Crosstalk between Sodium-Glucose Cotransporter Inhibitors and Sodium-Hydrogen Exchanger 1 and 3 in Cardiometabolic Diseases

Int J Mol Sci. 2021 Nov 24;22(23):12677. doi: 10.3390/ijms222312677.


Abnormality in glucose homeostasis due to hyperglycemia or insulin resistance is the hallmark of type 2 diabetes mellitus (T2DM). These metabolic abnormalities in T2DM lead to cellular dysfunction and the development of diabetic cardiomyopathy leading to heart failure. New antihyperglycemic agents including glucagon-like peptide-1 receptor agonists and the sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to attenuate endothelial dysfunction at the cellular level. In addition, they improved cardiovascular safety by exhibiting cardioprotective effects. The mechanism by which these drugs exert their cardioprotective effects is unknown, although recent studies have shown that cardiovascular homeostasis occurs through the interplay of the sodium-hydrogen exchangers (NHE), specifically NHE1 and NHE3, with SGLT2i. Another theoretical explanation for the cardioprotective effects of SGLT2i is through natriuresis by the kidney. This theory highlights the possible involvement of renal NHE transporters in the management of heart failure. This review outlines the possible mechanisms responsible for causing diabetic cardiomyopathy and discusses the interaction between NHE and SGLT2i in cardiovascular diseases.

Keywords: NHE1; NHE3; SGLT1; SGLT2; cardiovascular diseases; diabetes; sodium–glucose cotransporter inhibitors; sodium–hydrogen exchanger.

Publication types

  • Review

MeSH terms

  • Animals
  • Cardiovascular Diseases / drug therapy*
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / metabolism
  • Cardiovascular Diseases / pathology
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetic Cardiomyopathies / drug therapy*
  • Diabetic Cardiomyopathies / etiology
  • Diabetic Cardiomyopathies / metabolism
  • Diabetic Cardiomyopathies / pathology
  • Humans
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use*
  • Sodium-Hydrogen Exchangers / metabolism*


  • Sodium-Glucose Transporter 2 Inhibitors
  • Sodium-Hydrogen Exchangers