SGLT2 inhibitor-associated euglycemic DKA

Electrolyte Disordersmedium

A 63-year-old man with a history of CKD stage 3, type 2 diabetes mellitus, and congestive heart failure with preserved ejection fraction presents to the emergency department with a 3-day history of nausea, vomiting, and malaise. He receives most of his care at another health system and is unable to provide a current medication list. Physical examination reveals a BP of 121/71 mm Hg, heart rate of 92/min, respiratory rate of 26/min, and temperature of 37.3°C. His abdomen is soft and nontender, and the remainder of the examination is normal. Laboratory data: sodium 136 mEq/L (reference 136–145); potassium 3.6 mEq/L (3.5–5.0); chloride 99 mEq/L (98–106); total CO₂ 12 mEq/L (23–28); glucose 161 mg/dL (70–99, fasting); creatinine 2.0 mg/dL (baseline) (0.7–1.3); lipase 33 IU/mL (10–140); lactic acid 0.6 mmol/L (0.7–2.1). Urinalysis reveals 3+ ketones and 2+ glucose but is otherwise normal. Which ONE of the following medications is MOST LIKELY to be the cause of this patient's clinical presentation?

  1. A.Metformin
  2. B.Sitagliptin
  3. C.CanagliflozinCorrect
  4. D.Semaglutide

Explanation

This patient has euglycemic diabetic ketoacidosis (DKA) most likely caused by the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin. Euglycemic DKA (eDKA) is defined by high anion gap metabolic acidosis, ketosis, and lack of hyperglycemia (serum glucose ≤200 mg/dL). This patient meets the diagnostic criteria for eDKA with a high anion gap metabolic acidosis and ketonuria, which indicates underlying ketosis. Typically, underutilization of gluconeogenesis by the liver or increased urinary excretion of glucose causes eDKA. There are many potential causes of eDKA, including pregnancy, fasting, glycogen storage diseases, liver disease, alcohol use, and pancreatitis. SGLT2 inhibitors, such as canagliflozin, have also been associated with an increased risk of eDKA. The risk of eDKA with SGLT2 inhibitor use is low but elevated compared with placebo. The pathophysiology of eDKA in patients receiving SGLT2 inhibitors is complex but may involve the use of lower insulin doses in patients receiving SGLT2 inhibitors, with insufficient suppression of lipolysis, promotion of glucagon secretion, and decreased renal clearance of ketone bodies. Metformin is more commonly associated with lactic acidosis. The lactic acid in this case was normal, making metformin a less likely culprit. Semaglutide and sitagliptin have not been independently associated with eDKA. Both have been associated with pancreatitis, but the serum lipase was normal in this case.

Why each option

A.
Metformin causes lactic acidosis, but his lactate is 0.6 mmol/L, so it cannot explain the anion gap of 25 with ketonuria.
B.
Sitagliptin has not been independently associated with euglycemic DKA, and normal lipase argues against drug-associated pancreatitis.
C.
Correct. Anion gap 25, ketonuria, and glucose 161 mg/dL with glycosuria indicate euglycemic DKA, a recognized complication of SGLT2 inhibitors such as canagliflozin.
D.
Semaglutide can cause nausea and vomiting but is not independently associated with euglycemic DKA, and lipase is normal.

Reference: Peters AL, Diabetes Care 2015 (euglycemic DKA associated with SGLT2 inhibitors)

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