EMA to Review Diabetic Ketoacidosis Risk With SGLT2 Inhibitors

June 12, 2015

The European Medicines Agency (EMA) has begun a review of sodium-glucose cotransporter-2 (SGLT2) inhibitors used to treat type 2 diabetes to evaluate the risk for diabetic ketoacidosis ― a serious condition that normally only affects people with type 1 diabetes.

This comes just a month after the US Food and Drug Administration (FDA) issued a similar warning ― that use of these agents may lead to ketoacidosis requiring hospitalization; the US agency said it had identified 20 cases of diabetic ketoacidosis in patients treated with SGLT2 inhibitors from March 2013 to June 6, 2014. (Type 2 diabetes mellitus was noted as the indication in most of the cases cited by the FDA, type 1 diabetes mellitus was noted in a few cases, and for some cases, the indication was not specified.)

The EMA now says a total of 101 cases of diabetic ketoacidosis have been reported worldwide in EudraVigilance as of May 19, 2015, in patients treated with SGLT2 inhibitors for type 2 diabetes.

And although diabetic ketoacidosis is usually accompanied by high blood glucose levels, "in a number of these reports blood sugar levels were only moderately increased," the EMA says.

"These uncharacteristic blood levels could delay diagnosis and treatment," it warns, noting that "all [101] cases were serious and some required hospitalization."

Asked by Medscape Medical News at the American Diabetes Association Scientific Sessions earlier this week whether endocrinologists were concerned when the FDA had revealed this in May, Silvio Inzucchi, MD, of Yale Diabetes Center, New Haven, Connecticut, said they most certainly were.

The issue is particularly concerning because of the presentation, whereby a large number of patients appear to have "normal or just slightly high blood sugars," he noted. "It's a serious concern because it's euglycemic asymptomatic diabetic ketoacidosis."

SGLT2 inhibitors on the market in the United States and Europe include canagliflozin (Invokana, Janssen Pharmaceuticals), dapagliflozin (Farxiga/Forxiga, AstraZeneca Pharmaceuticals), and empagliflozin (Jardiance, Lilly/Boehringer), as well a number of combination products that include an SGLT2 inhibitor ― in Europe, these are marketed as Vokanamet (canagliflozin/metformin, Janssen-Cilag International), Xigduo (dapagliflozin/metformin, AstraZeneca), and Synjardy (empagliflozin/metformin, Boehringer Ingelheim).

In the United States, a combination product of empagliflozin plus the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (Glyxambi, Lilly/Boehringer) is also available.

The EMA says it will now review all available data on the risk for diabetic ketoacidosis with SGLT2 inhibitors "and consider whether any changes are needed in the way these medicines are used in the EU."

To put the 101 cases of diabetic ketoacidosis into context, the EMA says it is estimated that exposure to SGLT2 inhibitors "is over half a million patient-years. One patient-year is equivalent to 1 patient taking the medicine for 1 year."

"While the review is ongoing, healthcare professionals will be informed in writing of the risk of diabetic ketoacidosis and how to manage it," the agency states.

"Patients who have any concerns about their diabetes medicines should consult their doctor or pharmacist. It is important that patients with diabetes continue to take their prescribed treatment and do not stop treatment without first discussing with a healthcare professional."


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