How to manage a patient with high anion gap metabolic acidosis, high ketones, and low glucose levels who is on dapagliflozin (canagliflozin) but not diabetic?

Management of SGLT2 Inhibitor-Associated Euglycemic Ketoacidosis in a Non-Diabetic Patient

This patient has SGLT2 inhibitor-associated euglycemic ketoacidosis (euDKA), a life-threatening complication that requires immediate discontinuation of dapagliflozin, prompt treatment with intravenous insulin and dextrose, and aggressive fluid resuscitation. 1

Immediate Recognition and Diagnosis

This clinical presentation is classic for SGLT2 inhibitor-associated euglycemic ketoacidosis, which can occur even in non-diabetic patients taking these medications. 1, 2

Key diagnostic features to confirm:

• High anion gap metabolic acidosis with elevated ketones (β-hydroxybutyrate preferred over urine ketones) 3, 4
• Blood glucose typically <250 mg/dL (often much lower, as low as 75 mg/dL has been reported) 1, 5
• Signs of severe metabolic acidosis: nausea, vomiting, abdominal pain, dyspnea, generalized malaise 1
• Recent dapagliflozin use (effects can persist 3+ days after discontinuation, sometimes up to 2 weeks) 1, 6

Critical pitfall: The FDA label explicitly warns that ketoacidosis can present with blood glucose levels below those typically expected for DKA (less than 250 mg/dL), making this diagnosis easily missed. 1

Immediate Management Algorithm

Step 1: Discontinue Dapagliflozin Immediately

• Stop dapagliflozin immediately and permanently 1
• Do not restart until ketoacidosis has completely resolved and clinical stability is confirmed 1
• The FDA label states urinary glucose excretion persists for 3 days after discontinuation, but ketoacidosis effects can last 6+ days to 2 weeks 1, 6

Step 2: Initiate Insulin Therapy Despite Low Glucose

This is the critical intervention that differs from typical DKA management:

• Start continuous intravenous insulin infusion (0.1 units/kg/hour) to suppress ketogenesis 7, 3
• Simultaneously administer intravenous dextrose 5% with potassium chloride to prevent hypoglycemia while insulin suppresses ketone production 7, 8
• The American Diabetes Association recommends insulin therapy even when glucose is normal or low in ketoacidosis 7, 3

Step 3: Aggressive Fluid Resuscitation

• Initiate isotonic saline (0.9% NaCl) at 15-20 mL/kg/hour for the first hour 7, 3
• Assess volume status and adjust based on hemodynamic parameters 1
• Monitor for volume depletion complications, as dapagliflozin increases this risk 1

Step 4: Electrolyte Monitoring and Replacement

• Check electrolytes, glucose, blood urea nitrogen, creatinine, and venous pH every 2-4 hours 7, 3
• Potassium replacement is critical: use 1/3 potassium phosphate and 2/3 potassium chloride or acetate in IV fluids 7
• Monitor for severe hypokalemia (can be life-threatening) 6

Step 5: Monitor for Resolution

Resolution criteria (all must be met): 7, 4

• Serum bicarbonate ≥18 mEq/L
• Venous pH >7.3
• Anion gap normalized (typically <12 mEq/L)
• Blood ketones (β-hydroxybutyrate) normalized

Special Considerations for Non-Diabetic Patients

Critical recognition: The FDA label and recent case reports confirm that euglycemic ketoacidosis can occur in patients without diabetes mellitus taking SGLT2 inhibitors. 1, 2

• Non-diabetic patients were previously thought to have sufficient endogenous insulin to prevent ketoacidosis, but this assumption has been proven false 7
• The pathophysiology is identical: SGLT2 inhibitors alter the insulin/glucagon ratio, promoting ketogenesis regardless of diabetes status 7
• These patients may have even lower glucose levels at presentation due to intact insulin secretion 5

Prolonged Ketosis Warning

A critical pitfall: Ketosis can persist much longer than the 12.9-hour half-life of dapagliflozin would predict. 6

• Case reports document ketonemia persisting 6-9 days after dapagliflozin discontinuation 6
• Continue insulin therapy (transition to basal subcutaneous insulin) until ketones completely normalize 6, 8
• Do not stop insulin infusion prematurely, as anion gap may reopen 6

Transition to Subcutaneous Insulin

Once resolution criteria are met: 7, 8

• Continue IV insulin for 1-2 hours after initiating subcutaneous basal/bolus insulin regimen 7
• This overlap prevents rebound ketoacidosis 7
• Monitor closely for 24-48 hours after transition 8

Why This Patient Developed Ketoacidosis

Precipitating factors in this case: 1

• Reduced caloric intake (common trigger)
• Possible volume depletion
• SGLT2 inhibitor use in non-diabetic patient (off-label, increases risk)
• The FDA label lists all these as precipitating conditions for ketoacidosis 1

Long-Term Management

• Permanently discontinue dapagliflozin - do not rechallenge 1
• If the patient truly has no diabetes (confirm with HbA1c, C-peptide, autoantibodies), SGLT2 inhibitors should never have been prescribed for glycemic control 1
• If prescribed for heart failure or CKD, the risk-benefit must be reassessed given this life-threatening complication 7
• Patient education on never restarting this medication class 1

Monitoring During Hospitalization

• ICU-level care is typically required 2, 8
• Continuous cardiac monitoring (acidosis can trigger arrhythmias including ventricular tachycardia) 7, 8
• Serial arterial or venous blood gases every 2-4 hours until resolution 7, 3
• Renal function monitoring (acute kidney injury is common) 1