Cardiac effects of SGLT2 inhibitors: the sodium hypothesis

Cardiovasc Res. 2018 Jan 1;114(1):12-18. doi: 10.1093/cvr/cvx149.


The effects of intense glycaemic control on macrovascular complications in patients with type 2 diabetes are incompletely resolved, and many glucose-lowering medications negatively affect cardiovascular outcomes. Recently, the EMPA-REG OUTCOME trial revealed that empagliflozin, an inhibitor of the sodium-glucose cotransporter 2 (SGLT2), substantially reduced the risk of hospitalization for heart failure, death from cardiovascular causes, and all-cause mortality in patients with type 2 diabetes mellitus at high cardiovascular risk. Although several mechanisms may explain this benefit, plasma volume contraction and a metabolic switch favouring cardiac ketone bodies oxidation have recently been proposed as the major drivers. Recent experimental work has prompted a novel and intriguing hypothesis, according to which empagliflozin may reduce intracellular sodium (Na+) load observed in failing cardiac myocytes by inhibiting the sarcolemmal Na+/H+ exchanger. Since elevated intracellular Na+ hampers mitochondrial Ca2+ handling and thereby, deteriorates energy supply and demand matching and the mitochondrial antioxidative defence systems, empagliflozin may positively affect cardiac function by restoring mitochondrial function, and redox state in the failing heart. Here, we review the current evidence for such a third mechanistic hypothesis, which may foster heart failure and diabetes research into a new direction which harbours several potential targets for therapeutic intervention.

Keywords: Diabetes; EMPA-REG OUTCOME; Empagliflozin; Heart failure; Mitochondria; Sodium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / diagnosis
  • Cardiovascular Diseases / drug therapy*
  • Cardiovascular Diseases / mortality
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / mortality
  • Diuresis / drug effects
  • Energy Metabolism / drug effects
  • Hospitalization
  • Humans
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Risk Assessment
  • Risk Factors
  • Sodium-Glucose Transporter 2 / metabolism
  • Sodium-Glucose Transporter 2 Inhibitors / adverse effects
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use*
  • Treatment Outcome


  • Biomarkers
  • Blood Glucose
  • SLC5A2 protein, human
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors