4.6 Review

SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism

Journal

NATURE REVIEWS CARDIOLOGY
Volume 20, Issue 7, Pages 443-462

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41569-022-00824-4

Keywords

-

Ask authors/readers for more resources

SGLT2 inhibitors reduce heart failure events by directly acting on the failing heart, independent of renal tubular function. They restore cellular homeostasis through mechanisms such as promoting cytoprotective actions, increasing ATP synthesis, and inhibiting the accumulation of toxic metabolic by-products. These inhibitors also enhance autophagic flux, leading to the clearance of harmful substances and mitochondrial renewal.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure events by direct action on the failing heart that is independent of changes in renal tubular function. In the failing heart, nutrient transport into cardiomyocytes is increased, but nutrient utilization is impaired, leading to deficient ATP production and the cytosolic accumulation of deleterious glucose and lipid by-products. These by-products trigger downregulation of cytoprotective nutrient-deprivation pathways, thereby promoting cellular stress and undermining cellular survival. SGLT2 inhibitors restore cellular homeostasis through three complementary mechanisms: they might bind directly to nutrient-deprivation and nutrient-surplus sensors to promote their cytoprotective actions; they can increase the synthesis of ATP by promoting mitochondrial health (mediated by increasing autophagic flux) and potentially by alleviating the cytosolic deficiency in ferrous iron; and they might directly inhibit glucose transporter type 1, thereby diminishing the cytosolic accumulation of toxic metabolic by-products and promoting the oxidation of long chain fatty acids. The increase in autophagic flux mediated by SGLT2 inhibitors also promotes the clearance of harmful glucose and lipid byproducts and the disposal of dysfunctional mitochondria, allowing for mitochondrial renewal through mitochondrial biogenesis. This Review describes the orchestrated interplay between nutrient transport and metabolism and nutrient-deprivation and nutrient-surplus signalling, to explain how SGLT2 inhibitors reverse the profound nutrient, metabolic and cellular abnormalities observed in heart failure, thereby restoring the myocardium to a healthy molecular and cellular phenotype.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available