Interim update on risk of serious ketoacidosis associated with sodium-glucose cotransporter-2 (SGLT2) inhibitors

HSA would like to highlight overseas cases of diabetic ketoacidosis (DKA), ketoacidosis or ketosis that have been reported with sodium-glucose cotransporter-2 (SGLT2) inhibitors. Locally, HSA has also received three reports of DKA associated with SGLT2 inhibitors. HSA and several international regulatory agencies have embarked on the safety review of this potential signal of serious ketoacidosis with SGLT2 inhibitors in view of the local and international signals.

SGLT2 inhibitors are a new class of antidiabetic medication that works by increasing the renal excretion of glucose, thereby resulting in a reduction in plasma glucose concentration, independent of changes in insulin concentrations or peripheral insulin resistance.¹ Three SGLT2 inhibitors, namely canagliflozin (Invokana^TM, Johnson & Johnson Pte Ltd), dapagliflozin (Forxiga®, AstraZeneca Singapore Pte Ltd) and empagliflozin (Jardiance®, Boehringer Ingelheim Singapore Pte Ltd), have been registered locally since February 2014, April 2014 and December 2014, respectively. They are indicated as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus, as monotherapy, add-on combination therapy with other glucose-lowering agents including insulin, and/or initial combination therapy with metformin.

Overseas cases identified by international regulatory agencies

a) US Food and Drug Administration (FDA)

The US FDA issued a drug safety communication in May 2015 informing that it is investigating the risk of serious ketoacidosis associated with SGLT2 inhibitors.² The review was triggered by the identification of 20 cases of DKA, ketoacidosis or ketosis reported with SGLT2 inhibitors from the FDA Adverse Event Reporting System (FAERS) database from March 2013 through June 2014. A temporal association with SGLT2 inhibitor initiation was noted in all cases, with a median time-to-onset of two weeks (range 1 to 175 days). Of note was the atypical presentation of the DKA cases, in that glucose levels were only mildly elevated at less than 200mg/dL (or 11mmol/L) in some reports, as compared to glucose levels of greater than 250mg/dL (or 14mmol/L) typically seen in patients with type 1 diabetes. Half of the cases also did not identify a triggering factor for DKA. Upon the completion of its investigation, the US FDA will determine if changes are required in the labelling for this class of drugs.

b) European Medicines Agency (EMA)

In June 2015, the EMA highlighted that it has initiated a review to evaluate the risk of DKA associated with SGLT2 inhibitors at the request of the European Commission following identification of a safety signal.³ Using the search terms “DKA”, “ketoacidosis” and “ketosis”, a search in the Eudravigilance database in May 2015 for SGLT2 inhibitors identified 96 cases associated with canagliflozin, 46 cases associated with dapagliflozin and five cases associated with empagliflozin.

c) Health Canada

Health Canada initiated a safety review of SGLT2 inhibitors and risk of ketoacidosis in June 2015.⁴ A preliminary search of Health Canada’s adverse reaction database identified one report of DKA involving hospitalisation of a patient taking an SGLT2 inhibitor and other concomitant medications.

Local cases of DKA

HSA has been closely monitoring the safety profile of the SGLT2 inhibitors following their registration in Singapore. As of August 2015, HSA has received three local serious reports of DKA associated with SGLT2 inhibitors.

The first report involved a 60-year-old male patient who developed DKA after 43 days of canagliflozin therapy. His concomitant medications included insulin glargine, metformin, sitagliptin and thyroxine. Upon admission, his blood glucose level was 9.8mmol/L and his urine was positive for ketones (3+).

The second report involved a 43-year-old female patient who developed DKA after 11 days of canagliflozin therapy and was subsequently hospitalised for three days. Her concomitant medication included metformin, which she had been compliant in taking for more than five years. Upon admission, the patient had normal serum creatinine without any medical history of infections. Her blood glucose level was 16.3mmol/L and ketones were detected in her urine (3+).

The third report involved a 60-year-old female patient who was newly diagnosed with diabetes. She was initially thought to have type 2 diabetes mellitus and started on oral therapy, but the diagnosis was later changed to late-onset type 1 diabetes mellitus. The patient developed DKA after 81 days of dapagliflozin therapy. Upon admission, her blood glucose level was 13.7mmol/L and her urine was positive for ketones.

HSA’s actions and advisory

HSA is reviewing the current available information and seeking expert opinions from local clinicians on this risk to determine if there is a need for further regulatory actions. Dear Healthcare Professional Letters (DHCPLs) were issued by the three product licence holders in July 2015 to warn of serious and sometimes life-threatening cases of DKA during treatment with SGLT2 inhibitors.

While HSA’s review is ongoing, healthcare professionals are advised to remain vigilant to the signs and symptoms of DKA in patients who are prescribed SGLT2 inhibitors. Healthcare professionals are encouraged to counsel patients and caregivers on the symptoms of metabolic acidosis, such as tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy or mental status changes, and the need to seek medical attention promptly upon experiencing such symptoms.

Healthcare professionals are also encouraged to report any adverse reactions suspected to be associated with the use of SGLT2 inhibitors to the Vigilance and Compliance Branch of HSA.

HSA will provide an update on the outcome of our review when it is completed.

References

Healthcare professional, Industry member, Therapeutic Products

Published: 30 Sep 2015

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