Should sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as empagliflozin (Empagliflozin), be held prior to surgery?

Perioperative Management of SGLT2 Inhibitors

SGLT2 inhibitors should be discontinued 3-4 days before elective surgery to reduce the risk of perioperative euglycemic diabetic ketoacidosis. 1, 2

Specific Recommendations for SGLT2 Inhibitor Discontinuation

The 2024 American Heart Association/American College of Cardiology guideline provides clear direction on SGLT2 inhibitor management before surgery:

• Canagliflozin, dapagliflozin, and empagliflozin: Stop ≥3 days before scheduled surgery
• Ertugliflozin: Stop ≥4 days before scheduled surgery 1

This recommendation carries a Class 1 level of evidence, indicating strong consensus that SGLT2 inhibitors should be withheld before surgery to reduce the risk of perioperative metabolic acidosis.

Rationale for Discontinuation

SGLT2 inhibitors increase the risk of euglycemic diabetic ketoacidosis (eDKA) in the perioperative period due to several mechanisms:

• Surgical stress increases counterregulatory hormones
• Fasting state promotes ketogenesis
• SGLT2 inhibitors promote urinary glucose excretion while maintaining ketogenesis
• The resulting ketoacidosis can occur even with normal blood glucose levels, making it difficult to detect 1, 2

Data suggest that the risk of perioperative DKA is higher in patients taking SGLT2 inhibitors compared to those who are not (1.02 vs. 0.69 per 1000 patients, OR 1.48,95%CI 1.02–2.15) 1.

Evidence of Persistent Risk Despite Discontinuation

Several case reports demonstrate that euglycemic DKA can occur even when SGLT2 inhibitors are discontinued according to previous guidelines:

• A patient developed euglycemic DKA after coronary artery bypass surgery despite discontinuing empagliflozin 48 hours before surgery 3
• A case series of 4 patients who developed euglycemic DKA after coronary bypass surgery despite holding SGLT2 inhibitors for 1-5 days (54-151 hours) before surgery 4
• A patient developed EDKA 48 hours after last dose of empagliflozin and a day after neurosurgery 5

These cases highlight that the pharmacodynamic effects of SGLT2 inhibitors may persist longer than previously thought, supporting the current recommendation for a 3-4 day discontinuation period.

Perioperative Management Algorithm

1. Preoperative Phase:

   • Discontinue SGLT2 inhibitors 3-4 days before elective surgery 1, 2
   • Ensure adequate hydration
   • Target A1C <8% for elective surgeries when possible 1, 2
   • Consider alternative diabetes medications for glycemic control during the SGLT2 inhibitor washout period

2. Day of Surgery:

   • Hold metformin on the day of surgery 1, 2
   • Hold other oral glucose-lowering agents the morning of surgery
   • For patients on insulin: give one-half of NPH dose or 75-80% of long-acting analog insulin 1, 2
   • Target blood glucose range: 100-180 mg/dL (5.6-10.0 mmol/L) 1, 2

3. Postoperative Phase:

   • Monitor blood glucose every 2-4 hours while NPO
   • Use short or rapid-acting insulin as needed for glycemic control
   • Do not restart SGLT2 inhibitors until:
     • Patient is eating normally
     • Renal function is stable
     • No signs of acute illness or metabolic derangement 2

Pitfalls to Avoid

1. Inadequate discontinuation time: Previous guidelines recommended stopping SGLT2 inhibitors only 24 hours before surgery, which has proven insufficient based on case reports 3, 4, 5, 6, 7.

2. Failure to recognize euglycemic DKA: Unlike traditional DKA, euglycemic DKA presents with normal or only mildly elevated blood glucose levels, making diagnosis challenging. Be vigilant for unexplained anion gap metabolic acidosis even with normal glucose levels 3, 5.

3. Emergency surgeries: The risk of perioperative ketoacidosis is greater in emergency surgeries (1.1% vs. 0.17% in elective cases) 1. Extra vigilance is needed in these situations.

4. Overly strict glycemic targets: Perioperative glycemic targets tighter than 80-180 mg/dL do not improve outcomes and increase hypoglycemia risk 1, 2.

By following these evidence-based recommendations, clinicians can minimize the risk of SGLT2 inhibitor-associated complications while maintaining appropriate perioperative glycemic control.