The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure

Diabetologia. 2018 Oct;61(10):2098-2107. doi: 10.1007/s00125-018-4669-0. Epub 2018 Aug 22.


Inhibition of the sodium-glucose cotransporter (SGLT) 2 in the proximal tubule of the kidney has a broad range of effects on renal function and plasma volume homeostasis, as well as on adiposity and energy metabolism across the entire body. SGLT2 inhibitors are chiefly used in type 2 diabetes for glucose control, achieving reductions in HbA1c of 7-10 mmol/mol (0.6-0.9%) when compared with placebo. This glucose-lowering activity is proportional to the ambient glucose concentration and glomerular filtration of this glucose, so may be greater in those with poor glycaemic control and/or hyperfiltration at baseline. Equally, the glucose-lowering effects of SGLT2 inhibitors are attenuated in individuals without diabetes and those with a reduced eGFR. However, unlike the glucose-lowering effects of SGLT2 inhibitors, the spill-over of sodium and glucose beyond the proximal nephron following SGLT2 inhibition triggers dynamic and reversible realignment of energy metabolism, renal filtration and plasma volume without relying on losses into the urine. In addition, these processes are observed in the absence of significant glucosuria or ongoing natriuresis. In the long term, the resetting of energy/salt/water physiology following SGLT2 inhibition has an impact, not only on adiposity, renal function and blood pressure control, but also on the health and survival of patients with type 2 diabetes. A better understanding of the precise biology underlying the acute actions of SGLT2 inhibitors in the kidney and how they are communicated to the rest of the body will likely lead to improved therapeutics that augment similar pathways in individuals with, or even without, diabetes to achieve additional benefits.

Keywords: Diabetes; Glucose-lowering; Review; SGLT2; SGLT2 inhibitor; Sodium–glucose cotransporter 2; Type 2 diabetes.

Publication types

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

MeSH terms

  • Adiposity
  • Blood Glucose / metabolism
  • Blood Pressure / drug effects*
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetic Nephropathies / drug therapy
  • Diabetic Nephropathies / metabolism
  • Glomerular Filtration Rate
  • Glucosides / therapeutic use
  • Humans
  • Hyperglycemia / drug therapy
  • Hypoglycemic Agents / pharmacology
  • Kidney / drug effects*
  • Kidney Function Tests
  • Sodium-Glucose Transporter 2 / metabolism*
  • Sodium-Glucose Transporter 2 Inhibitors / pharmacology*
  • Weight Loss


  • Blood Glucose
  • Glucosides
  • Hypoglycemic Agents
  • SLC5A2 protein, human
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors