Lower-limb amputation (primarily of the toe) occurred at a rate of 6 per 1000 patient-years in patients treated with canagliflozin in the ongoing CANVAS trial, compared with an incidence of 3 per 1000 patient-years in those who received placebo, a letter from the manufacturer advises.
This increased risk was observed independent of predisposing factors, although the absolute risk was higher in patients with previous amputations, existing peripheral vascular disease or neuropathy. No dose response was observed.
The finding of the CANVAS study is currently under investigation, and any mechanism behind a possible link between canagliflozin treatment and an increased risk of amputation is as yet unknown.
In the meantime, healthcare professionals treating patients with canagliflozin are reminded of the need to:
- follow standard diabetes treatment guidelines for routine preventive foot care
- carefully monitor patients with risk factors for amputation events (eg, previous amputations, existing peripheral vascular disease or neuropathy)
- initiate early treatment for foot problems such as ulceration, infection, new pain or tenderness
- consider, as a precautionary measure, stopping canagliflozin treatment in patients who develop a significant complication, such as a lower-extremity skin ulcer, osteomyelitis or gangrene, at least until the condition has resolved
- monitor patients for signs and symptoms of loss of body water and salt and ensure that hydration is sufficient to prevent volume depletion
Healthcare providers should also remind patients to maintain routine preventive foot care; report ulceration, discoloration, new lower extremity pain or tenderness; and remain well hydrated.
Amputation rates in other studies
The CANVAS study enrolled patients with a history or high risk of cardiovascular disease. In the ongoing CANVAS-R study, which involves a similar population to CANVAS, there was a numerical imbalance in amputation events between the canagliflozin and placebo groups (16 events in the canagliflozin group and 12 events in the placebo group). No increase in the incidence of amputation was observed across 12 other completed phase III/IV clinical trials with a mean follow-up of 0.9 years (0.6 per 1000 patient-years in the canagliflozin groups and 2 per 1000 patient-years in control groups).