A 32-year-old man with poorly controlled type 2 diabetes (HbA₁c 11.2%) and acute coronary syndrome is admitted to the ICU. He is on metformin and a new SGLT2 inhibitor (empagliflozin). On day 2 of admission, he develops mild metabolic acidosis (pH 7.32, HCO₃⁻ 18 mEq/L) with elevated serum ketones (β-hydroxybutyrate 3.2 mmol/L) despite near-normal blood glucose (180 mg/dL). Urine ketones are positive. What is the most appropriate immediate next step in management?

Explanation

## Diagnosis: Euglycemic DKA (EDKA) This patient presents with a **rare but serious** complication of SGLT2 inhibitor therapy: - Metabolic acidosis (pH 7.32, HCO₃⁻ 18) with **elevated ketones** - **Near-normal or mildly elevated glucose** (180 mg/dL, not > 250 mg/dL) - Positive urine ketones - Recent initiation of SGLT2 inhibitor (empagliflozin) - Acute illness (ACS) as a precipitant **Key Point:** This is NOT classic DKA — the glucose is not severely elevated, yet ketones are high. This is **euglycemic DKA**, a distinct entity. ## Pathophysiology: How SGLT2 Inhibitors Cause Euglycemic DKA ```mermaid flowchart TD A[SGLT2 Inhibitor]:::action --> B[Increased urinary glucose excretion]:::outcome B --> C[Osmotic diuresis]:::outcome C --> D[Volume depletion]:::outcome D --> E[Activation of counter-regulatory hormones]:::outcome E --> F[Glucagon ↑, Cortisol ↑, Catecholamines ↑]:::outcome F --> G[Lipolysis ↑]:::outcome G --> H[FFA → Hepatic β-oxidation ↑]:::outcome H --> I[Ketone body production ↑]:::outcome J[Acute stress: ACS, infection]:::urgent --> K[Further ↑ counter-regulatory hormones]:::outcome K --> G I --> L[Metabolic acidosis]:::outcome L --> M[BUT glucose remains near-normal]:::outcome M --> N[Because SGLT2 inhibitors ↓ glucose reabsorption]:::outcome N --> O[Euglycemic DKA]:::outcome ``` ## Mechanism of Ketone Accumulation in EDKA 1. **SGLT2 inhibitors** increase urinary glucose excretion → osmotic diuresis → volume depletion 2. **Volume depletion** activates the sympathetic nervous system and renin-angiotensin-aldosterone system 3. **↑ Glucagon and catecholamines** stimulate hormone-sensitive lipase → massive lipolysis 4. **Hepatic β-oxidation** of FFA increases exponentially 5. **Acetyl-CoA exceeds TCA cycle capacity** → ketogenesis accelerates 6. **β-hydroxybutyrate and acetoacetate accumulate** → metabolic acidosis 7. **BUT glucose remains near-normal** because: - SGLT2 inhibitors promote urinary glucose loss - Acute illness may suppress hepatic gluconeogenesis - Insulin (though reduced) still has some effect **Clinical Pearl:** The **absence of severe hyperglycemia despite high ketones** is the diagnostic clue to euglycemic DKA. Classic DKA presents with glucose > 250 mg/dL AND high ketones. ## Management: Why Discontinue SGLT2 Inhibitor? **High-Yield:** The SGLT2 inhibitor is the **precipitant**, not the treatment. Discontinuing it: 1. **Stops osmotic diuresis** → restores intravascular volume 2. **Reduces counter-regulatory hormone activation** → decreases lipolysis 3. **Allows insulin to work more effectively** → suppresses ketogenesis 4. **Prevents recurrence** of euglycemic DKA **Key Point:** IV insulin infusion is still needed because: - The underlying defect is still **relative insulin deficiency** (despite normal glucose) - Insulin suppresses lipolysis and ketogenesis - Insulin promotes peripheral ketone utilization - Even though glucose is near-normal, ketones are being produced at a pathological rate ## Why NOT Continue SGLT2 Inhibitor? **Warning:** Continuing the SGLT2 inhibitor would perpetuate the osmotic diuresis and volume depletion, worsening the metabolic acidosis and ketone production. The drug must be stopped immediately.