EMA Extends Amputation Investigation to All SGLT2 Inhibitors

The European Medicines Agency (EMA)'s Pharmacovigilance Risk Assessment Committee (PRAC) has extended the scope of its investigation into the possible link between the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Invokana, Vokanamet, Janssen) and amputations to include other drugs of the same class.

Now, the PRAC's review will include the other SGLT2 inhibitor medicines dapagliflozin (Farxiga, Xigduo XR, AstraZeneca), and empagliflozin (Jardiance, Boehringer Ingelheim), based on the determination that the potential risk may be relevant for them as well.

In April 2016, PRAC launched a safety review of canagliflozinbased on an increase in amputations — mostly of the toes — seen in the ongoing long-term Canagliflozin Cardiovascular Assessment Study (CANVAS).

A 4.5-year interim analysis by the independent monitoring committee for the trial found that the rate of amputations per every 1000 patients was equivalent to seven for 100 mg/day and five for 300 mg/day of canagliflozin compared with three per 1000 patients taking placebo.

No such increase in amputations was seen in 12 other completed clinical trials with canagliflozin, although a small, statistically nonsignificant increase in the number of amputations occurred in another ongoing study calledCANVAS-R. Both CANVAS and CANVAS-R involve patients at high cardiovascular risk.

Based on all the data, the monitoring committee recommended that CANVAS continue through its scheduled 2017 completion.

In its April move, PRAC had requested more information from the company to assess whether canagliflozin causes an increase in lower-limb amputations and whether any changes are needed in the way the drug is used in the European Union.

FDA's Actions

In May, the US Food and Drug Administration (FDA) also issued a safety alert for canagliflozin based on the same data. Asked to clarify whether their investigation extends to other SGLT2 inhibitors, an FDA press representative responded by email, "As we stated in our May 18, 2016, drug safety communication, we have not determined whether canagliflozin increases the risk of leg and foot amputations….FDA is evaluating this safety issue across the class."

A Real Risk?

Commenting for Medscape Medical News in May, Simeon I Taylor, MD, professor of medicine, University of Maryland School of Medicine, Baltimore, said, "I am not certain this safety signal is real, but I do believe it is appropriate to take it seriously....The numbers are small, so it is premature to draw firm conclusions about whether the apparent increase in amputations represents a true risk of the drug or whether it results from random statistical variation."

But there is biological plausibility, he said, citing a case-control study of 12,240 type 2 diabetic residents of eight Dutch cities, in which it was noted that thiazide diuretics were associated with a 6.11-fold increase in the risk of lower-extremity amputation when compared with ACE inhibitors (Pharmacoepidemiol Drug Saf. 2004;13:139-146).

Thiazide diuretics and SGLT2 inhibitors "both promote natriuresis and volume contraction. So it is tempting to hypothesize that volume contraction and an associated decrease in lower-extremity perfusion might possibly contribute to pathophysiological mechanisms leading to amputation."

Until more is known, Dr Taylor advised, "It is prudent for physicians and patients to…take this recent information into account when selecting therapeutic options. This particular safety concern may be most relevant for patients with peripheral neuropathy who are at increased risk for amputations."

http://www.medscape.com/

Graham