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Risk of Euglycemic Diabetic Ketoacidosis After Initiation of an SGLT-2 Inhibitor

Jun 16, 2018
 

Detection of euglycemic diabetic ketoacidosis could be a challenge for physicians since this condition can mask an underlying diabetic ketoacidosis.

Using the database of Therapeutic Goods Administration (TGA) of the Australian Government Department of Health, the authors of “SGLT2 Inhibitor–Associated Euglycemic Diabetic Ketoacidosis” were able to assess all the Diabetes Ketoacidosis (DKA) cases from December 2015 to March 2017. The search terms “diabetic ketoacidosis,” “ketoacidosis,” and the brand/generic drug names were used to identify a total of thirteen cases of SGLT2 inhibitor associated DKA within the determined time frame.

Out of the thirteen cases, five had type 1 diabetes (T1D) and eight had type 2 diabetes (T2D), half of patients with type 2 diabetes were on insulin therapy. Nine patients were using dapagliflozin and four empagliflozin; nine patients required intensive care, all the thirteen required IV insulin and dextrose and one patient died because of cardiac complications.

According to the adverse event report provided by TGA, the medical team initially overlooked two DKA diagnoses and in another six patients, they were unable to correlate the SGLT2 inhibitors with DKA.

On the other hand, in the subsequent month of April 2017, 82 new notifications of SGLT2 inhibitors associated with DKA have been reported to the TGA. Reports include twenty-four patients with T2D and nine patients with T1D, but in most cases, the diabetes status was not documented. Two reports of DKA occurred with off-label drug use for weight loss or insulin resistance, both precipitated by a gastrointestinal illness. Eighteen reports of DKA were managed in intensive care, and sixteen were classified as life-threatening. The average duration of SGLT2 inhibitor use prior to DKA presentation was 11.6 weeks. The mean characteristics experienced for these patients were pH 7.06, bicarbonate 7.35 mmol/L, ketones 6.2 mmol/L, anion gap 23.7 mmol/L and blood glucose of 14.1 mmol/L (254mg/dL). A total of 85,851 SGLT2 inhibitor prescriptions were dispensed in South Australia over the 16 months of study duration.  This is an equivalent of 7,154 patients per year on SGLT2 inhibitor therapy, in which 13 of them presented SGLT2 inhibitor-associated DKA. The adverse event rate was 1.8 cases of SGLT2 inhibitor-associated DKA per 1,000 patient/year. Since DKA often occurs in the absence of marked hyperglycemia, the authors suggest temporary cessation of these drugs during acute illness or surgery.

On the other hand, they identified four key points regarding DKA and the further treatment:

  1. Most patients are unaware to recognize euglycemic DKA.
  2. Some physicians initially overlooked DKA due to relative normal blood glucose levels.
  3. Delayed treatment often occurs.
  4. Identifiable precipitants were often present and can be used to rule out any other condition.

Moreover, this case series could be used as a reminder to the physicians to consider ketosis in a patient who is taking SGLT2s despite their serum glucose levels being within the normal range.

Practice Pearls:

  • Consider ketosis in patients with DKA even if their serum glucose levels are normal.
  • A clinical intuition is often required to diagnose EDKA as normal blood glucose levels masquerade the underlying DKA and cause a diagnostic and therapeutic dilemma.
  • It is important to check the blood pH and urine ketones in all acute ill patients with diabetes regardless of blood glucose levels.

Reference:

Meyer EJ, Gabb G, Jesudason D. SGLT2 Inhibitor–Associated Euglycemic Diabetic Ketoacidosis: A South Australian Clinical Case Series and Australian Spontaneous Adverse Event Notifications. Diabetes Care. 2018;41(4). doi:10.2337/dc17-1721.

Kennen Munoz Munoz, Pharm. D. Candidate 2019, LECOM School of Pharmacy