The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) issued a recommendation late last week to include a warning for increased risk of lower limb amputations as an “uncommon side effect” on the labels for all SGLT-2 inhibitors. The recommendation will now be sent to CHMP for a final opinion on the inclusion of the warning on the labels. The EMA announcement noted that this recommendation is based on the increased risk of mostly toe amputations observed in interim analyses of the CANVAS and CANVAS-R cardiovascular outcomes trials for J&J’s Invokana (canagliflozin). The announcement acknowledged that no such increased risk has been observed in studies for AZ’s Farxiga (dapagliflozin) and Lilly/BI’s Jardiance (empagliflozin) thus far, yet the committee still recommends that the warning apply to these medications. While some have been surprised by the decision to expand the warning to include all three products in the class, especially in the case of Jardiance as long-term EMPA-REG OUTCOME CVOT data is already available for that particular drug with no reported increased risk – it appears that the EMA is taking a “better safe than sorry” approach. The EMA first initiated a safety review of the Invokana franchise specifically in April 2016 on this issue, followed by an expanded investigation to include Farxiga and Jardiance in July. The FDA initiated its own investigation of Invokana in May, and it’s unclear at this point whether the FDA is considering an official label warning for Invokana and whether all three SGLT-2 inhibitors are under safety review. The mechanism of increased risk is unknown at this point, as is whether the risk can be managed clinically. This updated label warning is the latest in a string of potential safety concerns for the SGLT-2 inhibitor class and we hope for greater clarity on these safety signals in the near future. We certainly hope that these concerns do not discourage the use of these agents, given glucose-lowering efficacy, low risk of hypoglycemia, weight loss benefits, and potential for cardio- and renal protection.
-- by Helen Gao and Kelly Close