Prolonged Ketosis in a Patient With Euglycemic Diabetic Ketoacidosis Secondary to Dapagliflozin

Abstract

Since the approval of sodium-glucose cotransporter 2 (SGLT2) inhibitors by the US Food and Drug Administration for type 2 diabetes, there have been several reports of euglycemic diabetic ketoacidosis in patients using this class of medication. We present a case of euglycemic diabetic ketoacidosis where ketonemia and glucosuria persisted well beyond the expected effect of dapagliflozin. Our patient is a 50-year-old woman with type 2 diabetes since age 35 who was taking metformin and dapagliflozin. She presented with fatigue, constipation, and 3 days of reduced oral intake. Laboratory data indicated anion gap acidosis, ketonemia, severe hypokalemia, and minimally elevated blood glucose. She was treated with sliding scale short-acting insulin and electrolyte replacement until hospital day 6, when endocrinology was consulted. An insulin drip was initiated due to persistent ketonemia and reopening of the anion gap, despite improved oral intake and normoglycemia. On stopping the insulin drip on day 9, the β-hydroxybutyrate increased again. It finally stabilized within normal range with the initiation of basal subcutaneous insulin. This case indicates that clinical effects of dapagliflozin persist much longer than the reported half-life of 12.9 hours would predict. To prevent this potentially dangerous complication, patients taking SGLT2 inhibitors who become ill should discontinue the medication, undergo ketone evaluation, and start basal insulin, if ketones are positive. In addition, patients should be educated to stop their SGLT2 inhibitor at least 1 week prior to elective procedures.

Recurrent diabetic ketoacidosis

“…SGLT2i have been associated with euglycemic diabetic ketoacidosis, a life-threatening emergency characterized by hyperglycemia with blood glucose levels < 200 mg/dL. This can result in delayed diagnosis and treatment with the potential for adverse metabolic consequences (25,26). We did not find in the literature cases of recurrent DKA among patients treated by SGLT2i, but the use of these drugs may lead to the development of potentially dangerous complications including DKA.…”

“…Patients taking SGLT2i who become ill should discontinue the medication, undergo prompt ketone evaluation and start basal insulin, if ketones are positive. In addition, patients should be educated to stop their SGLT2 inhibitor at least 1 week prior to elective procedures (26).…”

Review article: Ketoacidosis in the emergency department

“…Instruction of patients in home capillary ketone testing is advisable prior to discharge. While current recommendations are for cessation of SGLT2i for 3 days prior to elective surgery, prolonged ketonaemia with SGLT2i has led authors to recommend cessation at least 1 week prior to elective procedures . Trials of SGLT2i in non‐diabetic individuals are underway, some health professionals already using SGLT2i ‘off‐label’ in the management of obesity, cardiac and renal disease.…”

Sodium‐glucose co‐transporter type‐2 inhibitors: pharmacology and peri‐operative considerations

“…This was in the context of acute kidney injury, and is consistent with the prolonged elimination of the half‐life of SGLT2 inhibitors. The SGLT2 inhibitor effect can persist for up to 10 days even in the presence of normal renal function, increasing the risk of recurrent ketoacidosis and perhaps suggesting that the pharmacodynamic effect may persist beyond five elimination half‐lives . The time at which ketoacidosis developed postoperatively varied considerably, from one day to one month postsurgery.…”

“…Although the American Association of Clinical Endocrinologists and the American College of Endocrinology recommend stopping SGLT2 inhibitors at least 24 h before elective surgery, it may be appropriate to stop SGLT2 inhibitors approximately three days (or five half‐lives) before major surgery, given that the elimination half‐life of the SGLT2 inhibitors range from 11 h to 13 h and the pharmacodynamic effects may persist for several days . Given that the pharmacodynamic effects of SGLT2 inhibitors may outlast their predicted half‐life, some authors have recommended that they are ceased one week before elective surgery .…”