SGLT2 inhibitors and lower limb complications: the diuretic-induced hypovolemia hypothesis

Cardiovasc Diabetol. 2021 May 13;20(1):107. doi: 10.1186/s12933-021-01301-x.


In a recent meta-analysis of randomized controlled trials of sodium glucose co-transporter 2 inhibitors (SGLT2i) in patients with diabetes, Lin and colleagues showed a positive association between SGLT2i-induced blood pressure and weight reduction and the risk of lower limb events. These results support the potential mechanism of a volume depletion effect of SGLT2i to explain the increase risk of amputation observed with this pharmacological class. Since the first result of the CANVAS trial raised a concern regarding the risk of amputation with SGLT2i, this hypothesis emerged from studies showing a higher incidence of amputations in patients with diabetes using diuretics. Furthermore, recent data found that copeptin, a surrogate marker of hydration status was also associated with lower limb outcomes. In conclusion, this assumption of diuretic-induced hypovolemia explanation highlights the fact that medications that induce a contraction of plasma volume, both traditional and novel agents with a diuretic mode of action should be introduced cautiously in patients with diabetes at high risk of diabetic foot events.

Keywords: SGLT2 inhibitors; amputations; diuretics; hypovolemia; lower limb events.

Publication types

  • Comment

MeSH terms

  • Diabetes Mellitus, Type 2*
  • Diuretics
  • Humans
  • Hypovolemia
  • Lower Extremity
  • Sodium-Glucose Transporter 2 Inhibitors*


  • Diuretics
  • Sodium-Glucose Transporter 2 Inhibitors