What is an SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitor and how does it cause euglycemic diabetic ketoacidosis?

SGLT2 Inhibitors and Euglycemic Diabetic Ketoacidosis

SGLT2 inhibitors are medications that cause euglycemic diabetic ketoacidosis through multiple mechanisms including increased urinary glucose excretion, reduced insulin levels, and enhanced ketogenesis, creating a unique metabolic state where ketoacidosis occurs despite relatively normal blood glucose levels. 1

What are SGLT2 Inhibitors?

SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors are a class of medications that:

• Work by inhibiting renal tubular SGLT2, which is responsible for glucose reabsorption from urine
• Reduce the renal glucose threshold and promote urinary glucose excretion 2
• Currently available SGLT2 inhibitors in clinical practice include dapagliflozin, empagliflozin, canagliflozin, and sotagliflozin

SGLT2 inhibitors provide several benefits:

• Reduce HbA1c levels by approximately 0.5% to 1.0%
• Reduce body weight by 1.5 to 3.5 kg
• Lower systolic blood pressure by 3 to 5 mmHg
• Reduce risk of major cardiovascular adverse events, renal events, and hospitalization rates for heart failure 2

Mechanism of Euglycemic DKA

Euglycemic diabetic ketoacidosis (euDKA) is defined as ketoacidosis with blood glucose levels <250 mg/dL (often <200 mg/dL) 1. SGLT2 inhibitors cause euDKA through several pathways:

1. Increased urinary glucose excretion: SGLT2 inhibitors promote glycosuria, reducing blood glucose levels while not addressing the underlying ketogenic state 2, 1

2. Reduced insulin levels: As blood glucose levels decrease due to urinary excretion, patients or providers may reduce insulin doses, leading to relative insulin deficiency 2

3. Increased glucagon levels: SGLT2 inhibitors stimulate alpha cells to release glucagon, which promotes:

   • Increased lipolysis (breakdown of fat)
   • Enhanced ketone production in the liver 2, 1

4. Decreased renal clearance of ketones: SGLT2 inhibitors may reduce the kidney's ability to clear ketones, leading to their accumulation 2

5. Volume depletion: The osmotic diuresis caused by glycosuria can lead to dehydration, further concentrating ketones in the blood 3

The unique aspect of euDKA is that ketoacidosis occurs despite relatively normal blood glucose levels, which can delay diagnosis and treatment 1, 4.

Risk Factors for Euglycemic DKA

Several factors increase the risk of developing euDKA while on SGLT2 inhibitors:

• Reduced oral intake or fasting 1, 4, 5
• Acute illness or infection 6, 4
• Surgery or perioperative state 6
• Very low-carbohydrate or ketogenic diets 1, 7
• Excessive alcohol intake 1
• Insulin dose reduction 1
• Type 1 diabetes (higher risk than type 2) 1, 3
• Pregnancy 1
• History of previous DKA episodes 4
• Chronic pancreatitis 4
• Hepatic dysfunction 1

Clinical Presentation and Diagnosis

Euglycemic DKA presents with:

• Signs of metabolic acidosis: nausea, vomiting, abdominal pain, malaise, and shortness of breath
• Blood glucose levels <250 mg/dL (often <200 mg/dL)
• Elevated anion gap
• Positive urine or serum ketones
• Metabolic acidosis (low pH and bicarbonate) 1, 4

The absence of marked hyperglycemia often leads to delayed diagnosis, making it essential to monitor for ketones during acute illness, regardless of blood glucose levels 1, 4.

Prevention and Management

Prevention:

• Temporarily discontinue SGLT2 inhibitors during:
  • Acute illness
  • Surgical procedures (at least 3-4 days before elective procedures)
  • Prolonged fasting 1
• Avoid very low-carbohydrate or ketogenic diets while on SGLT2 inhibitors 1, 7
• Do not reduce or stop basal insulin even when not eating (for insulin-dependent patients) 1
• Monitor ketones during illness regardless of glucose levels 1

Management:

1. Immediately discontinue the SGLT2 inhibitor 1
2. Administer insulin to suppress ketogenesis 1
3. Provide glucose-containing fluids (may need higher concentrations of dextrose - 10% or 20%) to facilitate insulin administration while maintaining euglycemia 1
4. Replace electrolytes as needed 1
5. Monitor ketones until resolution 1
6. Consider continuous renal replacement therapy in severe cases 1

Important Clinical Considerations

• Euglycemic DKA can occur even 48 hours after discontinuation of SGLT2 inhibitors, suggesting their pharmacokinetic effects may persist longer than previously thought 6
• The absence of hyperglycemia can lead to delayed diagnosis and treatment 4
• Healthcare providers should conduct thorough medication reconciliation upon admission and closely monitor patients taking SGLT2 inhibitors, especially during acute illness 4
• SGLT2 inhibitors should be used with caution in patients with type 1 diabetes due to the higher risk of euDKA 3
• The risk of euDKA may increase as SGLT2 inhibitors are increasingly prescribed for non-diabetic indications such as heart failure and chronic kidney disease 5

By understanding the mechanisms and risk factors for euglycemic DKA associated with SGLT2 inhibitors, clinicians can better prevent, recognize, and manage this potentially life-threatening complication.