SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review

Diabetologia. 2018 Oct;61(10):2108-2117. doi: 10.1007/s00125-018-4670-7. Epub 2018 Aug 22.


Sodium-glucose cotransporter (SGLT)2 inhibitors have been demonstrated to reduce cardiovascular events, particularly heart failure, in cardiovascular outcome trials. Here, we review the proposed mechanistic underpinnings of this benefit. Specifically, we focus on the role of SGLT2 inhibitors in optimising ventricular loading conditions through their effect on diuresis and natriuresis, in addition to reducing afterload and improving vascular structure and function. Further insights into the role of SGLT2 inhibition in myocardial metabolism and substrate utilisation are outlined. Finally, we discuss two emerging themes: how SGLT2 inhibitors may regulate Na+/H+ exchange at the level of the heart and kidney and how they may modulate adipokine production. The mechanistic discussion is placed in the context of completed and ongoing trials of SGLT2 inhibitors in the prevention and treatment of heart failure in individuals with and without diabetes.

Keywords: Cardiovascular effects; Heart failure; Mechanisms; Review; SGLT2 inhibitors.

Publication types

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

MeSH terms

  • Adipokines / metabolism
  • Animals
  • Benzhydryl Compounds / pharmacology
  • Blood Glucose / metabolism
  • Cardiovascular Diseases / complications
  • Cardiovascular Diseases / drug therapy
  • Diabetes Complications / complications
  • Diabetes Complications / drug therapy
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Glucosides / pharmacology
  • Heart / drug effects*
  • Heart Ventricles / drug effects
  • Heart Ventricles / pathology
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Kidney / drug effects
  • Sodium-Glucose Transporter 2 Inhibitors / pharmacology*


  • Adipokines
  • Benzhydryl Compounds
  • Blood Glucose
  • Glucosides
  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 2 Inhibitors