Beyond the effects of lowering glycated hemoglobin, recent evidence for sodium-glucose cotransporter 2 (SGLT2) inhibitors has revolutionarily impacted the management of patients with heart failure. However, the mechanism of SGLT2 inhibitors that can explain the following features has not been clarified. First, SGLT2 inhibitors significantly reduced the risk of heart failure in the early stage. Second, SGLT2 inhibitors are effective in treating heart failure without increasing cardiac output. Third, the effects of SGLT2 inhibitors are incremental and complementary to those of conventional therapies for heart failure. Fourth, SGLT2 inhibitors can improve prognosis in patients with heart failure independent of the ejection fraction. Fifth, SGLT2 inhibitors show consistent effects on heart failure, irrespective of etiology. Based on the perspective of Guyton's physiology and clinical experiences that SGLT2 inhibitors reduced oxygen consumption of the whole body, we provided a demand-reducing theory that SGLT2 inhibitors alleviate the imbalance between oxygen demand and supply not by increasing cardiac output but by reducing oxygen consumption of the whole body, which can explain several unique characteristics of SGLT2 inhibitors.
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