What is the cause of euglycemic ketoacidosis associated with Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors like empagliflozin (Empagliflozin)?

Mechanism of Euglycemic Ketoacidosis Associated with SGLT2 Inhibitors

SGLT2 inhibitors like empagliflozin cause euglycemic diabetic ketoacidosis through a combination of increased urinary glucose excretion, reduced insulin levels, and enhanced ketogenesis, creating a unique metabolic state where ketoacidosis occurs despite relatively normal blood glucose levels.

Pathophysiological Mechanism

SGLT2 inhibitors cause euglycemic diabetic ketoacidosis through several interconnected mechanisms:

1. Urinary Glucose Excretion

   • SGLT2 inhibitors block glucose reabsorption in the proximal tubule of the kidney
   • This leads to significant urinary glucose excretion (glucosuria)
   • Blood glucose levels remain relatively normal despite metabolic derangements 1

2. Insulin Deficiency

   • Reduced blood glucose levels lead to decreased insulin secretion
   • Lower insulin levels create a state of relative insulin deficiency
   • This insulin deficiency is critical for ketogenesis 2, 1

3. Enhanced Ketogenesis

   • Reduced insulin levels promote:
     • Increased lipolysis (breakdown of fat)
     • Enhanced fatty acid oxidation
     • Accelerated ketone body production 1

4. Volume Depletion

   • SGLT2 inhibitors cause osmotic diuresis and volume contraction
   • This activates counter-regulatory hormones (glucagon, cortisol, catecholamines)
   • These hormones further stimulate ketogenesis 2, 3

Precipitating Factors

Several factors can trigger euglycemic DKA in patients taking SGLT2 inhibitors:

• Reduced caloric/carbohydrate intake (very low-carbohydrate or ketogenic diets) 1, 4
• Insulin dose reduction or omission 2, 3
• Acute illness or surgical stress 2, 5
• Alcohol consumption 2, 1
• Dehydration 1, 6
• Prolonged fasting 1, 3

Clinical Presentation

Euglycemic DKA presents uniquely compared to traditional DKA:

• Blood glucose levels <250 mg/dL (often <200 mg/dL) 3
• Signs of severe metabolic acidosis 2
• Symptoms including nausea, vomiting, abdominal pain, malaise, and shortness of breath 3
• Delayed diagnosis due to absence of marked hyperglycemia 5, 7

Prevention Strategies

To prevent euglycemic DKA in patients taking SGLT2 inhibitors:

• Discontinue SGLT2 inhibitors 3-4 days before elective procedures 2, 3
• Avoid very low-carbohydrate diets while on SGLT2 inhibitors 1, 4
• Maintain adequate insulin dosing - never abruptly reduce or discontinue insulin 2, 7
• Monitor for ketones during acute illness, regardless of blood glucose levels 1
• Temporarily discontinue SGLT2 inhibitors during acute illness 2, 3

Treatment Approach

When euglycemic DKA is suspected:

1. Discontinue the SGLT2 inhibitor immediately 3
2. Administer insulin to suppress ketogenesis 2
3. Provide glucose-containing fluids (often higher concentrations of dextrose needed) 1
4. Replace electrolytes as needed 6
5. Monitor ketones until resolution 8

Important Clinical Considerations

• The effects of SGLT2 inhibitors may persist longer than their reported half-lives 8
• Ketosis can continue for several days after drug discontinuation 8
• Diagnosis is often delayed due to normal or near-normal glucose levels 5, 7
• Elderly patients may present with nonspecific symptoms like altered mental status 6

Understanding this unique mechanism is essential for prompt recognition and appropriate management of this potentially life-threatening condition in patients taking SGLT2 inhibitors.