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Monday 7 August 2017

FDA Reports Further Support for Canagliflozin-Amputation Link

New data from the voluntary US Food and Drug Administration (FDA) adverse-event reporting system (FAERS) reinforce the current label warning about amputations for canagliflozin (Invokana, Invokamet, Janssen), a sodium-glucose cotransporter-2 (SGLT2) inhibitor for the treatment of type 2 diabetes.

An analysis of safety signal reports from FAERS was published online recently in Lancet Diabetes & Endocrinology by Gian Paolo Fadini, MD, PhD, and Angelo Avogaro, MD, PhD, of the division of metabolic diseases, department of medicine, University of Padova, Italy.

Among 66 reports of SGLT2-inhibitor–associated amputations, 57 (86%) involved canagliflozin. Moreover, two-thirds of those reports were among people with no discernible risk factors for amputation, "which, worryingly, points to an unpredictable effect of the drug," Dr Fadini told Medscape Medical News.

In May 2017, the FDA issued a boxed warning to the label of canagliflozin after an approximately doubled risk for lower-extremity amputations with the drug compared with placebo was seen during the Canagliflozin Cardiovascular Assessment Study (CANVAS) and A Study of the Effects of Canagliflozin on Renal Endpoints (CANVAS-R) trials. Those findings have since been published.

The same risk has not been seen in studies of the other SGLT2 inhibitors on the market, empagliflozin (Jardiance, Boehringer Ingelheim) and dapagliflozin (Farxiga, AstraZeneca).

Thus far, the FDA has not extended the label warning about amputations to other drugs in the class, although the European Medicines Agency (EMA) has, pending further investigation.

"Our data are the first to confirm the warning originated from CANVAS and tends to suggest this is not a class effect," Dr Fadini told Medscape Medical News.

However, he added, "at the moment, data are not sufficiently robust to modify canagliflozin use in favor of dapagliflozin/empagliflozin. So we can only reinforce, with independent data, the boxed warning issued by the FDA and call for caution when using canagliflozin in patients with the diabetic-foot syndrome."
Majority Have No Reported Risk Factors

Among more than nine million adverse event reports in the FAERS through March 31, 2017, 66 were SGLT2-inhibitor–associated amputations.

Of those, 57 (86%) listed canagliflozin as a suspect or concomitant drug. The patients had an average age of about 60 years, and most were men. Average treatment duration was about 1.5 years.

Based on indications, 11% of the patients appeared to have diabetic-foot syndrome (ie, ischemia, neuropathy, deformity, wounds, infections, and/or previous amputations). When the authors considered concomitant adverse events including wounds, necrosis, gangrene, or ischemia, the proportion with evident amputation risk factors totaled about 36%, whereas there were no such predictors in the other 64%.

The most common level of amputation was the toe, but there were 13 above-ankle leg or limb amputations, two multiple amputations, and one hand amputation. Three of those with amputations died.

The frequency of amputation among all FAERS reports listing canagliflozin as a suspect or concomitant drug was 3.4 per 1000.

Compared with non–SGLT2-inhibitor drugs for type 2 diabetes, the proportional reporting ratio for amputation as an adverse event with canagliflozin was 5.33 (P < .0001). In contrast, this ratio was 0.25 for dapagliflozin (P = .163) and 2.37 for empagliflozin (P = .054).

"In summary, this pharmacovigilance analysis confirms that use of canagliflozin, but not dapagliflozin or empagliflozin, might be associated with an increased risk of amputations," the doctors say, while noting there are "important limitations" of FAERS data.

"Deciphering predisposing factors and mechanisms of this rare adverse event will be crucial to maximize the benefits of SGLT2 inhibitors in clinical practice," Drs Fadini and Dr Avogaro conclude.

The study was supported by institutional grants from the University of Padova but received no specific funding. Dr Fadini has received grants, personal fees, and nonfinancial support from AstraZeneca and Eli Lilly; personal fees and nonfinancial support from Boehringer Ingelheim, Novo Nordisk, Sanofi, Abbott, and Novartis; nonfinancial support from Genzyme; and personal fees from Merck Sharp & Dohme. Dr Avogaro has received grants, personal fees, and nonfinancial support from AstraZeneca; grants and personal fees from Mediolanum; personal fees and nonfinancial support from Novartis and Servier; and personal fees from Boehringer Ingelheim, Janssen, Merck Sharp & Dome, Sanofi, Novo Nordisk, Lilly, and Takeda.''