How can Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors cause Diabetic Ketoacidosis (DKA)?

How SGLT2 Inhibitors Cause Diabetic Ketoacidosis (DKA)

SGLT2 inhibitors cause diabetic ketoacidosis through multiple mechanisms, primarily by altering the insulin/glucagon ratio, increasing lipolysis and ketone production, and decreasing renal clearance of ketone bodies, which can lead to both classic and euglycemic DKA. 1

Pathophysiological Mechanisms

SGLT2 inhibitors contribute to ketoacidosis through several interconnected pathways:

1. Altered Insulin/Glucagon Ratio

   • SGLT2 inhibitors lower glucose concentrations, which changes the insulin/glucagon ratio 1
   • SGLT2 is expressed in pancreatic α-cells, and inhibition promotes glucagon secretion 2
   • Increased glucagon levels stimulate hepatic ketogenesis

2. Enhanced Lipolysis and Ketone Production

   • When SGLT2 inhibitors are combined with insulin, insulin doses are often reduced to avoid hypoglycemia
   • Lower insulin levels may be insufficient to suppress lipolysis and ketogenesis 2
   • This leads to increased free fatty acid release and subsequent ketone body formation

3. Decreased Renal Clearance of Ketones

   • SGLT2 inhibitors may decrease urinary excretion of ketone bodies 2
   • This reduced renal clearance increases plasma ketone concentrations

4. Predisposition to Ketosis

   • SGLT2 inhibitors create a metabolic state that predisposes to ketosis
   • Any additional physiological stress can trigger rapid development of hyperketonaemia 1

Unique Features of SGLT2 Inhibitor-Associated DKA

Euglycemic DKA

• A hallmark of SGLT2 inhibitor-associated DKA is euglycemic ketoacidosis
• Blood glucose levels may be normal (<11.0 mmol/L or <200 mg/dL) despite significant ketoacidosis 1, 3
• This atypical presentation can delay diagnosis as traditional DKA screening relies on hyperglycemia

Clinical Characteristics

• Patients with SGLT2 inhibitor-induced DKA typically present with:
  • Lower glucose levels compared to traditional DKA (median 229 mg/dL vs. 458.5 mg/dL) 3
  • Similar severity of acidosis (pH, bicarbonate, anion gap) 3
  • Longer time to resolution (39 hours vs. 19 hours) 3
  • Increased fluid requirements (14L vs. 5.5L) 3
  • Longer hospitalization (11 days vs. 5.5 days) 3

Risk Factors and Precipitating Events

SGLT2 inhibitor-associated DKA is more likely to occur in the following situations:

• Insulin deficiency: Including patients with type 1 diabetes or insulin-dependent type 2 diabetes 4
• Insulin dose reduction or omission 4
• Severe acute illness 4
• Dehydration 4
• Surgery or perioperative period 1, 4
• Low-carbohydrate diets 4
• Excessive alcohol intake 4
• Prolonged fasting 1
• Emergency surgery (1.1% vs. 0.17% for elective surgery) 1

Prevention Strategies

To reduce the risk of SGLT2 inhibitor-associated DKA:

• Withhold SGLT2 inhibitors when precipitating factors develop 4
• Discontinue SGLT2 inhibitors before elective surgery (3 days before for canagliflozin, dapagliflozin, and empagliflozin; 4 days for ertugliflozin) 1
• Avoid inappropriate insulin dose reduction 4
• Follow sick day protocols 4
• Ensure adequate hydration 1
• Avoid prolonged fasting periods 1
• Consider glucose-containing intravenous fluids during unavoidable prolonged fasting 1

Clinical Implications

The risk of DKA with SGLT2 inhibitors requires vigilance but should be viewed in context:

• DKA is a rare but serious complication of SGLT2 inhibitor therapy 1, 5
• The risk is higher in patients with diabetes compared to those without (1 in 339 vs. 1 in 15,592) 1
• Patients may experience prolonged glucosuria and relapse of DKA during hospitalization 6
• Clinicians should maintain a high index of suspicion for DKA in any patient on SGLT2 inhibitors presenting with symptoms, even with normal glucose levels 4

By understanding these mechanisms and implementing appropriate preventive strategies, clinicians can minimize the risk of this serious complication while still allowing patients to benefit from the cardiorenal protective effects of SGLT2 inhibitors.