EMA on Lowering Risk of Diabetic Ketoacidosis With SGLT2 Inhibitors

February 12, 2016

The European Medicines Agency (EMA) is alerting doctors and other healthcare professionals to the possibility of atypical cases of diabetic ketoacidosis (DKA) associated with use of sodium-glucose cotransporter-2 (SGLT2) inhibitors, a relatively new class of oral medications used to treat type 2 diabetes.

The announcement follows a review, conducted by the EMA's Pharmacovigilance Risk Assessment Committee (PRAC), and aims to help minimize the risk of DKA associated with the use of this class of drugs.

The issue initially came to light in May 2015, when the US Food and Drug Administration issued a notice on the basis of 20 cases of DKA associated with SGLT2 inhibitors reported to the agency's adverse-event reporting system. A month later, the EMA initiated its review and identified 101 cases worldwide associated with type 2 diabetes.

Diabetic ketoacidosis is a serious complication of diabetes caused by low insulin levels. The issue is of considerable concern because ketoacidosis is not typically observed in patients with type 2 diabetes.

"Rare cases of this condition, including life-threatening ones, have occurred in patients taking SGLT2 inhibitors for type 2 diabetes, and a number of these cases have been atypical, with patients not having blood sugar levels as high as expected," states EMA.

Patients with type 1 diabetes who have DKA typically have very high glucose levels.

Be Aware of DKA Symptoms, Prescribe With Caution

An atypical presentation of DKA can delay diagnosis and treatment, so doctors and others treating diabetes patients should therefore consider the possibility of ketoacidosis in those taking SGLT2 inhibitors who have symptoms consistent with the condition, even if blood glucose levels are not high, the EMA adds.

And "patients taking any of these medicines should be aware of the symptoms of DKA, including rapid weight loss, nausea or vomiting, abdominal pain, excessive thirst, fast and deep breathing, confusion, unusual sleepiness or tiredness, a sweet smell to the breath, a sweet or metallic taste in the mouth, or a different odor to urine or sweat," EMA urges.

If they have any of these symptoms, patients should contact a healthcare professional. If DKA is suspected or confirmed, treatment with the SGLT2 inhibitor should be stopped immediately "and should not be restarted unless another cause for the ketoacidosis is identified and resolved," states EMA

For their part, when considering SGLT2 therapy, prescribers should exercise caution in patients with risk factors for ketoacidosis and inform patients of the risk factors.

These include low reserve of insulin-secreting cells, conditions that restrict food intake or can lead to severe dehydration, a sudden reduction in insulin, or an increased requirement for insulin due to illness, surgery, or alcohol abuse.

In addition, the PRAC recommends temporarily stopping SGLT2-inhibitor treatment in patients in the hospital for major surgical procedures or due to serious illness.

More Prescribing of SGLT2 Inhibitors After EMPA-REG?

Despite the concerns, US organizations such as the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) have advised that use of SGLT2 inhibitor drugs should continue in patients with type 2 diabetes, in line with current recommendations.

Cases of DKA associated with off-label use of SGLT2 inhibitors in type 1 diabetes have also been reported; the AACE also said that the investigational use of this drug class in type 1 should continue, since initial results have shown a promising impact on glycemic control.

There three SGLT2 inhibitors currently on the market in the European Union for use in type 2 diabetes are empagliflozin (Boehringer Ingelheim/Eli Lilly), canagliflozin (Johnson & Johnson/Janssen), and dapagliflozin (AstraZeneca/Bristol-Myers Squibb), and they are available (alone or in combination with metformin) under the following trade names: Ebymect, Edistride, Forxiga, Invokana, Jardiance, Synjardy, Vokanamet, and Xigduo.

Use of these agents received a boost with the results of the EMPA-REG OUTCOME study, reported last September, in which empagliflozin was shown to offer a survival benefit for the first time, in addition to lowering blood glucose, in type 2 diabetes patients with established cardiovascular disease, and Boehringer Ingelheim, which markets the agent, has recently applied to the US FDA to add a claim for cardiovascular risk reduction to the labeling for empagliflozin.

A recent Medscape poll of doctors has indicated that the EMPA-REG findings have led to an increase in prescribing, at least of this specific agent.

European Medicines Agency. Published February 12, 2016. Available here.


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