Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

Abstract

In five large-scale trials involving >40 000 patients, sodium-glucose cotransporter 2 (SGLT2) inhibitors decreased the risk of serious heart failure events by 25-40%. This effect cannot be explained by control of hyperglycaemia, since it is not observed with antidiabetic drugs with greater glucose-lowering effects. It cannot be attributed to ketogenesis, since it is not causally linked to ketone body production, and the benefit is not enhanced in patients with diabetes. The effect cannot be ascribed to a natriuretic action, since SGLT2 inhibitors decrease natriuretic peptides only modestly, and they reduce cardiovascular death, a benefit that diuretics do not possess. Although SGLT2 inhibitors increase red blood cell mass, enhanced erythropoiesis does not favourably influence the course of heart failure. By contrast, experimental studies suggest that SGLT2 inhibitors may reduce intracellular sodium, thereby preventing oxidative stress and cardiomyocyte death. Additionally, SGLT2 inhibitors induce a transcriptional paradigm that mimics nutrient and oxygen deprivation, which includes activation of adenosine monophosphate-activated protein kinase, sirtuin-1, and/or hypoxia-inducible factors-1 /2 . The interplay of these mediators stimulates autophagy, a lysosomally-mediated degradative pathway that maintains cellular homeostasis. Autophagy-mediated clearance of damaged organelles reduces inflammasome activation, thus mitigating cardiomyocyte dysfunction and coronary microvascular injury. Interestingly, the action of hypoxia-inducible factors-1 /2 to both stimulate erythropoietin and induce autophagy may explain why erythrocytosis is strongly correlated with the reduction in heart failure events. Therefore, the benefits of SGLT2 inhibitors on heart failure may be mediated by a direct cardioprotective action related to modulation of pathways responsible for cardiomyocyte homeostasis.In four large-scale clinical trials in patients with type 2 diabetes followed for 2-5 years who largely did not have a diagnosis of heart failure at the time of study entry, patients assigned to treatment

SHANK3 Co-ordinately Regulates Autophagy and Apoptosis in Myocardial Infarction

“…Our previous research proved that the increase of autophagy level helped to restore cardiac function and alleviate cardiac remodeling under hypoxic injury conditions (Hu et al, 2016). On the contrary, if the level of autophagy cannot be increased correspondingly after suffering the injury, it will lead to further deterioration of heart function (Hu et al, 2016;Packer, 2020).…”

Repurposing Antidiabetic Drugs for Cardiovascular Disease

“…For example, it is known that metformin stimulates autophagy via activating AMPK and sirtuin-1 (SIRT1) and by this way, may contribute to the cardioprotective effects seen in experimental models of HF (Gundewar et al, 2009). Recent studies revealed that SGLT2i may exert cardioprotective effects by stimulating autophagy (Levine et al, 2015), which may involve the activation of AMPK and SIRT1 (Packer, 2020). The overlap in the mechanism of action between metformin and SGLT2i may be the reason for the reduced cardioprotective effects of SGLT2i in patients with metformin treatment at baseline, when compared to the non-metformin group (Packer, 2020).…”

“…Recent studies revealed that SGLT2i may exert cardioprotective effects by stimulating autophagy (Levine et al, 2015), which may involve the activation of AMPK and SIRT1 (Packer, 2020). The overlap in the mechanism of action between metformin and SGLT2i may be the reason for the reduced cardioprotective effects of SGLT2i in patients with metformin treatment at baseline, when compared to the non-metformin group (Packer, 2020).…”

“…Off-target effects on SGLT1 and direct binding of SGLT2i to NHE-1 are questionable but the regulation of Na + , H + , and Ca 2+ in cardiomyocytes and in specific microdomains may contribute to cardioprotective effects of SGLT2i (Pabel et al, 2018). Of note, the increase in haematocrit and levels of erythropoietin through treatment with SGLT2i were recently discussed to trigger autophagy and reduce reactive oxygen species (ROS) in the heart and thus may represent another indirect effect contributing to cardioprotection (Packer, 2020).…”

<p>SGLT2 Inhibitors: A Novel Player in the Treatment and Prevention of Diabetic Cardiomyopathy</p>

“…12 In addition, they cannot be ascribed to natriuretic effect, since diuretic therapy has been associated with increased risk of CVD and mortality in patients with HF. [13][14][15][16] As a consequence, accumulating evidence has been gathered in an attempt to figure out the possible underlying mechanisms of cardioprotection. In view of the rapid decline in risk of HHF, it can be speculated that the benefits of SGLT2Is are due to the direct effects on the heart itself, namely improved DCM, instead of metabolic improvement.…”