In a 52-year-old man with uncontrolled diabetes, recent right middle cerebral artery infarction, on metformin (Trajenta), empagliflozin (Jardiance), clopidogrel (Coplavix), and a statin, who had two episodes of ketoacidosis (first with hyperglycemia, second with tachycardia and severe hypertension), what other possible etiologies should be considered and what are the next steps in management?

Recurrent Ketoacidosis in a Post-Stroke Patient on Jardiance: Differential Diagnosis and Management

Stop Jardiance permanently and investigate for pheochromocytoma or other catecholamine-excess states given the recurrent ketoacidosis with severe hypertension (200/100 mmHg) and tachycardia despite SGLT2 inhibitor discontinuation.

Immediate Recognition: SGLT2 Inhibitor-Induced Euglycemic DKA

The first episode of ketoacidosis with a glucose of only 13 mmol/L (234 mg/dL) in a patient on empagliflozin (Jardiance) is classic euglycemic diabetic ketoacidosis (eDKA), a well-recognized complication of SGLT2 inhibitors 1. The recent stroke itself is a known precipitating factor for eDKA in patients taking these medications 2.

Why SGLT2 Inhibitors Should Not Be Used in This Context

• SGLT2 inhibitors are NOT recommended for routine inpatient use due to the risk of euglycemic DKA, particularly in patients with poor oral intake 1.
• The medication should be discontinued immediately during any acute illness (stroke qualifies) and not restarted until 3–4 days after metabolic stability is achieved 1, 3.
• Empagliflozin has a half-life of 12–14 hours, but persistent eDKA can occur for 7–12 days after the last dose due to ongoing renal effects 4.

Critical Problem: Recurrent Ketoacidosis After Jardiance Discontinuation

The second episode of ketoacidosis occurring AFTER Jardiance was withheld is the key diagnostic challenge. This suggests an alternative or additional precipitating factor beyond the SGLT2 inhibitor.

Alternative Etiologies to Investigate

1. Pheochromocytoma or Catecholamine Excess (Most Likely)

The combination of:

• Recurrent ketoacidosis
• Severe hypertension (200/100 mmHg)
• Tachycardia
• Recent stroke (which can be caused by pheochromocytoma)

This triad strongly suggests a catecholamine-excess state 3. Pheochromocytoma can precipitate DKA through:

• Inhibition of insulin secretion
• Increased lipolysis and ketogenesis
• Stress-induced metabolic decompensation

2. Recurrent Cerebrovascular Events

• Stroke itself is a recognized precipitating factor for DKA 3, 2.
• The severe hypertension and tachycardia may indicate:
  • Extension of the original MCA infarction
  • New hemorrhagic transformation
  • Increased intracranial pressure
  • Autonomic dysregulation from brainstem involvement

3. Occult Infection or Sepsis

• Infection is the most common precipitating factor for DKA 3.
• Post-stroke patients are at high risk for:
  • Aspiration pneumonia
  • Urinary tract infection (especially if catheterized)
  • Central line infections
  • Pressure ulcer infections

4. Myocardial Infarction

• MI can both precipitate and be masked by DKA 3.
• The severe hypertension and tachycardia could represent cardiogenic stress.

5. Insulin Non-Compliance or Inadequate Dosing

• Insulin omission or inadequacy is a common DKA trigger 3.
• Verify that basal insulin was continued during the acute illness and that doses were adequate.

Immediate Diagnostic Workup

Essential Laboratory Studies

• 24-hour urine metanephrines and catecholamines or plasma free metanephrines to rule out pheochromocytoma 3
• Repeat head CT or MRI to assess for stroke extension, hemorrhagic transformation, or new infarction 3
• Troponin and ECG to rule out myocardial infarction 3
• Blood, urine, and sputum cultures if infection is suspected 3
• Chest X-ray to evaluate for aspiration pneumonia 3
• β-hydroxybutyrate levels (preferred over urine ketones) to monitor ketosis resolution 3, 5
• Serial arterial or venous blood gases every 2–4 hours to track acidosis 3

Critical Monitoring Parameters

• Check serum potassium every 2–4 hours during active DKA treatment, as total body potassium depletion is universal even if initial levels appear normal 3
• Monitor for cerebral edema, especially given the recent stroke: altered mental status, headache, neurological deterioration 3

Management Algorithm

Step 1: Treat the Current DKA Episode

• Aggressive IV fluid resuscitation: Start with 0.9% NaCl at 15–20 mL/kg/hour (≈1–1.5 L) in the first hour 3
• Continuous IV regular insulin infusion at 0.1 U/kg/hour after confirming serum potassium ≥3.3 mEq/L 3
• Add 20–30 mEq potassium per liter of IV fluid (2/3 KCl + 1/3 KPO₄) once adequate urine output is confirmed and K⁺ is 3.3–5.5 mEq/L 3
• When glucose falls to 250 mg/dL, switch to 5% dextrose with 0.45–0.75% NaCl while continuing insulin to prevent hypoglycemia and ensure complete ketoacidosis resolution 3
• Continue insulin infusion until DKA resolution: pH >7.3, bicarbonate ≥18 mEq/L, anion gap ≤12 mEq/L 3, 5

Step 2: Permanently Discontinue Jardiance

• SGLT2 inhibitors should be stopped indefinitely in this patient given the recurrent eDKA 1, 3
• Do not restart empagliflozin even after metabolic stability, as the risk of recurrence is too high in the setting of recent stroke and acute illness 1, 3

Step 3: Investigate for Underlying Precipitants

• Obtain imaging and laboratory studies as outlined above to identify the cause of the second episode 3
• Treat any identified infection with appropriate antibiotics 3
• Manage hypertensive emergency if blood pressure remains severely elevated (200/100 mmHg suggests hypertensive urgency/emergency) 1

Step 4: Transition to Appropriate Diabetes Regimen

• Administer basal insulin (glargine, detemir, or NPH) 2–4 hours BEFORE stopping IV insulin to prevent rebound hyperglycemia and recurrent ketoacidosis 3
• Start a multiple-dose insulin regimen with basal plus prandial rapid-acting insulin once the patient can eat 3
• Continue Trajenta (linagliptin, a DPP-4 inhibitor) as it is safe and effective in the hospital setting with low hypoglycemia risk 1
• Continue statin and Coplavix (aspirin + clopidogrel) for secondary stroke prevention 1

Common Pitfalls to Avoid

• Never restart SGLT2 inhibitors during acute illness or within 3–4 days of metabolic stability 1, 3
• Do not stop insulin infusion when glucose falls to 250 mg/dL; instead, add dextrose and continue insulin until ketoacidosis fully resolves 3
• Do not start insulin if serum potassium is <3.3 mEq/L; aggressively replace potassium first to avoid life-threatening arrhythmias 3
• Do not use nitroprusside-based urine ketone tests for monitoring; they miss β-hydroxybutyrate, the predominant ketone body 3, 5
• Do not assume the second episode is simply "residual" SGLT2 inhibitor effect; actively search for alternative precipitants 3, 4

Long-Term Management Considerations

• Patient education on sick-day management: Never stop basal insulin, check ketones during illness, seek immediate care if unable to tolerate oral intake 3
• Ensure follow-up with endocrinology to optimize diabetes regimen without SGLT2 inhibitors 3
• If pheochromocytoma is confirmed, refer to surgery for definitive treatment after appropriate alpha- and beta-blockade 3