Is it safe to prescribe dapagliflozin (SGLT2 inhibitor) to a patient with ketonuria (presence of ketones in the urine)?

Dapagliflozin Should Not Be Prescribed to Patients with Ketonuria

Dapagliflozin is contraindicated in patients with ketonuria due to the significantly increased risk of euglycemic diabetic ketoacidosis (euDKA), which can be life-threatening. 1, 2

Understanding the Risk of Euglycemic DKA

• SGLT2 inhibitors like dapagliflozin increase the risk of euglycemic diabetic ketoacidosis, which is characterized by metabolic acidosis and ketosis without marked hyperglycemia (blood glucose <250 mg/dL) 1
• The presence of ketones in urine (ketonuria) indicates that the patient is already in a ketotic state, which would be dangerously exacerbated by initiating dapagliflozin 2
• Euglycemic DKA is particularly dangerous because the absence of significant hyperglycemia often delays recognition and treatment of this potentially life-threatening condition 1, 2

Mechanism of Increased Risk

• Dapagliflozin promotes urinary glucose excretion independent of insulin, which can:
  • Increase glucagon levels, leading to enhanced lipolysis and ketone production 2
  • Cause volume depletion, further increasing stress hormones 3
  • Reduce renal clearance of ketones, exacerbating ketosis 2

Risk Factors and Precipitating Conditions

• Patients with existing ketonuria are already demonstrating metabolic derangement that puts them at higher risk 1, 2
• Other risk factors that would compound this danger include:
  • Poor oral intake or fasting 1
  • Acute illness 3
  • Insulin dose reduction 3
  • Surgery or procedures requiring fasting 4, 5

Clinical Implications

• Euglycemic DKA associated with SGLT2 inhibitors can be severe and require intensive care management 1, 6
• Cases have been reported where euDKA recurred even after 8 days of discontinuing the SGLT2 inhibitor, with persistent ketonuria and glucosuria for up to 11 days 5
• The American Diabetes Association and KDIGO consensus report emphasizes the importance of monitoring for ketosis in patients taking SGLT2 inhibitors 3

Alternative Approaches

• For patients with ketonuria, prioritize:
  • Addressing the underlying cause of ketosis before considering an SGLT2 inhibitor 3
  • Using alternative glucose-lowering agents that don't increase ketone production 3
  • If an SGLT2 inhibitor is eventually considered (after resolution of ketonuria), implement strict monitoring protocols including:
    • Blood or urine ketone testing 3
    • Patient education on signs/symptoms of ketoacidosis 3
    • Sick day protocols with instructions to hold the medication during illness 3

Additional Safety Considerations

• SGLT2 inhibitors like dapagliflozin also increase the risk of urinary tract infections 7
• Male patients with urinary tract outlet obstruction may be at particularly high risk for urinary tract infections when taking dapagliflozin 7
• The medication should be withheld for at least 3 days prior to major surgery or procedures requiring prolonged fasting 4

In conclusion, the presence of ketonuria represents a clear contraindication to initiating dapagliflozin therapy due to the substantially increased risk of developing life-threatening euglycemic diabetic ketoacidosis. Alternative glucose-lowering therapies should be selected until the underlying cause of ketosis is identified and resolved.