Canada Reviews Diabetic Ketoacidosis Risk With SGLT2 Inhibitors

June 30, 2015

Health Canada has become the latest regulatory agency to begin a safety review into the risk of the serious side effect of diabetic ketoacidosis (DKA) associated with use of sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Two such agents, dapagliflozin (Forxiga, AstraZeneca) and canagliflozin (Invokana, Johnson & Johnson), are approved in Canada to improve blood glucose control in patients with type 2 diabetes, along with diet and exercise.

Although DKA is well-recognized in type 1 diabetics, it rarely occurs in patients with type 2 diabetes. One of the most concerning aspects of the DKA associated with SGLT2-inhibitor use is that, in most cases, it is euglycemic — that is, glucose levels are not significantly increased, so patients have few symptoms and are not aware of what is happening.

The Canadian move follows a similar review into the risk of DKA associated with SGLT2-inhibitor use launched recently by the European Medicines Agency (EMA).

The EMA has reported 101 cases of DKA worldwide in patients with type 2 diabetes. The US FDA also issued a warning on this, in May, having documented 20 cases of euglycemic DKA linked to SGLT2-inhibitor use, most of which were in patients with type 2 diabetes.

SGLT2 inhibitors have also been used off label in patients with type 1 diabetes, but following this association with DKA, experts have warned doctors against such use. A recently published case series reported euglycemic diabetic ketoacidosis (DKA) in nine patients, seven of whom had type 1 diabetes and two type 2 diabetes.

Health Canada says it has received one report of diabetic ketoacidosis involving the hospitalization of a 56-year-old male taking one of the SGLT2 inhibitors. The patient was taking other medications at the time and further assessment will be conducted.

The agency says it will review the available information and will determine whether changes are needed in the prescribing information for this class of drugs. Health Canada will communicate the results of its review once it is complete.

While the review is progressing, it is advising Canadians of this potential risk and encouraging them to report adverse reactions. Symptoms of ketoacidosis include difficulty breathing, feeling very thirsty, vomiting, abdominal pain, nausea, loss of appetite, confusion, and unusual tiredness.

"Seek urgent medical attention if you think you have these symptoms," it warns patients. "You should not stop treatment with Forxiga or Invokana without first consulting a healthcare professional."

For healthcare professionals, the agency has this advice: "Evaluate patients with type 2 diabetes [who are] taking an SGLT2 [inhibitor] and who show signs of diabetic ketoacidosis regardless of blood sugar levels."

Treatment with an SGLT2 inhibitor should be discontinued if acidosis is confirmed, and appropriate measures should be taken to treat the acidosis and monitor glucose levels.

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