FDA Warns of Amputation Risk With Antidiabetic Agent

Amos Gonzales
May 17, 2017

CANVAS and CANVAS-R, two large clinical trials that began in 2009 with 10,000 patients on canagliflozin or a placebo, released early data previous year that prompted the FDA to warn about amputation risks.

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Canagliflozin is prescribed alongside diet and exercise to help patients with type 2 diabetes lower their blood sugar. The most common amputations resulting from canagliflozin therapy were of the toe and middle of the foot, although above-knee and below-knee leg amputations were also reported. It inhibits the sodium-glucose cotrasporter-2, and its effects are measured through the amount of sugar in the patient's urine, as the drug focuses its effects on the kidneys. 99 out of 140 amputated patients receiving the drug had their toe or mid-foot removed, while amputations involving the leg and the knee accounted for 41 out of 140 amputations.

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The study was focused on determining how canagliflozin affected the renal endpoints in adults with type 2 diabetes.

The warning comes after the agency reviewed data from two randomized, placebo controlled trials (CANVAS and CANVAS-R) that showed rates of lower-extremity amputations were doubled in the active drug groups, irrespective of dose.

Over one year, amputation risk for patients in CANVAS and CANVAS-R was equivalent to 5.9 and 7.5 out of every 1000 patients treated with canagliflozin, respectively, compared with 2.8 and 4.2 out of every 1000 patients treated with placebo.

The FDA said that the new warnings need to include a boxed warning, which is reserved for drugs with most serious possible adverse events. History of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers are all factors that may put patients at an increased risk. Doctors, on the other hand, are advised to consider factors that can predispose patients to amputations before starting the treatment.

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