When can metformin be restarted in a patient with resolved diabetic ketoacidosis (DKA) who was previously on metformin and dapagliflozin (SGLT2 inhibitor)?

Restarting Metformin After Diabetic Ketoacidosis

Metformin should be restarted after complete resolution of DKA, when acidosis has resolved, the patient is hemodynamically stable, and renal function has normalized, typically 24-48 hours after resolution of ketoacidosis. 1

Timing for Medication Restart

Metformin

• Wait until complete resolution of ketoacidosis before restarting metformin 1
• Ensure the following criteria are met before restarting:
  • Normal anion gap
  • No evidence of acidosis
  • Stable renal function with eGFR ≥30 mL/min/1.73m² 1
  • Patient is hemodynamically stable
  • Normal oral intake has resumed

SGLT2 Inhibitors (Dapagliflozin)

• Dapagliflozin should NOT be restarted after an episode of DKA 2, 3
• SGLT2 inhibitors are associated with euglycemic DKA, a dangerous complication that can occur even with near-normal blood glucose levels 2, 4
• Clinical effects of dapagliflozin can persist much longer than its reported half-life of 12.9 hours, potentially causing prolonged ketosis 3

Monitoring After Restarting Metformin

1. Renal Function Monitoring:

   • For eGFR 45-59 mL/min/1.73m²: Monitor every 3-6 months
   • For eGFR 30-44 mL/min/1.73m²: Monitor every 3 months
   • Reduce metformin dose to 1000 mg/day if eGFR is 30-44 mL/min/1.73m² 1

2. Signs of Lactic Acidosis:

   • Monitor for symptoms such as malaise, myalgias, respiratory distress, abdominal pain
   • Check lactate levels if symptoms develop

3. Glycemic Control:

   • Regular blood glucose monitoring to ensure adequate control
   • Adjust insulin or other antihyperglycemic medications as needed

Alternative Medication Considerations

For Patients with eGFR ≥20 mL/min/1.73m²

• Consider GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide) as they have proven cardiovascular benefits 1
• DPP-4 inhibitors can be considered as they have neutral effects on heart failure risk 1

For Patients with eGFR <20 mL/min/1.73m²

• GLP-1 receptor agonists are preferred 1
• Weekly options: dulaglutide, semaglutide
• Daily option: liraglutide

Important Precautions

• Avoid restarting SGLT2 inhibitors after an episode of DKA due to high risk of recurrence 2, 3, 4, 5
• Educate patients about the risk of euglycemic DKA with SGLT2 inhibitors
• Instruct patients to temporarily discontinue metformin during any acute illness, especially those with:
  • Dehydration
  • Sepsis
  • Hypotension
  • Major surgery 6

Common Pitfalls to Avoid

1. Restarting medications too early: Ensure complete resolution of DKA before restarting metformin
2. Failing to adjust metformin dose based on renal function
3. Restarting SGLT2 inhibitors after DKA (should be permanently discontinued)
4. Overlooking the need for insulin during the transition period
5. Inadequate monitoring of renal function after restarting metformin

Remember that euglycemic DKA can occur with SGLT2 inhibitors even with near-normal blood glucose levels, making it a challenging diagnosis. After a DKA episode, the safest approach is to permanently discontinue SGLT2 inhibitors and carefully restart metformin only after complete resolution of ketoacidosis and stabilization of the patient's condition.