Consumers and health professionals are advised that the TGA is working with sponsors of sodium glucose co-transporter 2 (SGLT2) inhibitors to update medicine information documents to strengthen warnings about the risk of diabetic ketoacidosis with these medicines. In particular, the risk is increased in people who undergo surgical or medical procedures. This action has been prompted by an increase in the number of local reports received by the TGA of diabetic ketoacidosis occurring in people being treated with these medicines in Australia.
SGLT2 inhibitors belong to a class of medicine that helps to control the levels of blood sugar (glucose) in patients with type 2 diabetes mellitus. These prescription medicines are typically used in conjunction with diet and exercise and in combination with other medicines.
SGLT2 inhibitors currently marketed in Australia are dapagliflozin and empagliflozin. Brand names for dapagliflozin-containing products are Forxiga, Qtern and Xigduo XR. Brand names for empagliflozin-containing products are Jardiance, Jardiamet and Glyxambi.
There is a known association between treatment with SGLT2 inhibitors and diabetic ketoacidosis and there is information about this potential side effect in the Product Information and Consumer Medicine Information documents for these products. The TGA has also previously published an article about this issue in its health professional-targeted medicine safety bulletin, Medicines Safety Update, in October 2015.
Diabetic ketoacidosis is an acute complication of diabetes, in which substances called ketone bodies build up in the blood. Early signs and symptoms of diabetic ketoacidosis, typically developed over 24 hours, include abdominal pain, nausea, vomiting, anorexia (loss of appetite), excessive thirst, difficult breathing, unusual fatigue and sleepiness. It typically presents with high glucose levels, however atypical diabetic ketoacidosis occurring at lower levels of blood glucose, known as 'euglycaemic ketoacidosis', may also occur. If diabetic ketoacidosis is not diagnosed early and treatment initiated, more serious signs and symptoms including dehydration, deep gasping breathing, confusion and coma can potentially develop.
The TGA continues to receive reports of diabetic ketoacidosis, including some reports of 'euglycaemic ketoacidosis'. A number of reports involved patients who had undergone a surgical operation or a medical procedure requiring anaesthesia or light sedation, including cardiovascular, bariatric, orthopaedic or gastrointestinal procedures.
Reports received by the TGA also included cases in which patients with type 1 diabetes had been prescribed an SGLT2 inhibitor. SGLT2 inhibitors are not registered for use in patients with type 1 diabetes.
Risk factors in other cases included patients experiencing acute illness, such as infections, gastrointestinal conditions, cardiovascular conditions, dehydration, malnourishment/reduced caloric intake and non-adherence with insulin or reductions in insulin dose.
Information for consumers
If you or someone you provide care for takes an SGLT2 inhibitor, such as dapagliflozin (Forxiga, Qtern or Xigduo XR) or empagliflozin (Jardiance, Jardiamet or Glyxambi), please be aware of this issue.
The early signs of diabetic ketoacidosis include abdominal pain, nausea, vomiting, anorexia (loss of appetite), excessive thirst, difficult breathing, unusual fatigue and sleepiness. Seek immediate medical attention if you are experiencing any of these symptoms.
Additionally, if you are planning to undergo a surgical procedure, talk to your doctor.
If you have any questions or concerns about this issue, speak to your diabetes nurse educator or other health professional.
Information for health professionals
As of 21 March 2018, the TGA Database of Adverse Event Notifications (DAEN) contains 219 reports of diabetic ketoacidosis (or metabolic acidosis) involving either empagliflozin or dapagliflozin as a suspected medicine. An increase in reporting began to emerge in mid-2017. 57 reports have been received since December 2017 (empagliflozin 30 reports and dapagliflozin 27). Potential precipitating factors were not specified in all reports. Of the 57 reports received since December 2017, 17 describe the use of an SGLT2 inhibitor in the period before or after a major surgical or medical procedure. There were 7 reports in which patients with type 1 diabetes had been prescribed an SGLT2 inhibitor. SGLT2 inhibitors are not registered for use in patients with type 1 diabetes. In 14 reports, an acute medical illness was described. Multiple factors predisposing to diabetic ketoacidosis were described in some cases.
If you are treating patients with an SGLT2 inhibitor, you are reminded of the potential risk of diabetic ketoacidosis. Factors that predispose diabetic patients to ketoacidosis include:
- surgery
- acute illness, particularly infections
- insulin dose reduction
- a low carbohydrate diet
- malnourishment/reduced caloric intake
- severe dehydration
- previous ketoacidosis
- insulin deficiency from any cause (such as insulin pump failure, history of pancreatitis or pancreatic surgery)
- alcohol abuse.
Treatment with an SGLT2 inhibitor should be ceased prior to major surgery. Treatment may be restarted once the patient's condition has stabilised following surgery and oral intake is normal. For other clinical situations known to predispose to ketoacidosis, consider monitoring for ketoacidosis and temporarily ceasing the SGLT2 inhibitor.
You are advised to educate patients about the signs and symptoms of diabetic ketoacidosis and instruct them to immediately seek medical advice if any such symptoms are experienced.
Patients presenting with signs and symptoms of diabetic ketoacidosis should be assessed for metabolic acidosis, even if their blood glucose levels are below 14 mmol/L, to avoid delayed diagnosis and treatment.
Advice on the perioperative management of patients relating to this issue has been published by the Australian Diabetes Society under the heading 'ALERT - Severe Euglycaemic Ketoacidosis with SGLT2 Inhibitor Use in the Perioperative Period'.
Reporting problems
Consumers and health professionals are encouraged to report problems with medicines or vaccines. Your report will contribute to the TGA's monitoring of these products.
The TGA cannot give advice about an individual's medical condition. You are strongly encouraged to talk with a health professional if you are concerned about a possible adverse event associated with a medicine or vaccine.