How do I manage euglycemic diabetic ketoacidosis in a patient on empagliflozin (Jardiance)?

Management of Euglycemic Diabetic Ketoacidosis Related to Jardiance (Empagliflozin)

Immediately discontinue empagliflozin and initiate standard DKA treatment with intravenous insulin infusion and dextrose-containing fluids, even though blood glucose levels are normal or only mildly elevated. 1

Immediate Recognition and Diagnosis

Euglycemic DKA presents with blood glucose typically <250 mg/dL (often <200 mg/dL), venous pH <7.3, bicarbonate <15-18 mEq/L, and positive serum or urine ketones, making it easily missed because clinicians expect hyperglycemia in DKA 2. The condition can occur even 8-12 days after the last dose of empagliflozin due to prolonged pharmacologic effects and persistent glucosuria 3.

Key diagnostic pitfall: Do not rely on nitroprusside-based urine ketone tests alone, as they only detect acetoacetate and acetone but miss β-hydroxybutyrate, the predominant ketoacid in DKA 2. Direct measurement of serum β-hydroxybutyrate is the preferred diagnostic method 2.

Acute Treatment Protocol

Insulin Therapy

• Start continuous intravenous regular insulin infusion at 0.1 units/kg/hour (or 5-10 units/hour for adults), which is the cornerstone of treatment for all DKA regardless of glucose level 2
• Do not use subcutaneous insulin for moderate-to-severe euglycemic DKA; intravenous administration is required for reliable absorption and rapid titration 2
• Continue insulin infusion until ketoacidosis resolves (pH >7.3, bicarbonate ≥18 mEq/L, anion gap normalized), not just until glucose normalizes 2

Fluid and Dextrose Management

• Initiate isotonic saline (0.9% NaCl) at 15-20 mL/kg/hour (or 1-1.5 L) in the first hour to correct volume depletion, which is universally present due to the osmotic diuresis from empagliflozin 2
• Add dextrose 5-10% to intravenous fluids once blood glucose falls below 250 mg/dL (or immediately if glucose is already <250 mg/dL at presentation) to prevent hypoglycemia while continuing insulin to suppress ketogenesis 2, 1
• Maintain blood glucose between 150-200 mg/dL during treatment by adjusting dextrose concentration (5%, 10%, or even 12.5%) rather than stopping insulin 2

Potassium Replacement

• Do not start insulin until serum potassium is ≥3.3 mEq/L, as insulin drives potassium intracellularly and can precipitate life-threatening hypokalemia 2
• If initial potassium is <3.3 mEq/L, give 20-30 mEq/hour potassium chloride until level reaches 3.3 mEq/L before starting insulin 2
• Once insulin is started and potassium is 3.3-5.3 mEq/L, add 20-30 mEq potassium to each liter of intravenous fluid (use 2/3 KCl and 1/3 KPO₄) 2

Bicarbonate Therapy

Bicarbonate is generally not indicated unless pH is <6.9, in which case give 50 mmol sodium bicarbonate in 200 mL sterile water infused over 1 hour 2. If pH is 6.9-7.0, bicarbonate may be considered but is not routinely necessary 2.

Monitoring During Treatment

• Draw blood every 2-4 hours for serum electrolytes, glucose, BUN, creatinine, and venous pH until DKA resolves 2
• Venous pH (which is typically 0.03 units lower than arterial pH) and anion gap are sufficient to monitor acidosis resolution; repeat arterial blood gases are unnecessary 2
• Monitor serum β-hydroxybutyrate if available, as it provides the most accurate assessment of ketoacidosis resolution 2

Resolution Criteria and Transition

DKA is resolved when all three criteria are met: glucose <200 mg/dL, serum bicarbonate ≥18 mEq/L, and venous pH >7.3 2.

When transitioning from intravenous to subcutaneous insulin:

• Start a multiple-dose subcutaneous insulin regimen (combination of rapid-acting and long-acting insulin) 2
• Overlap intravenous insulin infusion for 1-2 hours after the first subcutaneous dose to prevent rebound ketoacidosis, as subcutaneous insulin has delayed onset 2

Prevention of Recurrence

Permanent Discontinuation of Empagliflozin

Do not restart empagliflozin after an episode of euglycemic DKA, as the risk of recurrence is substantial and the condition can be life-threatening 1, 4, 5. The pharmacologic effects of SGLT2 inhibitors persist beyond several half-lives, with glucosuria and ketonuria documented up to 11 days after the last dose 3.

Patient Education on Risk Factors

Euglycemic DKA with empagliflozin is triggered by:

• Acute illness with reduced oral intake, fever, vomiting, or diarrhea 1, 4
• Surgical stress and postoperative states 4, 5
• Decreased carbohydrate intake or fasting states 4, 5
• Volume depletion from any cause 1, 4
• Reduction or omission of insulin doses in insulin-requiring patients 1

Preoperative Management

Empagliflozin must be stopped at least 3 days (preferably 7-10 days) before any elective surgery or procedure requiring prolonged fasting to allow complete drug clearance and prevent postoperative euglycemic DKA 1, 5, 3.

Alternative Glucose-Lowering Strategies

After discontinuing empagliflozin, consider:

• GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide) for cardiovascular protection without DKA risk, usable when eGFR >30 mL/min/1.73 m² 2, 1
• Insulin therapy remains fully effective regardless of renal function and carries no DKA risk when used appropriately 2
• DPP-4 inhibitors (linagliptin requires no dose adjustment at any eGFR) provide modest glucose lowering without ketoacidosis risk 2

Critical Safety Considerations

• Euglycemic DKA can occur in both type 1 and type 2 diabetes patients taking empagliflozin 6, 7
• The condition may present with nonspecific symptoms (nausea, vomiting, malaise, confusion) that delay diagnosis because glucose is near-normal 4, 5, 7
• Maintain at least low-dose basal insulin in all insulin-requiring patients even during illness, as complete insulin cessation dramatically increases DKA risk when combined with SGLT2 inhibitor effects 1, 5
• Relapse of euglycemic DKA can occur days after initial treatment if the drug has not been fully cleared 3