SGLT2 Inhibitors and Lower Limb Complications: the Diuretic-induced Hypovolemia Hypothesis

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.