How do SGLT2 (sodium-glucose linked transporter 2) inhibitors cause euglycemic diabetic ketoacidosis (DKA)?

Mechanism of SGLT2 Inhibitor-Induced Euglycemic DKA

SGLT2 inhibitors cause euglycemic diabetic ketoacidosis through a combination of insulin deficiency, increased glucagon levels, and volume depletion, resulting in ketosis despite normal or only mildly elevated blood glucose levels (<200 mg/dL). 1

Pathophysiological Mechanism

SGLT2 inhibitors contribute to euglycemic DKA through several interconnected mechanisms:

• Insulin/Glucagon Ratio Alteration: SGLT2 inhibitors lower glucose levels by promoting urinary glucose excretion, which changes the insulin-to-glucagon ratio, predisposing patients to ketosis 1
• Increased Ketogenesis: The altered hormonal environment leads to a metabolic shift from glucose to lipid utilization, increasing ketone production 2
• Volume Depletion: The diuretic action of SGLT2 inhibitors causes intravascular volume contraction, which can further exacerbate ketosis 3
• Reduced Renal Clearance of Ketones: Some evidence suggests SGLT2 inhibitors may decrease the renal clearance of ketones, contributing to ketone accumulation 4

Risk Factors for Euglycemic DKA

Several conditions increase the risk of developing euglycemic DKA in patients taking SGLT2 inhibitors:

• Reduced Caloric Intake: Very low-carbohydrate diets, fasting, or poor oral intake 1
• Insulin Reduction or Omission: Decreasing insulin doses or stopping insulin therapy 5
• Acute Illness: Intercurrent infections or other acute medical conditions 1, 5
• Surgery: Particularly major procedures requiring fasting 1
• Alcohol Consumption: Excessive alcohol intake 1
• Pancreatic Disorders: History of pancreatitis or pancreatic surgery 5
• Pregnancy: Pregnant individuals are at higher risk 1
• Autoimmunity: Presence of autoimmune conditions 1
• Type 1 Diabetes: Off-label use in type 1 diabetes carries particularly high risk 1, 6

Clinical Presentation

Euglycemic DKA presents with:

• Normal or Mildly Elevated Glucose: Blood glucose <200 mg/dL, which can delay diagnosis 1
• Metabolic Acidosis: High anion gap acidosis with pH <7.3 1
• Elevated Ketones: Increased blood and/or urine ketones 1
• Nonspecific Symptoms: Nausea, vomiting, abdominal pain, malaise, shortness of breath 3

Prevention and Management

To prevent SGLT2 inhibitor-induced euglycemic DKA:

• Temporary Discontinuation: Withhold SGLT2 inhibitors at least 3 days before elective surgery or procedures requiring fasting 1, 7
• Patient Education: Counsel patients about symptoms and risk factors 1
• Sick Day Management: Provide detailed instructions on medication adjustments during illness 1
• Ketone Monitoring: Advise monitoring of urine or blood ketones during high-risk situations 1
• Maintain Basal Insulin: Patients should not stop or hold basal insulin even when not eating 1

For management of established euglycemic DKA:

• Prompt Recognition: Assess for ketoacidosis in patients with symptoms regardless of glucose levels 3
• Discontinue SGLT2 Inhibitor: Stop the medication immediately 3
• Standard DKA Protocol: Treat with insulin, fluids, and carbohydrate replacement 3
• Close Monitoring: Monitor for resolution of acidosis and ketosis 1

Incidence and Clinical Significance

• Relatively Rare: DKA is uncommon in people with type 2 diabetes treated with SGLT2 inhibitors (0.6–4.9 events per 1,000 patient-years) 1
• Increased Risk: Meta-analyses show a relative risk of 2.46 (95% CI 1.16–5.21) in randomized controlled trials and 1.74 (95% CI 1.07–2.83) in observational studies 1
• Higher Risk in Specific Populations: Perioperative risk is higher (1.02 vs. 0.69 per 1000 patients) 1
• Emergency vs. Elective Surgery: Higher incidence in emergency (1.1%) vs. elective surgery (0.17%) 1

Special Considerations

• Non-Diabetic Patients: Recent evidence shows euglycemic ketoacidosis can occur even in patients without diabetes taking SGLT2 inhibitors 1
• Delayed Diagnosis: The absence of significant hyperglycemia often delays recognition by both patients and providers 6, 5
• Mortality Risk: Fatal cases of ketoacidosis have been reported with SGLT2 inhibitors 3

Understanding the mechanism of SGLT2 inhibitor-induced euglycemic DKA is essential for early recognition, prompt treatment, and effective prevention of this potentially life-threatening complication.