Canagliflozin and Amputation Risk: Evidence So Far

Abstract

The CANVAS program detected a 2-fold increased risk of lower limb amputation in patients treated with canagliflozin compared with those with placebo. This adverse effect was not confirmed in the CREDENCE trial. Moreover, randomized controlled trials with other agents in this class, dapagliflozin and empagliflozin, did not detect increased risk of amputation. Observational studies, cohort studies, and pharmacovigilance reports with sodium-glucose cotransporter 2 inhibitor (SGLT2i) have reported conflicting results. Whether this adverse event is a drug effect specific to canagliflozin, or a SGLT2i class effect, remains controversial. Until more evidence emerges, clinicians should avoid using SGLT2i, especially canagliflozin, in patients with previous amputations or existing foot ulceration.

Euglycemic diabetic ketoacidosis in a patient on sodium-glucose cotransporter 2 inhibitors

“…8 Canagliflozin trials found an increased incidence of lower-limb amputation. 9 However, subsequent studies have not replicated these findings. As a drug class SGLT2 inhibitors do not appear…”

“…This led the FDA to recommend postmarketing surveillance studies 8. Canagliflozin trials found an increased incidence of lower-limb amputation 9. However, subsequent studies have not replicated these findings.…”

“…As a drug class SGLT2 inhibitors do not appear to significantly increase the risk of lower-limb amputations, but specific agents such as canagliflozin may be associated with a slight increased risk for amputation in patients with comorbid atherosclerotic disease 5. More research is needed in patients who have an increased risk for amputation at baseline (those with neuropathy, peripheral vascular disease, diabetic foot wound) 9. Whether SGLT2 inhibitors should be used in these patients is controversial.…”

“…5 More research is needed in patients who have an increased risk for amputation at baseline (those with neuropathy, peripheral vascular disease, diabetic foot wound). 9 Whether SGLT2 inhibitors should be used in these patients is controversial.…”

A Wealth of Science

“…Brookes et al 2 have shown that nutritional deficiencies may predict diabetic foot amputations. Relevant to amputations, Papadokostaki et al 3 provide a review of amputation risk associated with the antidiabetic drug canagliflozin. Salutini et al 4 conducted a survey among Italian experts to achieve a consensus on diabetic foot management.…”