SGLT 2 inhibitors and diabetic ketoacidosis

Last edited 11/2020 and last reviewed 08/2023

Following a review of the cases, EMA has recommended updating the product information of SGLT2 inhibitors to list diabetic ketoacidosis as a rare adverse reaction (affecting up to 1 in 1,000 patients) (1)

Patients taking these medicines should be aware of the symptoms of diabetic ketoacidosis, including rapid weight loss, nausea or vomiting, stomach 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 odour to urine or sweat. Patients should contact a doctor or the nearest hospital straightaway if they have any of these symptoms (2)

SGLT2 inhibitors increase the risk for diabetic ketoacidosis, particularly in patients with type 1 diabetes and those with certain high risk conditions

• in some cases blood glucose levels are normal or only mildly elevated, a condition known as euglycaemic ketoacidosis - this can delay the diagnosis
• it is advised to check ketones in patients taking SGLT2 inhibitors with symptoms or precipitating factors for ketoacidosis regardless of blood glucose levels (3)

In DKA associated with use of SGLT2 inhibitors:

• over a third of patients with ketoacidosis associated with SGLT2 inhibitor have normal or only mildly elevated blood glucose levels (<13.9 mmol/L, <250 mg/dL) - referred to as euglycaemic diabetic ketoacidosis (3)
• diagnosis can be delayed because of the absence of hyperglycaemia and the less severe polyuria polydipsia, owing to the milder degree of hyperglyacemia-induced osmotic diuresis

Possible predisposing conditions for the development of diabetic ketoacidosis in patients taking SGLT2 inhibitors include:

• excessive alcohol use or illicit drug use
• adherance to a very low carbohydrate or ketogenic diet
• unwillingness or inability to monitor ketone bodies
• pregnancy
• past history of diabetic ketoacidosis
• use of an insulin pump
• inappropriate reduction of insulin dose when using SGLT2 inhibitor
• late-onset autoimmune diabetes of adulthood (LADA)

Possible precipitating factors for diabetic ketoacidosis in patients taking SGLT2 inhibitors include:

• volume depletion/dehydration
• vomiting
• prolonged or vigorous exercise
• a failure of insulin pump or insulin infusion site
• acute illness
• hospitalisation for surgery
• travel where there has been a disruption of usual insulin regime

Information for healthcare professionals (1)

• rare cases of diabetic ketoacidosis, including life-threatening ones, have occurred in patients taking SGLT2 inhibitors, used to treat type 2 diabetes. A number of these cases were atypical with patients having only moderately raised blood sugar levels and some of them occurred during off-label use and clinical trials in patients with type 1 diabetes
  
  
• always consider the possibility of diabetic ketoacidosis in patients taking SGLT2 inhibitors who have non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness
  
  
• inform patients of the signs and symptoms of diabetic ketoacidosis and advise them to seek medical advice immediately if they develop such signs and symptoms
  
  
• stop treatment with SGLT2 inhibitors immediately if diabetic ketoacidosis is suspected or confirmed, and do not re-start treatment unless another clear precipitating factor for the condition is identified and resolved
  
  
• stop treatment with SGLT2 inhibitors temporarily in patients undergoing major surgical procedures or hospitalised due to acute serious medical illnesses. Treatment may be restarted once the patient's condition has stabilised

SGLT2 inhibitors: monitor ketones in blood during treatment interruption for surgical procedures or acute serious medical illness (2):

• SGLT2 inhibitor treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses and ketone levels measured, preferably in blood rather than urine. Treatment may be restarted when the ketone values are normal and the patient's condition has stabilised
  
  
• Advice for healthcare professionals:
  • interrupt sodium-glucose co-transporter 2 (SGLT2) inhibitor treatment in patients who are hospitalised for major surgical procedures or acute serious medical illnesses
  • monitor ketones during this period – measurement of blood ketone levels is preferred to urine
  • restart treatment with the SGLT2 inhibitor once ketone values are normal and the patient’s condition has stabilised
  • report suspected adverse drug reactions to SGLT2 inhibitors to the Yellow Card Scheme

Diagnosis of diabetic ketoacidosis if on an SGLT2 inhibitor (3):

• because blood glucose levels are often lower in diabetic ketoacidosis associated with SGLT2 inhibitor use - euglycaemic diabetic ketoacidosis - then the omostic diuresis associated with diabetic ketoacidosis occuring in other circumstances is not always a prominent symptom
• if clinical features suggestive of possible diabetic ketoacidosis then
diagnosic features are:
• increased ketones in blood (beta-hydroxybutyrate >= 3 mmol/L) or urine (ketonuria ++ or higher on urine dipsticks) - note that blood ketone testing is preferred over urine test strips as it is more accurate for detecting onset and resolution of ketosis
• acidosis—serum bicarbonate <15 mmol/L and/or blood pH <7.3

Reference:

• EMA (16/2/16).EMA confirms recommendations to minimise ketoacidosis risk with SGLT2 inhibitors for diabetes
• MRHA (18/3/2020). SGLT2 inhibitors: monitor ketones in blood during treatment interruption for surgical procedures or acute serious medical illness
• Musso G et al. Diabetic ketoacidosis with SGLT2 inhibitors.BMJ 2020;371:m4147 http://dx.doi.org/10.1136/bmj.m4147