Can SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors cause euglycemic diabetic ketoacidosis (DKA) in patients with normal insulin levels and normal insulin sensitivity?

SGLT2 Inhibitors Can Cause Euglycemic DKA Even in Patients with Normal Insulin Levels and Sensitivity

Yes, SGLT2 inhibitors can cause euglycemic diabetic ketoacidosis (DKA) in patients with normal insulin levels and normal insulin sensitivity. 1, 2

Mechanism of Euglycemic DKA with SGLT2 Inhibitors

• SGLT2 inhibitors lower glucose concentrations by promoting urinary glucose excretion, which alters the insulin/glucagon ratio and predisposes patients to ketosis, regardless of their baseline insulin status 2
• This mechanism can lead to ketoacidosis even when blood glucose levels remain below the typical threshold for DKA (< 250 mg/dL) 3
• Recent evidence challenges the previous belief that people without diabetes mellitus have sufficient insulin concentrations to prevent significant ketosis 1
• When physiological stress occurs, counterregulatory hormones drive hyperketonaemia, potentially leading to euglycemic DKA 2

Evidence Supporting Euglycemic DKA in Non-Diabetic Patients

• Multiple case reports document euglycemic DKA in patients without diabetes mellitus who were taking SGLT2 inhibitors 1, 2
• The pathophysiology remains the same in patients with or without diabetes mellitus 1
• The FDA drug label for dapagliflozin specifically warns about ketoacidosis risk with blood glucose levels below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL) 3

Risk Factors and Precipitating Conditions

• Precipitating conditions include: 3, 2

  • Reduced oral intake or fasting
  • Surgery or invasive procedures
  • Dehydration
  • Excessive alcohol intake
  • Acute febrile illness
  • Reduced caloric intake
  • Ketogenic diet
  • Volume depletion

• The risk of perioperative DKA is higher in patients taking SGLT2 inhibitors compared to those not taking them (1.02 vs. 0.69 per 1000 patients) 1, 2

• Emergency surgery carries a higher risk of DKA than elective surgery (1.1% vs. 0.17%) 1, 2

Clinical Presentation and Diagnostic Challenges

• Euglycemic DKA often presents with vague symptoms and near-normal glucose levels, which can delay diagnosis 4
• Signs and symptoms include: 3
  • Nausea
  • Vomiting
  • Abdominal pain
  • Generalized malaise
  • Shortness of breath
• The absence of significant hyperglycemia can delay recognition of the emergent nature of the problem by patients and providers 5

Prevention Strategies

• SGLT2 inhibitors should be withheld for at least 3 days prior to major surgery or procedures associated with prolonged fasting 3
• Resume SGLT2 inhibitors only when the patient is clinically stable and has resumed oral intake 3
• Maintain adequate hydration and avoid prolonged fasting periods 2
• Monitor glucose and ketone levels during high-risk periods 2
• Educate patients on the signs and symptoms of ketoacidosis and instruct them to seek immediate medical attention if these occur 3

Management of Suspected Euglycemic DKA

• Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis 3
• If ketoacidosis is suspected, discontinue the SGLT2 inhibitor immediately 3
• Promptly evaluate and treat ketoacidosis with intravenous insulin, dextrose-containing fluids, and electrolyte replacement 4, 6
• Monitor patients for resolution of ketoacidosis before considering restarting SGLT2 inhibitors 3

Important Considerations

• Ketoacidosis and glucosuria may persist longer than typically expected after discontinuing SGLT2 inhibitors 3
• Urinary glucose excretion persists for 3 days after discontinuation, but there have been reports of ketoacidosis lasting greater than 6 days and up to 2 weeks after stopping SGLT2 inhibitors 3
• The risk of euglycemic DKA exists as a continuum rather than having a defined threshold when it will not occur 2

In summary, healthcare providers should remain vigilant for this rare but serious condition in all patients taking SGLT2 inhibitors, regardless of their diabetes status or insulin sensitivity, particularly during periods of physiological stress.