EMA instructs warning about SGLT2 inhibitors to appeal on labels

Jack Woodfield
Mon, 13 Feb 2017
EMA instructs warning about SGLT2 inhibitors to appeal on labels
The European Medicines Agency (EMA) has determined that sodium-glucose co-transporter 2 (SGLT2) inhibitors, which treat type 2 diabetes, should state an increased risk of lower-limb amputation in the prescribing information.

SGLT2 inhibitors help to reduce blood glucose levels by excreting excess sugar through urine. They have been approved as a type 2 diabetes treatment in the UK since 2013.

This warning has been made following an EMA investigation into two ongoing clinical trials with canagliflozin (marketed as Invokana) in patients at high risk of cardiovascular events. Both trials found an increased risk of amputation, mostly of toes, among users of the drug.

But the warning specifies that the lower-limb amputation risk would be an "uncommon side effect", occurring in between one and 10 per 1,000 patients.

In the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial, the rate of amputations per every 1,000 patients was equivalent to seven for 100mg/day of canagliflozin and five for 300 mg/day. This compared with three per 1,000 patients taking placebo.

The CANVAS-R trial, a related study of renal end points, also found a small increase in amputations among canagliflozin users. However, no such increase was observed in 12 other completed clinical trials of the drug.

"The mechanism by which canagliflozin may increase the risk of amputation is still unclear," according to a statement from the EMA's Pharmacovigilance Risk Assessment Committee (PRAC).

"An increased risk has not been seen in studies with other medicines in the same class, dapagliflozin (Forxiga) and empagliflozin (Jardiance). However, data available to date are limited and the risk may also apply to these other medicines. Further data are expected from ongoing studies with canagliflozin, dapagliflozin, and empagliflozin."

The PRAC has recommended that a warning about lower-limb amputation risk should be included in the prescribing information for all SGLT2 inhibitors.

Clinicians are advised to consider ceasing SGLT2 inhibitor treatment if a patient is developing foot problems, such as ulcers or infections.
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