How does Empagliflozin (Empagliflozin) cause Diabetic Ketoacidosis (DKA)?

Mechanism of Empagliflozin-Induced Diabetic Ketoacidosis

Empagliflozin causes diabetic ketoacidosis through multiple pathways including increased glucagon levels leading to enhanced lipolysis and ketone production, reduced insulin doses, and decreased renal clearance of ketones, with the unique feature of potentially causing euglycemic ketoacidosis where blood glucose may remain below 200 mg/dL. 1

Pathophysiological Mechanisms

Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, can lead to diabetic ketoacidosis (DKA) through several distinct mechanisms:

1. Increased Ketone Production:

   • Elevates glucagon levels, which stimulates lipolysis
   • Enhanced fatty acid oxidation leads to increased ketone body formation
   • Shifts metabolism toward fat utilization and ketogenesis

2. Reduced Insulin Levels:

   • May lead to decreased insulin doses in patients on insulin therapy
   • Relative insulin deficiency promotes ketogenesis
   • Impairs the body's ability to suppress ketone production

3. Decreased Renal Clearance:

   • SGLT2 inhibitors reduce renal excretion of ketone bodies
   • Contributes to ketone accumulation in the bloodstream 1

Euglycemic Diabetic Ketoacidosis

A particularly dangerous aspect of empagliflozin-induced DKA is the presentation as euglycemic DKA:

• Blood glucose levels may remain <200 mg/dL despite severe ketoacidosis 2, 3
• Makes diagnosis challenging and often delayed in emergency settings
• Patients may present with symptoms of DKA but without marked hyperglycemia 4

Risk Factors for Empagliflozin-Induced DKA

Several conditions increase the risk of developing DKA while on empagliflozin:

• Reduced caloric/carbohydrate intake or fasting 1, 3
• Acute illness or infection
• Surgical procedures
• Insulin dose reduction or omission
• Alcohol consumption
• Type 1 diabetes (off-label use) 4
• Following ketogenic diets 3

Clinical Presentation

Patients with empagliflozin-induced DKA typically present with:

• Nausea and vomiting
• Abdominal pain
• Dyspnea
• Lethargy or confusion
• Clinical dehydration
• Metabolic acidosis with elevated anion gap
• Ketonemia and ketonuria
• Blood glucose levels that may be normal or only mildly elevated 2, 5

Prevention and Management

To prevent empagliflozin-induced DKA:

• Sick Day Management:

  • Temporarily discontinue empagliflozin during acute illness
  • Maintain adequate hydration and carbohydrate intake

• Perioperative Management:

  • Discontinue empagliflozin 3-4 days before elective surgery 1
  • Monitor ketones regardless of blood glucose levels

• Treatment of Established DKA:

  • Intravenous fluids
  • Insulin infusion (even with normal glucose levels)
  • Dextrose administration to allow continued insulin therapy
  • Discontinuation of empagliflozin 3

Important Clinical Considerations

• DKA can occur even weeks after initiating empagliflozin 5
• The diagnosis may be obscured by concurrent metabolic derangements 6
• Patients may not present with classic DKA symptoms due to lower glucose levels
• Always check for ketones in patients on SGLT2 inhibitors presenting with nonspecific symptoms 2

Monitoring Recommendations

For patients on empagliflozin:

• Educate about signs and symptoms of DKA
• Consider ketone monitoring during periods of illness
• Maintain adequate hydration and carbohydrate intake
• Never abruptly discontinue insulin therapy

The risk of DKA should be balanced against the significant cardiovascular and renal benefits of empagliflozin, particularly in patients with type 2 diabetes with established cardiovascular disease or chronic kidney disease 1.