How should I manage a 65-year-old woman with type 2 diabetes on sitagliptin, metformin, and empagliflozin (Jardiance) who has mild ketonemia (0.9 mmol/L) with a normal blood glucose of 104 mg/dL?

Immediate Management of Euglycemic Diabetic Ketoacidosis in a Patient on SGLT2 Inhibitor Therapy

Stop empagliflozin (Jardiance) immediately and do not restart until ketonuria has completely resolved and metabolic stability is confirmed, because SGLT2 inhibitors cause euglycemic diabetic ketoacidosis even when blood glucose is normal. 12

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Urgent Assessment for Diabetic Ketoacidosis

• Check venous blood gas or serum bicarbonate immediately to assess for metabolic acidosis; a bicarbonate < 18 mmol/L or pH < 7.3 confirms DKA regardless of the normal glucose level of 104 mg/dL. 3
• Measure serum β-hydroxybutyrate if available; a level > 3.0 mmol/L confirms ketoacidosis even with euglycemia. 3
• Calculate the anion gap from the basic metabolic panel; an anion gap > 12 mmol/L supports DKA. 3
• Assess for precipitating factors including recent illness, reduced caloric intake, prolonged fasting, alcohol use, or any acute stressor that may have triggered ketogenesis. 32

Immediate Discontinuation of Empagliflozin

• Discontinue empagliflozin immediately because the FDA has issued a specific warning that SGLT2 inhibitors cause ketoacidosis in the absence of significant hyperglycemia, and continuation during metabolic stress accelerates progression to full DKA. 12
• Do not restart empagliflozin until (1) ketonuria has completely resolved on repeat urinalysis and (2) fasting glucose has been consistently 80–130 mg/dL for at least 2 weeks on basal insulin. 3
• Educate the patient to stop empagliflozin and seek urgent care if nausea, vomiting, abdominal pain, or dyspnea develop, as these are signs of euglycemic DKA. 132

DKA Management Protocol (If Confirmed)

• Hospitalize immediately with intravenous insulin infusion, aggressive isotonic fluid resuscitation (typically 1–2 L normal saline in the first hour), and electrolyte replacement (especially potassium) when DKA criteria are met (pH < 7.3, bicarbonate < 18 mmol/L, β-hydroxybutyrate > 3.0 mmol/L, anion gap > 12). 3
• Continue IV insulin until the anion gap closes and ketones clear, then transition to subcutaneous basal-bolus insulin. 3

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Glycemic Control – Basal Insulin Initiation

• Initiate basal insulin (insulin glargine or degludec) at 10 units once daily or 0.2 U/kg body weight while continuing metformin, because the patient's current regimen (sitagliptin, metformin, empagliflozin) is insufficient to prevent ketogenesis. 34
• Titrate basal insulin by 2–4 units every 3 days until fasting glucose consistently reaches 80–130 mg/dL without hypoglycemia. 34
• Maintain metformin at the maximal tolerated dose (up to 2000 mg daily) because it lowers insulin requirements, provides cardiovascular benefit, and carries minimal hypoglycemia risk when combined with basal insulin. 35

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SGLT2-Inhibitor Re-initiation Criteria

• Do not restart empagliflozin until ketonuria has completely resolved on repeat urinalysis and fasting glucose has been consistently 80–130 mg/dL for at least 2 weeks on basal insulin. 3
• When these conditions are met, resume empagliflozin 25 mg daily for its proven cardiovascular and renal protective effects, which are independent of glucose lowering. 36
• Monitor closely for recurrent ketosis during the first month after restarting empagliflozin, checking urine ketones if any symptoms develop. 32

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GLP-1 Receptor Agonist Addition (If Needed)

• If HbA1c remains > 7% after 3 months of optimized metformin + basal insulin + empagliflozin, add a GLP-1 receptor agonist (e.g., semaglutide, titrated to 1 mg weekly) rather than further insulin intensification. 35
• GLP-1 RA therapy typically yields an additional 0.6–0.8% HbA1c reduction and 2–5 kg weight loss with minimal hypoglycemia risk. 35

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Monitoring & Follow-Up Schedule

• Weeks 1–2: Daily fasting glucose checks to guide basal insulin titration; repeat urinalysis to confirm ketone clearance before empagliflozin restart. 34
• Month 1: Review fasting glucose trends, insulin dose adequacy, and hypoglycemia episodes; consider empagliflozin restart if criteria met. 3
• Month 3: Measure HbA1c (target < 7%); add GLP-1 RA if HbA1c > 7% despite optimized therapy. 35
• Month 6 + Beyond: Continue HbA1c monitoring every 3 months until target achieved, then every 6 months; perform annual lipid panel, renal function tests, and comprehensive metabolic panel. 3

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Common Pitfalls to Avoid

• Do not delay insulin initiation while awaiting oral agents; the presence of ketonuria with normal glucose signals inadequate insulin coverage requiring prompt basal insulin. 3
• Do not restart empagliflozin until ketonuria has resolved and glucose is stable, as SGLT2 inhibitors markedly increase DKA risk under metabolic stress. 132
• Do not discontinue metformin when adding insulin; it remains foundational therapy unless contraindicated. 35
• Do not assume an asymptomatic presentation excludes DKA; euglycemic DKA can occur with minimal symptoms, especially in SGLT2-inhibitor users. 132
• Do not wait beyond 3 months to intensify therapy if HbA1c remains above target, as therapeutic inertia raises complication risk. 35

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Patient Education Priorities

• DKA warning signs: Advise the patient to stop empagliflozin and seek urgent care if nausea, vomiting, abdominal pain, shortness of breath, or reduced oral intake develop. 132
• Hypoglycemia recognition & treatment: Teach symptoms (shakiness, sweating, confusion) and the 15–20 g fast-acting carbohydrate rule. 34
• Insulin injection technique: Emphasize proper subcutaneous administration, site rotation, and storage. 34
• Medication adherence: Stress the importance of daily metformin, basal insulin, and, when appropriate, empagliflozin for long-term complication prevention. 35