What medications are associated with an increased risk of euglycemic Diabetic Ketoacidosis (DKA)?

Medications Associated with Euglycemic Diabetic Ketoacidosis

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the primary class of medications responsible for euglycemic diabetic ketoacidosis (euDKA), a potentially life-threatening condition characterized by metabolic acidosis with ketosis despite normal or only mildly elevated blood glucose levels (<200 mg/dL). 1

SGLT2 Inhibitors and euDKA Risk

Specific Medications

• Canagliflozin
• Empagliflozin
• Dapagliflozin
• Ertugliflozin
• Sotagliflozin (SGLT1/2 inhibitor)

Risk Factors for euDKA with SGLT2 Inhibitors

1. Patient-Related Factors:

   • Type 1 diabetes (highest risk) 2
   • Late-onset type 1 diabetes (LADA) (approximately 5-10% of adult-onset diabetes) 1
   • Insulin deficiency states
   • History of DKA

2. Precipitating Factors:

   • Surgical procedures 3
   • Reduced food intake or fasting 1
   • Acute illness 1
   • Alcohol consumption 1
   • Substantial reduction in insulin dose (>20%) 1
   • Very low-carbohydrate diets 1
   • Dehydration 1
   • Pregnancy 1
   • Liver failure 1

Mechanism of euDKA

SGLT2 inhibitors promote euDKA through:

• Increased urinary glucose excretion without affecting ketone clearance
• Reduced insulin and increased glucagon levels
• Volume depletion
• Non-insulin-dependent glucose clearance 2

Risk Quantification

The risk of DKA in patients receiving SGLT2 inhibitors is approximately 3.7 times higher than with other diabetes medications 4. In type 2 diabetes, DKA incidence with SGLT2 inhibitors ranges from 0.6-4.9 events per 1,000 patient-years 1.

Clinical Presentation and Diagnostic Challenges

• Patients often present with normal or minimally elevated blood glucose (<200 mg/dL) 1, 5
• Common symptoms include nausea, vomiting, abdominal pain, and generalized weakness 1, 6
• The absence of significant hyperglycemia frequently delays recognition of the emergent nature of the condition 2, 5

Prevention and Monitoring

1. Patient Selection:

   • Use with extreme caution in type 1 diabetes 2
   • Assess for risk factors before prescribing

2. Patient Education:

   • Inform patients about euDKA risk and symptoms
   • Advise seeking immediate medical attention if symptoms develop
   • Instruct on ketone monitoring during illness

3. Medication Management:

   • Discontinue SGLT2 inhibitors:
     • 3-4 days before scheduled surgery
     • During acute illness
     • When food intake is significantly reduced
   • Avoid substantial insulin dose reductions (>20%) when initiating SGLT2 inhibitors 1

4. Monitoring:

   • Measure urine or blood ketones in symptomatic patients or during illness, particularly when glucose exceeds 200 mg/dL 1
   • Monitor closely when initiating in high-risk patients

Treatment of euDKA

• Immediate discontinuation of SGLT2 inhibitor
• Intravenous insulin and dextrose infusions
• Fluid resuscitation
• Electrolyte monitoring and replacement
• Close monitoring of acid-base status

Key Pitfalls to Avoid

1. Delayed Diagnosis: Normal or minimally elevated glucose levels may lead to missed or delayed diagnosis of DKA
2. Inadequate Monitoring: Failure to check ketones in symptomatic patients on SGLT2 inhibitors
3. Inappropriate Patient Selection: Using in high-risk patients without proper education and monitoring
4. Medication Continuation: Failure to discontinue SGLT2 inhibitors during acute illness or before surgery

SGLT2 inhibitors provide significant cardiovascular and renal benefits but require vigilance regarding the risk of euDKA, especially in high-risk situations and vulnerable populations.