What are the risks of euglycemic diabetic ketoacidosis (DKA) associated with Jardiance (Empagliflozin)?

Jardiance (Empagliflozin) and Euglycemic DKA: Risks and Management

Empagliflozin (Jardiance) significantly increases the risk of euglycemic diabetic ketoacidosis (eDKA), a potentially life-threatening complication that can occur despite normal or only mildly elevated blood glucose levels (<200 mg/dL). 1, 2

Risk Factors and Mechanism

Euglycemic DKA associated with SGLT2 inhibitors like Jardiance occurs through several mechanisms:

• Pathophysiology:

  • Promotes glycosuria while reducing insulin and increasing glucagon levels
  • Stimulates lipolysis and enhances ketone production in the liver
  • Reduces renal clearance of ketones, leading to their accumulation 2

• Specific Risk Factors:

  • Very-low-carbohydrate or ketogenic diets
  • Prolonged fasting or reduced caloric intake
  • Dehydration
  • Excessive alcohol intake
  • Presence of autoimmunity
  • Insulin dose reduction
  • Acute illness or infection
  • Surgical procedures
  • Pregnancy
  • Hepatic dysfunction 1, 2

Clinical Presentation

Euglycemic DKA presents with:

• Severe metabolic acidosis symptoms (nausea, vomiting, abdominal pain, malaise)
• Shortness of breath
• Blood glucose levels <250 mg/dL (often <200 mg/dL)
• Elevated anion gap
• Positive ketones in blood or urine 2, 3

Diagnosis Challenges

The diagnosis of eDKA is challenging because:

• Absence of marked hyperglycemia often leads to delayed diagnosis
• Clinicians may not suspect DKA with normal or only mildly elevated glucose levels
• Traditional DKA screening may miss these cases 3

Prevention Strategies

To prevent eDKA in patients taking Jardiance:

• Temporary Discontinuation:

  • Stop Jardiance during acute illness
  • Discontinue 3-4 days before elective surgical procedures
  • Hold during critical illness or prolonged fasting 1, 2

• Patient Education:

  • Avoid very-low-carbohydrate diets
  • Never discontinue insulin (for insulin-dependent patients)
  • Monitor ketones during illness regardless of glucose levels
  • Recognize symptoms requiring immediate medical attention 2

• Insulin Management:

  • Provide detailed instructions on insulin dose adjustments during illness
  • Maintain basal insulin even when not eating 1

Management of Suspected eDKA

When eDKA is suspected:

1. Immediately discontinue Jardiance
2. Administer insulin to suppress ketogenesis
3. Provide glucose-containing fluids (may need higher concentrations of dextrose 10% or 20%)
4. Replace electrolytes as needed
5. Monitor ketones until resolution 2

Important Considerations

• eDKA is a rare but serious complication with a relative risk of 2.46 (95% CI 1.16–5.21) in randomized controlled trials 1
• The incidence rate is approximately 0.6–4.9 events per 1,000 patient-years in people with type 2 diabetes treated with SGLT2 inhibitors 1
• Pregnant individuals may be particularly vulnerable to eDKA and should be counseled about the risks 1
• Readily available clinical support can help patients self-manage hyperglycemia during illness and prevent emergency department visits 1

Despite these risks, SGLT2 inhibitors provide significant cardiovascular and renal benefits for appropriate patients, making proper risk assessment, patient education, and monitoring essential components of safe prescribing.