What is the definition and diagnosis of euglycemic diabetic ketoacidosis (DKA) in patients with a history of diabetes, particularly those using SGLT2 (sodium-glucose cotransporter 2) inhibitors?

Definition and Diagnosis of Euglycemic Diabetic Ketoacidosis

Euglycemic DKA is defined by ketone concentrations >3.0 mmol/L, pH <7.3, and either glucose <11.0 mmol/L (<200 mg/dL) or normal glucose levels, occurring in patients with a history of diabetes mellitus or those on SGLT2 inhibitors. 1

Definition

Euglycemic DKA represents a diagnostic challenge because it presents with metabolic acidosis and elevated ketones despite relatively normal blood glucose levels. The key distinguishing feature from classic DKA is the absence of marked hyperglycemia. 1, 2

Diagnostic Thresholds

• Blood glucose: <11.0 mmol/L (<200 mg/dL) or <250 mg/dL, depending on the guideline referenced 1, 3, 2
• Ketones: β-hydroxybutyrate >3.0 mmol/L 1
• pH: <7.3 1, 3
• Serum bicarbonate: <18 mEq/L 3
• Anion gap: Elevated (>10-12 mEq/L) 3
• History requirement: The "D" in DKA requires either glucose >11.0 mmol/L OR a history of diabetes mellitus 1

Diagnostic Approach

Measure β-hydroxybutyrate specifically in blood for diagnosis—do not rely on nitroprusside-based urine or blood ketone tests, as these do not measure β-hydroxybutyrate, the predominant ketone in DKA. 1, 3

Essential Laboratory Tests

• Arterial blood gas: To confirm metabolic acidosis (pH <7.3) 3, 2
• Serum β-hydroxybutyrate: Preferred ketone measurement (>3.0 mmol/L diagnostic) 1, 3
• Plasma glucose: May be near-normal or only mildly elevated 3, 2
• Electrolytes with calculated anion gap: Elevated anion gap confirms high anion gap metabolic acidosis 3, 2
• Serum bicarbonate: <18 mEq/L 3
• Blood urea nitrogen/creatinine: Assess volume depletion 3
• Complete blood count: Evaluate for infection as precipitant 3

Clinical Presentation Clues

The absence of significant hyperglycemia delays recognition by both patients and providers, making clinical suspicion paramount in SGLT2 inhibitor users. 4, 5, 6

Key symptoms to identify:

• Gastrointestinal symptoms: Nausea, vomiting, abdominal pain (present in majority of cases) 3
• Kussmaul respirations: Deep, labored breathing indicating metabolic acidosis 3
• Volume depletion signs: Tachycardia, hypotension, poor skin turgor 3
• Weakness and malaise: Frequently reported 3
• Altered mental status: Can range from alert to lethargic 3

SGLT2 Inhibitor-Specific Considerations

SGLT2 inhibitors are the leading cause of euglycemic DKA in contemporary practice, with an incidence of 0.6–4.9 events per 1,000 patient-years and a relative risk of 2.46 compared to placebo. 7

High-Risk Scenarios for SGLT2 Inhibitor Users

• Acute illness or infection: Particularly respiratory infections like influenza 7, 4
• Reduced caloric intake: Very-low-carbohydrate/keto diets, prolonged fasting, poor oral intake during illness 7, 8
• Insulin dose reduction: >20% reduction in insulin dose 7
• Volume depletion and dehydration: 7
• Perioperative period: Risk persists even with >72 hours of drug cessation 1
• Excessive alcohol consumption: 7

Populations at Elevated Risk

• Type 1 diabetes patients: Substantially increased risk (5-10% of adult-onset diabetes may be misclassified) 7
• Latent autoimmune diabetes in adults (LADA): Often misdiagnosed as type 2 diabetes 7
• Patients with pancreatic insufficiency: 7
• Pregnant individuals with pregestational diabetes: 7
• Patients without diabetes mellitus: Recent reports challenge the assumption that non-diabetics have sufficient insulin to prevent ketosis 1

Critical Diagnostic Pitfalls

Do not use nitroprusside-based ketone tests (standard urine dipsticks or blood ketone meters using this method) for diagnosis or monitoring, as they measure acetoacetate and acetone but not β-hydroxybutyrate. 1, 3

• Nitroprusside tests may be falsely reassuring or even show increasing ketones during successful treatment as β-hydroxybutyrate converts to acetoacetate 1, 3
• The absence of positive urine ketones does NOT rule out euglycemic DKA 2
• Near-normal glucose levels can create false reassurance and delay diagnosis 4, 5, 6

Differential Diagnosis to Exclude

Euglycemic DKA is a diagnosis of exclusion—rule out other causes of high anion gap metabolic acidosis: 2

• Alcoholic ketoacidosis: Distinguished by clinical history; glucose rarely >250 mg/dL 3
• Lactic acidosis: Check lactate levels 3
• Toxic ingestions: Salicylates, methanol, ethylene glycol 3
• Uremia: Check renal function 3

Monitoring During Treatment

Use β-hydroxybutyrate levels to monitor treatment response—resolution of acidosis or reduction in blood β-hydroxybutyrate marks successful treatment, not nitroprusside-based ketone measurements. 1, 3