How to manage euglycemic ketoacidosis in patients taking SGLT2 (sodium-glucose cotransporter 2) inhibitors?

Management of Euglycemic Ketoacidosis in Patients Taking SGLT2 Inhibitors

Immediately discontinue the SGLT2 inhibitor and initiate treatment with intravenous dextrose-containing fluids (D5W or D10W) along with insulin therapy, as the glycosuric effects of SGLT2 inhibitors can persist for 3-4 days after discontinuation, prolonging the ketoacidotic state. 1, 2

Acute Management Protocol

Initial Assessment and Diagnosis

• Recognize the diagnostic challenge: Euglycemic DKA presents with blood glucose <250 mg/dL despite metabolic acidosis (pH <7.3), elevated ketones, and high anion gap metabolic acidosis with serum bicarbonate <18 mEq/L 1
• Measure both blood glucose AND ketone levels, as normal glucose can mask the severity of ketoacidosis 3, 4
• Check serum electrolytes, particularly potassium, as replacement will be necessary during treatment 4

Treatment Strategy

• Start glucose-containing IV fluids immediately (D5W or D10W) to induce endogenous insulin secretion and stop ketogenesis 2, 5
• Administer intravenous insulin therapy to suppress ketone production 4, 2
• Provide aggressive potassium replacement as needed during insulin therapy 4
• Continue dextrose-containing fluids even after acidosis begins to resolve, as SGLT2 inhibitor effects persist for 3-4 days 1, 6
• Expect prolonged treatment duration: A single dose of SGLT2 inhibitor can remain effective for over 100 hours, causing massive urinary glucose excretion and prolonging euglycemic DKA 6

Key Management Difference from Classic DKA

• In euglycemic DKA, glucose-containing IV fluids are used from the start, whereas classic DKA typically begins with normal saline 2
• The immediate glucose administration helps trigger endogenous insulin secretion in patients with residual beta-cell function 5
• Minimal insulin may be required in non-diabetic patients taking SGLT2 inhibitors for heart failure, as their insulin secretory capacity is preserved 5

Prevention Strategies

Perioperative Management

• Withhold SGLT2 inhibitors 3-4 days before elective surgery (canagliflozin, dapagliflozin, empagliflozin ≥3 days; ertugliflozin ≥4 days) 7, 1
• For day procedures, withhold the day before and day of the procedure 7, 1
• Do not restart until patient is eating and drinking normally AND capillary ketones are <0.6 mmol/L 8, 1
• Emergency surgery carries higher DKA risk (1.1%) versus elective surgery (0.17%) 3, 1

High-Risk Situations Requiring SGLT2 Inhibitor Discontinuation

• Prolonged fasting or reduced oral intake 7, 3, 5
• Critical medical illness or physiological stress 7, 3
• Excessive alcohol intake 3
• Dehydration 3
• Surgery or invasive procedures 3, 1

Patient Education ("Sick Day Protocol")

• Temporarily withhold SGLT2 inhibitors during illness, excessive exercise, or alcohol intake 7
• Maintain adequate hydration and continue eating if possible 7, 3
• Check blood glucose AND ketone levels more frequently during high-risk periods 7, 8
• Seek immediate medical attention for symptoms of ketoacidosis: nausea, vomiting, abdominal pain, dyspnea, or generalized weakness 7, 3

Special Populations at Higher Risk

Type 1 Diabetes and Insulin-Dependent Patients

• SGLT2 inhibitors are not FDA-approved for type 1 diabetes 7
• Avoid substantial initial insulin dose reductions (>20%) when adding SGLT2 inhibitors 3
• Approximately 5-10% of adult-onset diabetes is late-onset type 1 diabetes, carrying increased DKA risk 3
• Abrupt discontinuation of long-term insulin therapy when transitioning to SGLT2 inhibitors significantly increases euglycemic DKA risk 4

Non-Diabetic Patients on SGLT2 Inhibitors for Heart Failure

• Non-diabetic patients are still at risk for euglycemic ketoacidosis, as they may lack sufficient insulin reserves during stress to prevent significant ketosis 1, 5
• The first documented cases of severe ketoacidosis in non-diabetic patients taking SGLT2 inhibitors for heart failure demonstrate this risk is real 5
• These patients require the same preventive measures and monitoring as diabetic patients 1

Critical Pitfalls to Avoid

• Do not assume normal glucose excludes DKA: The euglycemic presentation can delay diagnosis and treatment 4, 2
• Do not restart SGLT2 inhibitors in patients who have already developed DKA, as this may increase severity or prolong the ketoacidotic state 6
• Do not use standard DKA protocols without glucose-containing fluids: Immediate dextrose administration is essential in euglycemic DKA 2, 5
• Do not initiate SGLT2 inhibitors in patients on very low energy diets, as these diets already induce ketosis and the combination creates significant ketoacidosis risk 1
• Do not underestimate the duration of SGLT2 inhibitor effects: Clinical effects persist 3-4 days beyond plasma half-life, requiring prolonged vigilance 1, 6

Monitoring Requirements

• Monitor blood glucose and ketone levels regularly during SGLT2 inhibitor therapy 8, 3
• Intensify monitoring during illness, fasting, or perioperative periods 8, 3
• Check capillary ketones before restarting SGLT2 inhibitors post-surgery, with target <0.6 mmol/L 8, 1
• Higher-risk patients (type 1 diabetes, surgical patients, reduced kidney function) require closer monitoring 8