Mechanisms and clinical research progress of SGLT2i in improving exercise tolerance in patients with heart failure

Exercise intolerance is a primary clinical manifestation of heart failure (HF) that significantly reduces patients’ quality of life and independently predicts adverse prognosis. Despite reducing mortality and hospitalization, guideline-directed medical therapy has limited effects on exercise capacity. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have consistently reduced HF hospitalization and improved patient-reported symptoms and health status, as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ), whereas their effects on objective exercise capacity, such as 6-minute walk distance (6MWD) and peak oxygen consumption (peak VO 2 ), have been less consistent across trials, with pooled effects below commonly cited minimal clinically important difference thresholds. This review compares the evidence maturity of the hemodynamic and peripheral skeletal muscle pathways through which SGLT2i may enhance exercise tolerance. Regarding hemodynamics, the reduction in exercise-induced pulmonary capillary wedge pressure (PCWP) and may improve right ventricular–pulmonary artery (RV-PA) coupling provide a plausible mechanism, although direct evidence is mainly from HFpEF and mediation has not been demonstrated across the broader HF population. Regarding skeletal muscle, animal and human biopsy studies suggest potential modulation of AMPK signaling and reduced myofiber atrophy, but the independent contribution remains unvalidated. These differences in evidence maturity highlight the need to distinguish mechanistic findings, patient-reported health status, and objective functional outcomes when evaluating SGLT2i.