Diabetes Drug Found to Increase Risk of Amputations


The FDA has required new warnings be added to drug labels.

The US Food and Drug Administration (FDA) has included a prominent boxed warning on canagliflozin (Invokana, Invokamet, Invokamet XR), a type 2 diabetes medication that has been found to increase the risk of leg and foot amputations, according to an FDA statement.

The warning comes on the heels of new data from two large clinical trials — CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus). The two trials showed that leg and foot amputations occurred about twice as often in patients treated with canagliflozin compared to patients treated with placebo.

Amputations were most common in the toe and middle of the foot, the statement said, but also occurred on the leg, both above and below the knee. Additionally, some patients had multiple amputations that involved both limbs.

“Health care professionals should, before starting canagliflozin, consider factors that may predispose patients to the need for amputations. These factors include a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers,” the statement read.

The CANVAS trial showed that over a year’s time, the risk of amputation for patients were equivalent to 5.9 out of every 1000 patients treated with canagliflozin, compared to 2.8 out of every 1000 patients treated with placebo. In the CANVAS-R trial, those numbers grew to 7.5 out of every 1000 patients and 4.2 out of every 1000 patients, respectively.

This is not the first FDA warning regarding canagliflozin. In 2016, the FDA strengthened existing warnings about the risk of acute kidney injury for canagliflozin and dapagliflozin, another type 2 diabetes medication.

From canagliflozin’s original approval in March 2013 until October 2015, the FDA received reports of 101 confirmable cases of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin or dapagliflozin use. This only included reports that were submitted to the FDA, so there were likely additional cases of which the FDA was unaware.

Canagliflozin is a prescription medicine used with diet and exercise to lower blood sugar in adults with type 2 diabetes. It belongs to a class of drugs called sodium-glucose cotransporter-2 (SGLT2) inhibitors. It lowers the blood sugar by causing the kidneys to remove sugar from the body through the urine.

According to Janssen Pharmaceuticals, the marketers behind canagliflozin, while the incidence of lower-limb amputation was low, the highest incidence of amputations across all treatments was seen in patients with prior amputation.

"Canagliflozin remains an important treatment option for people with type 2 diabetes," said Sarah Freeman, Janssen spokesperson. "We are working with FDA to include this information in the prescribing information for canagliflozin and look forward to the presentation of the full CANVAS Program results at the American Diabetes Association Scientific Sessions in June."

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