely due to weight loss.
Hypothesis: Semaglutide exerts beneficial effects in cardiometabolic HFpEF through mechanisms beyond central actions related to appetite suppression and weight loss.
Methods: Male ZSF1 obese rats, a model of HFpEF possessing genetic mutations that drive obesity (LEPR) and hypertension (SHHF-Mcc-/fa ^cp) were treated with either vehicle (saline) or semaglutide (30 nmol/kg, subcutaneously, twice weekly) for 16 weeks, starting at 10 weeks of age (n=6/group). Echocardiography, exercise performance, invasive hemodynamics, vascular reactivity, and circulating oxidative stress markers were assessed.
Results: Semaglutide transiently reduced food intake but failed to induce weight loss as the ZSF1 Ob rats treated with semaglutide continued to gain weight for 16 weeks. However, semaglutide significantly alleviated the severity of HFpEF as evidenced by reduced blood glucose levels (131 ± 4 vs. 328 ± 19 mg/dl, p < 0.0001), increased exercise distance, improved diastolic function, and decreased left ventricular end-diastolic pressure, enhanced endothelium-dependent vascular relaxation, and decreased systemic oxidative stress.
Conclusion: Semaglutide exerts beneficial effects in an animal model of obesity-driven HFpEF, independent of weight loss. These findings suggest that semaglutide may have pleiotropic actions beyond its metabolic effects, making it a promising therapeutic option for HFpEF, including patients who are resistant to weight loss.