Critical examination of mechanisms underlying the reduction in heart failure events with SGLT2 inhibitors: identification of a molecular link between their actions to stimulate erythrocytosis and to alleviate cellular stress

Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of serious heart failure events, even though SGLT2 is not expressed in the myocardium. This cardioprotective benefit is not related to an effect of these drugs to lower blood glucose, promote ketone body utilization or enhance natriuresis, but it is linked statistically with their action to increase haematocrit. SGLT2 inhibitors increase both erythropoietin and erythropoiesis, but the increase in red blood cell mass does not directly prevent heart failure events. Instead, erythrocytosis is a biomarker of a state of hypoxia mimicry, which is induced by SGLT2 inhibitors in manner akin to cobalt chloride. The primary mediators of the cellular response to states of energy depletion are sirtuin-1 and hypoxia-inducible factors (HIF-1α/HIF-2α). These master regulators promote the cellular adaptation to states of nutrient and oxygen deprivation, promoting mitochondrial capacity and minimizing the generation of oxidative stress. Activation of sirtuin-1 and HIF-1α/HIF-2α also stimulates autophagy, a lysosome-mediated degradative pathway that maintains cellular homoeostasis by removing dangerous constituents (particularly unhealthy mitochondria and peroxisomes), which are a major source of oxidative stress and cardiomyocyte dysfunction and demise. SGLT2 inhibitors can activate SIRT-1 and stimulate autophagy in the heart, and thereby, favourably influence the course of cardiomyopathy. Therefore, the linkage between erythrocytosis and the reduction in heart failure events with SGLT2 inhibitors may be related to a shared underlying molecular mechanism that is triggered by the action of these drugs to induce a perceived state of oxygen and nutrient deprivation.