From obesity and sedentary lifestyle to energetic and metabolic failure: empagliflozin and semaglutide reverse mitochondrial and metabolic dysfunction in experimental HFpEF

Background HFpEF accounts for nearly half of all heart failure cases and carries substantial morbidity and mortality. Beyond hemodynamic abnormalities, it is now increasingly recognized as a systemic metabolic disorder driven by obesity, insulin resistance, and chronic low-grade inflammation. Mitochondrial dysfunction plays a central role, leading to impaired myocardial energetics, oxidative stress, and unmet energy demands. This metabolic shift promotes microvascular dysfunction and myocardial stiffness. Consequently, metabolic modulation has emerged as a therapeutic priority. While SGLT-2 inhibitors are established in guideline-directed therapy, GLP-1 receptor agonists represent a promising class not yet formally incorporated into HFpEF guidelines. Methods HFpEF was induced in mice through a high-fat diet and mimic sedentary lifestyle to mirror the metabolic stressors observed in human patients. We investigated a 3-month treatment regimen comparing the SGLT-2 inhibitor Empagliflozin (10 mg/kg) and the GLP-1 analogue Semaglutide (120 μg/kg). Cardiac function, structural remodeling, and body composition were assessed via echocardiography, CT imaging, and NT-proBNP levels. Underlying mitochondrial network changes were analyzed through Western blot (biogenesis, fusion, and mitophagy markers) and enzyme activity assays. Results Both interventions effectively reversed the HFpEF phenotype. We observed a significant reduction in abdominal and subcutaneous fat volumes, leading to direct cardiac relief. The pathological increase in left ventricular mass in the HFpEF group (LV Mass: 160.62±5.27 mg) was attenuated by both SGLT-2i (145.76±5.71 mg,) and GLP-1RA (134.06±3.79 mg, P<0.01). This structural improvement reversed diastolic stiffness, as the E/e' ratio normalized from 32.45±2.1 to 29.65±1.12 (SGLT-2I) and 29.24±2,16 (GLP-1RA), alongside a tendentious reduction in NT-proBNP levels. This recovery was driven by a restoration of the mitochondrial network. PGC1-α expression, which was suppressed to 44.7% of control levels in the HFpEF group, was significantly reignited to 160.7% by SGLT2i (vs. HFpEF P<0.001) and 138.3% by GLP-1RA (vs. HFpEF P<0.01) relative to controls. Beyond biogenesis, both therapies enhanced mitochondrial quality by restoring fusion machinery (MFN2, OPA1) and boosting Citrate synthase (P<0.05) and NADH-cytochrome c oxidoreductase activities SGLT2I vs HFpEF P<0.05). Ultrastructural analysis confirms the restoration of healthy mitochondrial architecture. Conclusion Our findings demonstrate that the clinical benefits of SGLT-2i and GLP-1RA in HFpEF are fundamentally linked to the repair of the heart's mitochondria by reducing systemic metabolic stress and directly fixing the energetic ‘misfiring’ at the core of the disease. These results explain the mechanism behind the effects of the drugs providing evidence for broader clinical integration of metabolic-targeted interventions.