The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus

Annu Rev Med. 2015;66:255-70. doi: 10.1146/annurev-med-051013-110046. Epub 2014 Oct 17.

Abstract

The kidneys in normoglycemic humans filter 160-180 g of glucose per day (∼30% of daily calorie intake), which is reabsorbed and returned to the systemic circulation by the proximal tubule. Hyperglycemia increases the filtered and reabsorbed glucose up to two- to three-fold. The sodium glucose cotransporter SGLT2 in the early proximal tubule is the major pathway for renal glucose reabsorption. Inhibition of SGLT2 increases urinary glucose and calorie excretion, thereby reducing plasma glucose levels and body weight. The first SGLT2 inhibitors have been approved as a new class of antidiabetic drugs in type 2 diabetes mellitus, and studies are under way to investigate their use in type 1 diabetes mellitus. These compounds work independent of insulin, improve glycemic control in all stages of diabetes mellitus in the absence of clinically relevant hypoglycemia, and can be combined with other antidiabetic agents. By lowering blood pressure and diabetic glomerular hyperfiltration, SGLT2 inhibitors may induce protective effects on the kidney and cardiovascular system beyond blood glucose control.

Keywords: body weight; diabetic nephropathy; glomerular hyperfiltration; gluconeogenesis; glucose reabsorption; hypertension; sodium-glucose cotransporter.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Benzhydryl Compounds / therapeutic use
  • Blood Glucose / metabolism
  • Canagliflozin
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Glucosides / therapeutic use
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Kidney / metabolism
  • Sodium-Glucose Transporter 2 / metabolism
  • Sodium-Glucose Transporter 2 Inhibitors*
  • Thiophenes / therapeutic use

Substances

  • Benzhydryl Compounds
  • Blood Glucose
  • Glucosides
  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Thiophenes
  • Canagliflozin
  • dapagliflozin
  • empagliflozin