CaMKII and GLUT1 in heart failure and the role of gliflozins

Biochim Biophys Acta Mol Basis Dis. 2020 Jun 1;1866(6):165729. doi: 10.1016/j.bbadis.2020.165729. Epub 2020 Feb 14.


Empagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has been shown to reduce mortality and hospitalization for heart failure in diabetic patients in the EMPA-REG-OUTCOME trial (Zinman et al., 2015). Surprisingly, dapagliflozin, another SGLT2 inhibitor, exerted comparable effects on clinical endpoints even in the absence of diabetes mellitus (DAPA-HF trial) (McMurray et al., 2019). There is a myriad of suggested underlying mechanisms ranging from improved glycemic control and hemodynamic effects to altered myocardial metabolism, inflammation, neurohumoral activation and intracellular ion homeostasis. Here, we review the effects of gliflozins on cardiac electro-mechanical coupling with an emphasis on novel CaMKII-mediated pathways and on cardiac glucose and ketone metabolism in the failing heart. We focus on empagliflozin as it is the gliflozin with the most abundant experimental evidence for direct effects on the heart. Where useful, we aim to compare empagliflozin to other gliflozins. To facilitate understanding of empagliflozin-induced alterations, we first give a short summary of the pathophysiological role of CaMKII in heart failure, as well as cardiac changes of glucose and ketone body metabolism in the failing heart.

Keywords: CaMKII; Cardiac metabolism; Empagliflozin; GLUT1; Heart failure; SGLT2 inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Benzhydryl Compounds / therapeutic use
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics*
  • Glucose Transporter Type 1 / genetics
  • Glucosides / therapeutic use
  • Heart Failure / drug therapy
  • Heart Failure / genetics*
  • Heart Failure / pathology
  • Humans
  • Ketone Bodies / metabolism
  • Myocardium / metabolism
  • Myocardium / pathology
  • Signal Transduction / drug effects
  • Sodium-Glucose Transporter 2 / drug effects
  • Sodium-Glucose Transporter 2 / genetics*
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use*


  • Benzhydryl Compounds
  • Glucose Transporter Type 1
  • Glucosides
  • Ketone Bodies
  • SLC2A1 protein, human
  • SLC5A2 protein, human
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • empagliflozin