Elsevier

JACC: Heart Failure

Volume 11, Issue 1, January 2023, Pages 106-114
JACC: Heart Failure

Methodology and Mechanisms Corner
Potential Interactions When Prescribing SGLT2 Inhibitors and Intravenous Iron in Combination in Heart Failure

https://doi.org/10.1016/j.jchf.2022.10.004Get rights and content
Under a Creative Commons license
open access

Highlights

  • Sodium-glucose cotransporter 2 (SGLT2) inhibitors change iron biomarkers in a manner that mimics iron deficiency.

  • These changes reflect relief of inflammation-related changes in iron homeostasis, not a reduction in cytosolic iron.

  • SGLT2 inhibitors alleviate iron deficiency, explaining their ability to promote erythrocytosis and cardiomyocyte adenosine triphosphate production.

  • Further studies are needed before intravenous iron supplements are prescribed to patients receiving SGLT2 inhibitors.

Abstract

In patients with heart failure, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to decrease hepcidin and ferritin and increase transferrin receptor protein, changes that are typically indicative of worsening absolute iron deficiency, as would be seen with poor dietary intake or gastrointestinal bleeding, neither of which is provoked by SGLT2 inhibitors. Therefore, 2 alternative conceptual frameworks may explain the observed pattern of changes in iron homeostasis proteins. According to the “cytosolic iron depletion hypothesis,” the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor is related to a decline in cytosolic Fe2+ that occurs after drug-induced erythropoietin-related increase in iron use. Erythropoietin-mimetics (eg, darbepoietin) elicit this type of iron-deficiency pattern of response, and it is typically accompanied by erythropoietin resistance that is alleviated by intravenous iron supplementation. In contrast, according to the “cytosolic iron repletion hypothesis,” the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor represents a direct action of these drugs: 1) to reverse inflammation-related increases in hepcidin and ferritin, and, thus, alleviate functional blocks on iron utilization; and 2) to increase in sirtuin-1 signaling, which suppresses hepcidin, accelerates the degradation of ferritin, and up-regulates transferrin receptor protein. Through either or both mechanisms, direct suppression of hepcidin and ferritin would be expected to increase cytosolic Fe2+, thus allowing an unattenuated erythrocytic response to erythropoietin without the need for intravenous iron supplementation. The totality of clinical evidence supports the “cytosolic iron repletion hypothesis” because SGLT2 inhibitors elicit a full and sustained erythrocytosis in response to erythropoietin, even in overtly iron-deficient patients and in the absence of intravenous iron therapy. Therefore, the emergence of an iron-deficiency pattern of response during SGLT2 inhibition does not reflect worsening iron stores that are in need of replenishment, but instead, represents potential alleviation of a state of inflammation-related functional iron deficiency that is commonly seen in patients with chronic heart failure. Treatment with intravenous iron may be unnecessary and theoretically deleterious.

Key Words

ferritin
ferroptosis
hepcidin
intravenous iron
sodium-glucose cotransporter 2 (SGLT2) inhibitors

Abbreviations and Acronyms

ATP
adenosine triphosphate
SGLT2
sodium-glucose cotransporter 2
SIRT1
sirtuin-1

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