Euglycemic DKA: It’s not a Myth

Background: Diabetic ketoacidosis (DKA) is traditionally defined as a triad of hyperglycemia (>250mg/dL), anion gap acidosis, and increased plasma ketones. There is another entity that providers must be aware of known as euglycemic DKA (euDKA), which is essentially DKA without the hyperglycemia (Serum glucose <200 mg/dL). Euglycemic DKA is a rare entity that mostly occurs in patients with type 1 diabetes, but can possibly occur in type 2 diabetes as well. The exact mechanism of euDKA is not entirely known, but has been associated with partial treatment of diabetes, carbohydrate food restriction, alcohol intake, and inhibition of gluconeogenesis. euDKA, can also be associated with sodium-glucose cotransporter 2 (SGLT-2) inhibitor medications.  These medications first came onto the market in 2013 and are FDA approved for the treatment of type 2 diabetes, however many physicians use them off-label for type I diabetes due to their ability to improve average glucose levels, reduce glycemic variability without increasing hypoglycemia, and finally promote weight loss.

Does euDKA Exist even in Patients not Using SGLT-2 Inhibitors?

• The short answer is YES. Munro JF et al [5] reviewed a case series of 37 episodes of euDKA in a publication from 1973.  Although, dated and not robust evidence some take home messages can be derived:
  • All but one episode was in insulin dependent diabetics
  • Vomiting was the most frequent symptom of euDKA in 32% of patients
  • Management in most cases consisted of: Intravenous fluids and electrolyte replacement.
  • No deaths occurred in this case series

What are the Names of the SGLT-2 Inhibitors?

• Ipragliflozin (Suglat) – Approved in Japan
• Dapagliflozin (Farxiga) – 1^st SGLT2 Inhibitor Approved; Approved in US
• Luseogliflozin (Lusefi) – Approved in Japan
• Tofogliflozin (Apleway; Deberza) – Approved in Japan
• Canagliflozin (Invokana) – Approved in US & Canada
• Empagliflozin (Jardiance) – Approved in US

How do SGLT-2 Inhibitors Cause euDKA?

What is the Evidence that SGLT-2 Inhibitors Cause euDKA?

• Again, not robust but there are a few publications of case reports and case series
  • Peters AL et al. 2015: Case Series of 13 Cases [1]
  • Hine et al. Case Report of 2 Cases [3]
  • Hayami et al. Single Case Report [4]

Discussion:

• euDKA could be completely missed if just looking at the serum blood glucose alone. This could lead to worse outcomes for patients not started on treatment
• The exact incidence of euDKA in patients taking SGLT-2 inhibitors is really unknown, as this entity may be under reported or even completely missed
• The treatment of euDKA will be nearly identical to DKA:
  • IVF: Treat dehydration; In addition to balanced crystalloids, may need to start fluids with dextrose sooner in the treatment process, due to the serum blood glucose already being low (i.e. <200mg/dL),
  • IV Insulin:  Close the anion gap and reverse the metabolic acidosis

Clinical Take Home Point: In patients with diabetes mellitus, on a SGLT-2 inhibitor and/or carbohydrate food restriction, who present with nausea/vomiting, fatigue, or the development of a metabolic acidosis, checking a urine and/or serum ketones is critical to not miss a case of euDKA.

References:

1. Peters AL et al. Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment with Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care 2015; 38 (9): 1687 – 93. PMID: 26078479
2. Ogawa W and Sakaguchi K. Euglycemic Diabetic Ketoacidosis Induced by SGLT2 Inhibitors: Possible Mechanism and Contributing Factors. J Diabetes Investig 2016; 7 (2): 135 – 8. PMID: 27042263
3. Hine J et al. SGLT Inhibition and Euglycemic Diabetic Ketoacidosis. Lancet Diabetes Endocrinal 2015; 3: 503 – 504. PMID: 26025388
4. Hayami T et al. Case of Ketoacidosis by a Sodium-Glucose Cotransporter 2 Inhibitor in a Diabetic Patient with a Low-Carbohydrate Diet. J Diabetes Investig 2015; 6: 587 – 590. PMCID: PMC4578500
5. Munro JF et al. Euglycemic Diabetic Ketoacidosis. BMJ 1973; 2 (5866: 578 – 80. PMID: 4197425

For More Thoughts on This Topic Checkout:

• Craig Cocchio at Emergency Medicine PharmD: Euglycemic DKA from SGLT2 Inhibitors: Don’t Worry, I Can’t Pronounce Them Either
• Anton Helman at EM Cases: Best Case Ever 58 Euglycemic DKA
• Priyanka Kailash at EM Docs: Euglycemic DKA Secondary to SGLT2 Inhibitors

Post Peer Reviewed By: Anand Swaminathan (Twitter: @EMSwami)