Background: Treatment with sodium-glucose co-transporter-2-inhibitors (SGLT2-Is), such as
canagliflozin, has been associated with an increased risk of lower limb amputations (LLAs) in type 2
diabetes mellitus (T2DM). However, conflicting results have been reported for different SGLT2-Is and
the underlying mechanism is unclear.
Objective: To investigate the risk of LLA and diabetic foot ulcer with SGLT2-I use compared to other
anti-diabetic drugs and to explore hypovolemia as a potential underlying mechanism.
Methods: A cohort study was conducted using data from the Clinical Practice Research Datalink GOLD
(2013-2019). The study population (N=51,847) consisted of T2DM patients over 18 years of age with at least
one prescription of a non-insulin anti-diabetic drug. Concomitant diuretic use and the presence of signs of
hypovolemia were determined to assess the potential underlying mechanism. Cox proportional hazard models
were used to estimate the hazard ratio (HR) for LLA in current SGLT2-I use versus current sulphonylurea
(SU) use. Analyses were adjusted for lifestyle variables, comorbidities, and concomitant drug use.
Results: Current SGLT2-I use was not associated with an increased risk of LLA compared to current SU
use (fully adjusted HR 0.70; 95% confidence interval 0.38-1.29). Concomitant use of diuretics and the
presence of signs of hypovolemia were not associated with an increased risk of LLA.
Conclusion: Use of SGLT2-Is, with or without signs of hypovolemia, was not associated with an increased
risk of LLA or DFU versus current SU use. Future studies powered to detect potential differences
between individual SGLT2-Is are required to rule out a canagliflozin-specific effect.