What are the causes of euglycemic diabetic ketoacidosis (DKA)?

Causes of Euglycemic Diabetic Ketoacidosis (DKA)

Euglycemic DKA is primarily caused by insulin deficiency combined with specific precipitating factors including SGLT2 inhibitor therapy, reduced food intake, pregnancy, alcohol use, and liver failure. 1

Definition and Diagnostic Criteria

Euglycemic DKA is defined as diabetic ketoacidosis with plasma glucose levels below 200 mg/dL (11.1 mmol/L). It accounts for approximately 10% of all DKA cases and requires either the presence of hyperglycemia or a prior history of diabetes for diagnosis. 1

Major Causes of Euglycemic DKA

1. SGLT2 Inhibitor Therapy

• Mechanism: SGLT2 inhibitors promote urinary glucose excretion, leading to lower blood glucose levels while still allowing ketosis to develop due to relative insulin deficiency
• Risk factors in patients using SGLT2 inhibitors: 1, 2
  • Very-low-carbohydrate or ketogenic diets
  • Prolonged fasting
  • Dehydration
  • Excessive alcohol intake
  • Presence of autoimmunity
  • Insulin dose reduction
  • Acute febrile illness
  • Reduced caloric intake due to illness or surgery

2. Pregnancy

• Up to 2% of pregnancies with pregestational diabetes (mostly type 1) are complicated by DKA 1
• Pregnant individuals may present with euglycemic DKA, particularly in the setting of hyperemesis
• Diagnosis may be hindered by mixed acid-base disturbances 1

3. Alcohol Use

• Alcohol consumption, particularly heavy use, can precipitate euglycemic DKA 1, 3
• Mechanism involves inhibition of gluconeogenesis while promoting ketogenesis

4. Reduced Food Intake

• Decreased caloric intake or fasting can trigger euglycemic DKA in susceptible individuals 1, 3
• Often occurs in combination with other risk factors

5. Liver Failure

• Hepatic dysfunction can lead to euglycemic DKA due to impaired glucose production 1

6. Other Reported Causes

• Insulin use prior to hospital admission (reducing glucose but not fully suppressing ketogenesis) 3
• Cocaine abuse 3
• Pancreatitis 3
• Sepsis 3
• Chronic liver disease and cirrhosis 3

High-Risk Populations

Euglycemic DKA can occur in both type 1 and type 2 diabetes, but certain populations are at higher risk:

1. Type 1 diabetes patients:

   • Absolute insulin deficiency makes these patients particularly vulnerable
   • Risk is higher with missed insulin doses or intercurrent illness 1

2. Type 2 diabetes patients on SGLT2 inhibitors:

   • While uncommon (0.6-4.9 events per 1,000 patient-years), risk is elevated compared to non-SGLT2 inhibitor therapy 1
   • Meta-analysis shows relative risk of 2.46 (95% CI 1.16-5.21) in randomized controlled trials 1

3. Pregnant women with diabetes:

   • Particularly those with type 1 diabetes
   • Physiologic changes in pregnancy can mask typical DKA symptoms 1

Clinical Presentation and Diagnostic Challenges

Euglycemic DKA presents a diagnostic challenge because:

1. Blood glucose levels are below the typical DKA threshold (<200 mg/dL)
2. Signs and symptoms may include:
   • Nausea, vomiting, abdominal pain
   • Generalized malaise, shortness of breath
   • Dehydration and severe metabolic acidosis 2

Prevention Strategies

To prevent euglycemic DKA, especially in high-risk patients:

1. For patients on SGLT2 inhibitors: 2, 4

   • Temporarily discontinue SGLT2 inhibitors during acute illness or surgery
   • Avoid very-low-carbohydrate diets while on these medications
   • Monitor for ketones during illness, even if blood glucose is not elevated
   • Discontinue SGLT2 inhibitors 3-4 days before elective procedures

2. For insulin-dependent patients: 1

   • Do not stop or hold basal insulin even when not eating
   • Provide detailed instructions on insulin dose adjustments during illness or fasting
   • Encourage immediate contact with diabetes care team if DKA is suspected

3. For pregnant patients with diabetes: 1

   • Counsel on signs and symptoms of DKA
   • Emphasize importance of seeking immediate medical attention if DKA is suspected

Management Considerations

When euglycemic DKA is suspected:

1. Assess for ketoacidosis regardless of blood glucose levels
2. If confirmed, discontinue SGLT2 inhibitors if applicable
3. Treatment requires insulin, fluid, and carbohydrate replacement
4. Higher concentrations of dextrose (10% or 20%) may be needed to facilitate insulin administration while maintaining euglycemia 3

Conclusion

Recognizing the various causes of euglycemic DKA is critical for prompt diagnosis and treatment. The increasing use of SGLT2 inhibitors has brought renewed attention to this condition, but clinicians should remain vigilant for all potential causes, especially in high-risk populations.