Diabetes Drug Gets FDA Warning Due to Amputation Risk

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

The FDA will now require Johnson & Johnson to add a boxed warning to its Invokana/Invokamet labels.

Final results from two 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) - showed that leg and foot amputations occurred about twice as often in patients treated with canagliflozin compared with patients treated with placebo.

Before prescribing canagliflozin, according to the FDA's advice, healthcare professionals should consider factors that might predispose patients to amputations, including a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. In May 2016 the FDA noted a correlation between Invokana and amputation risk, but required more evidence to prove causality.

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The amputations were most commonly of the toe and middle of the foot, though some involved the leg, below and above the knee. This warning is an update to the safety communication issued on May 18, 2016. In the other, which enrolled 5,814 patients, 7.5 out of 1,000 patients receiving canagliflozin had a foot or leg amputation that year, compared to 4.2 out of 1,000 of the patients receiving a placebo.

Leerink analyst Seamus Fernandez expects Lilly to benefit from an influx of Invokana patients transitioning to one of its diabetes meds, Jardiance. Canagliflozin is SGLT2 inhibitor indicated to lower blood glucose levels in patients with type 2 diabetes along with diet and exercise. The drug works by helping to remove excess sugar through urine. Untreated, type 2 diabetes can lead to serious problems, including blindness, nerve and kidney damage, and heart disease.

He predicted the "immediate reaction" from doctors would be to switch patients away to either Jardiance or AstraZeneca's SGLT2 entrant, Farxiga, just as they years ago switched patients from GlaxoSmithKline's Avandia to Takeda's Actos in the wake of concerns about a potential Avandia cardiovascular risk. "We believe a dramatic impact on the class is unlikely", he said, noting that the company's situation "could be further mitigated by a directionally positive result" from the outcomes studies on CV risk reduction.

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