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

Nature Reviews Cardiology volume 20, pages 443–462 (2023)Cite this article

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Abstract

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 by-products 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.

Key points

  • Sodium–glucose cotransporter 2 (SGLT2) inhibitors have a direct cytoprotective effect on the failing heart that is mediated by SGLT2-independent actions to increase nutrient-deprivation signalling and autophagic flux, thereby reducing cellular stress, promoting mitochondrial health and renewal, and decreasing pro-inflammatory signalling and apoptosis.

  • The failing heart is characterized by upregulation of glucose transporter type 1 (GLUT1) levels, increased glycolysis and impaired glucose oxidation, which lead to cytosolic accumulation of deleterious glucose intermediates that can activate mechanistic target of rapamycin (mTOR) and suppress nutrient-deprivation signalling.

  • The failing heart has increased uptake but decreased oxidation of long-chain fatty acids, which impairs ATP production and leads to cytosolic accumulation of deleterious lipid intermediates that result from impaired mitochondrial function and nutrient-deprivation signalling; the cytosolic accumulation of amino acids can promote the activation of mTOR.

  • SGLT2 inhibitors reverse heart failure-related abnormalities in glucose, long-chain fatty acid and amino acid uptake and metabolism by inhibiting GLUT1 (potentially) and by promoting nutrient-deprivation signalling and restoring mitochondrial health and renewal, which increases nutrient oxidation and oxidative phosphorylation and reduces the cytosolic accumulation of deleterious glucose and lipid by-products.

  • The ketonaemia that accompanies SGLT2 inhibition does not act as an energy substrate for ATP production but might promote nutrient-deprivation signalling, reduce the activation of pro-inflammatory pathways and increase autophagic flux.

  • SGLT2 inhibitors might facilitate ATP and haemoglobin production by increasing the pool of bioreactive cytosolic Fe2+ as a result of the SGLT2 inhibitor-induced decrease in hepcidin and ferritin levels, thereby alleviating the state of inflammation-mediated functional iron deficiency that is observed in heart failure.

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Fig. 1: Cytoprotective effects of SGLT2 inhibitors are mediated through modulation of cardiac nutrient transport and metabolism and augmentation of nutrient-deprivation signalling.
Fig. 2: Mechanisms by which augmented autophagic flux reduces cellular stress.
Fig. 3: Cytotoxic effects of GLUT1 upregulation, increased glycolysis and impaired glucose oxidation in heart failure.
Fig. 4: Mechanisms and consequences of increased uptake and impaired oxidation of long-chain fatty acids in heart failure.
Fig. 5: Potential mechanisms by which increased ketogenesis during SGLT2 inhibition can have favourable effects on cellular health in heart failure.
Fig. 6: Mechanisms of SGLT2 inhibitor-mediated increase in cytosolic ferrous iron levels, enhanced erythrocytosis and augmented iron-facilitated ATP production in cardiomyocytes.

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    Milton Packer

  2. Imperial College London, London, UK

    Milton Packer

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During the past 3 years, M.P. has received consulting fees from AbbVie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa and Salamandra, entirely related to the design and execution of clinical trials.

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Packer, M. SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism. Nat Rev Cardiol 20, 443–462 (2023). https://doi.org/10.1038/s41569-022-00824-4

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