Euglycemic DKA Secondary to SGLT2 inhibitors

Authors: Priyanka Kailash (MS-4, Campbell University School of Osteopathic Medicine), Kevin Weaver, DO (Program Director, Lehigh Valley Health Network), and Krystle Shafer, MD (Attending Physician, York Hospital) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

A 35-year-old male with a past medical history of type 2 diabetes arrives at the Emergency Department (ED) with altered mental status, nausea, vomiting, and diffuse abdominal pain that started 10 hours ago. The patient was recently started on an SGLT2 inhibitor. On examination, the patient is tachycardic (HR 126) and tachypneic (RR 25), with normal blood pressure (110/90). He is further noted to have dry mucous membranes and poor skin turgor. Blood glucose is noted to be 140 mg/dl, serum ketones 6.2 mmol/L, and arterial pH of 6.9. The patient is diagnosed with euglycemic DKA and quickly admitted to ICU for treatment.

Pathogenesis of Typical DKA

Two major complications from type 1 diabetes mellitus and type 2 diabetes mellitus are diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). DKA is typically seen in younger individuals, while HHS is typically seen in older patients(1).

In the pathogenesis of typical DKA, the body experiences a starved state. Insulin deficiency (either through decreased production or decrease sensitivity) leads to the inactivation of GLUT4 receptors on cells. GLUT4 receptors function to help transport glucose molecules into cells so that it can be converted into energy. Without GLUT4 receptor activation, the glucose entry into cells remains shut. Thus, the cells start to experience a starved state. To compensate, the body activates an alternative energy pathway – lipolysis. Lipolysis works by increasing the delivery of free fatty acids to the liver along with an increase in glucagon production. Lipolysis, along with an increase in glucagon production, results in free fatty acid oxidation and production of ketone bodies. Thus, this pathogenesis results in the four hallmark signs seen in patients with DKA(2, 3, 4, 8) – Hyperglycemia (>250mg/dl), hyperketonemia (4.2-11.0 mmol/L), glycosuria (2-4mg.min-1kg-1), and metabolic acidosis (<7.35 pH)

Euglycemic DKA

In the past, there has been reports of euglycemic DKA in pregnant women with diabetes mellitus, which was postulated to be a result of ketogenic changes during pregnancy. However, recently with the relatively new advent of sodium-glucose co-trasnposter2 (SGLT2) inhibitors, there have been considerably more cases of euglycemic DKA(5, 6).

Pathogenesis of Euglycemic DKA(7,8)

There are currently three theories for the hallmark signs seen in the euglycemic DKA (blood glucose levels <200mg/dl + hyperketonemia (4.2-11.0 mmol/L) + metabolic acidosis (<7.35 pH)):

  • SGLT-2 inhibitors work by preventing glucose reabsorption from the proximal renal tubules. The resulting glycosuria suppresses insulin release from the pancreatic beta-cells.  This triggers a cascade of events including lipolysis, free fatty acid oxidation, and ultimately an increased ketone body production.
  • The decrease in insulin also deactivates acetyl-CoA carboxylase, which further deactivates malonyl-CoA. Malonyl-CoA functions to inhibit carnitine palmitoyltransferase-I (CPT-I). CPT-I, thus not being inhibited by malonyl-CoA, functions to further promote beta-oxidation of fatty acids by increasing the transport of fatty acids into the mitochondria.
  • SGLT2 inhibitors directly and indirectly stimulates glucagon secretion. Glucagon inhibits acetyl-CoA carboxylase, which inhibits malonyl-CoA, which activates CPT-1. This promotes beta-oxidation of fatty acids by stimulating CPT-I activity once again.

FDA’s Role in SGLT2 Inhibitors 

The U.S Food and Drug Administration (FDA) issued a drug communication warning about the increased risk of euglycemic diabetic ketoacidosis with the use of sodium-glucose-cotransporter 2 inhibitors in May 2015. The decision was made by the FDA after 20 clinical cases of euglycemic DKA secondary to SGLT2 inhibitors were considered that required hospitalization of between May 2013 and June 2014(9).

As of May 2015, a total of 101 cases of euglycemic DKA secondary to SGLT2 inhibitors were reported worldwide, with an estimated exposure of 500,000 patient/year.

Risk Factors for Euglycemic DKA

The FDA has identified several risk factors that predispose patients to develop euglycemic DKA secondary to SGLT2 inhibitor use.  These risk factors include patients treated with insulin AND SGLT2 inhibitors, patients who are suffering from other concurrent illnesses, patients who have reduced their insulin doses, patients who have reduced food or fluid intake, and patients with a history of alcohol abuse(10).

Treatment

The treatment for euglycemic DKA is similar to typical DKA treatment(11)

  • Hydration: This is the first and most important step in the initial management of DKA patients. Administer 1 to 1.5 L of isotonic intravenous fluid (0.9% saline or lactated ringers) in the first hour.  Subsequent fluid replacement depends on the patient’s hydration status, serum electrolytes, serum glucose, and urinary output.
  • Insulin: Intravenous insulin is a necessary component in the management of DKA patients, but should not be administered until an accurate serum potassium level has been determined. Most resources recommend an insulin infusion of 0.1 u/kg/h be administered.  Insulin boluses should be avoided in order to prevent iatrogenic complications.  The insulin infusion should be continued until the patient’s hyperglycemia has resolved, acidosis has corrected, and the anion gap has normalized on two consecutive lab tests.
  • Dextrose: 5% Dextrose should be added to the intravenous fluid in all patients diagnosed with euglycemic DKA. This should coincide with the start of the insulin infusion in order to prevent iatrogenic hypoglycemia.
  • Potassium: Patients in DKA often have normal or high serum potassium levels despite having a large deficit secondary to their severe acidosis. Therefore, the serum potassium level should be checked before insulin treatment is initated as insulin will cause the potassium to shift from the intravascular space into the intracellular space.  This can cause severe hypokalemia and potentiate life-threating arrhythmias.   Insulin should not be administered unless potassium values are >3 to 3.5 mEq/L.  Additionally, 20-40 mEq/L of potassium may need to be added to IVF if the initial potassium level is less than <5.0 mEq/L.  Potassium levels should be monitored every 2 hours while on an insulin drip.

Take-Home Points

  • Increased awareness is needed in the emergency medicine community regarding SGLT-2 inhibitors precipitating euglycemic DKA.
  • Euglycemic DKA is dangerous if it is not diagnosed and treated appropriately.
  • Appropriate testing for patients on SGLT-2 inhibitors presenting with signs and symptoms suggestive of DKA requires appropriate laboratory testing, which should include a VBG, urine and serum ketones.
  • Once the diagnosis has been confirmed, treatment for DKA should be initiated immediately.
  • Hydration, insulin, and potassium are part of the three hallmark treatments.

 

References / Further Reading:

  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.
  2. Kemperman FA, Weber JA, Gorgels J, et al. The influence of ketoacids on plasma creatinine assays in diabetic ketoacidosis. Journal of Internal Medicine. 2000; 248:511.
  3. Kitabchi AE, Umpierrez GE, Fisher JN, Murphy MB, Stentz FB. Thirty years of personal experience in hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Journal of Clinical Endocrinology Metabolism. 2008; 93(5):1541.
  4. Nair S, Yadav D, Pitchumoni CS. Association of diabetic ketoacidosis and acute pancreatitis: observations in 100 consecutive episodes of DKA. American Journal of Gastroenterology. 2000; 95:2795.
  5. Ogawa, W. and Sakaguchi, K. (2016), Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. Journal Diabetes Invest. 2010; 7:135–138.
  6. Rosenstoc J, Ferrannini E. Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern with SGLT2 Inhibitors. Diabetes Care. September 2015; 38(9): 1638-1642.
  7. Wataru O, Sakaguchi K. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. Journal of Diabetes Investigation. March 2016; 7(2): 135-138.
  8. Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. Journal of Clinical Endocrinology Metabolism. 2015; 100:2849.
  9. European Medicines Agency. Review of diabetes medicines called SGLT2 inhibitors started: risk of diabetic ketoacidosis to be examined [Internet]. June 2015. Available from http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SGLT2_inhibitors__20/Procedure_started/WC500187926.pdf. Accessed 22 June 2015.
  10. S. Food and Drug Administration. Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood [Internet], 15 May 2015. Available from http://www.fda.gov/downloads/Drugs/DrugSafety/UCM446954.pdf. Accessed 25 February 2017.
  11. Gosmanov A, Gosmanova E, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes Metab Syndr Obes. 2014; 7:255-264.

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