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Aims Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like glucagon-like peptide receptor agonist (GLP-1 RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide (Lira) and the SGLT2i dapagliflozin (Dapa). Methods and results Aged (18–22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high-fat diet (HFD) for 12 weeks. After 8 weeks HFD, angiotensin II (ANGII), was administered for 4 weeks via osmotic mini pumps. HFD + ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling, and metabolic dysregulation with inflammation. The multiple hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement, lung congestion, and elevated blood pressures. Treatment with Lira attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapa treatment improved glucose handling, but had mild effects on the HFpEF phenotype. Conclusions We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and the development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for the treatment of HFpEF. [ABSTRACT FROM AUTHOR]