Canagliflozin Comeback? New Data on the Risk of Amputation

Authors:
Julie Dally, PharmD, BCPS, BCACP
Amanda Schartel, PharmD, BCACP

Reviewers:
Courtney Davis, PharmD, BCACP
Michael Takach, PharmD, BCACP

CITATION: Fralick M, Kim SC, Schneeweiss S, Everett BM, Glynn RJ, Patorno E. Risk of amputation with canagliflozin across categories of age and cardiovascular risk in three US nationwide databases: cohort study. BMJ 2020; 370: m2812.

The Problem

Patients with diabetes are 10 times more likely to experience lower limb amputations than the general population and amputations have very significant morbidity, mortality, and financial implications.¹  While common risk factors for amputation in patients with diabetes include poor glycemic control, diabetic peripheral neuropathy, or peripheral arterial disease, canagliflozin use was implicated in the CANVAS and CANVAS-R trials.²  These studies incidentally found a two-fold increase in the risk of lower limb amputations with canagliflozin compared to placebo, resulting in an FDA boxed warning in 2017.³ This was particularly concerning in light of recent guidelines recommendation making sodium-glucose cotransporter 2 (SGLT2) inhibitors a preferred second line therapy for high-risk patients based on their favorable cardiovascular and renal protective effects.^4,5  However, the CANVAS Program trials were not specifically designed to evaluate the risk of lower-extremity amputations.  Clearly, we need more information about the magnitude of risk when canagliflozin is used widely in a general population and who is at most risk.