How soon before surgery should Synjardy (empagliflozin and metformin) be discontinued?

Perioperative Management of Synjardy (Empagliflozin/Metformin)

Discontinue Synjardy at least 3-4 days before surgery due to the empagliflozin component's risk of euglycemic diabetic ketoacidosis, and stop the metformin component the night before surgery to prevent lactic acidosis.

Timing of Discontinuation

Empagliflozin (SGLT2 Inhibitor Component)

• Stop empagliflozin 3-4 days (72-96 hours) before elective surgery to minimize the risk of perioperative euglycemic diabetic ketoacidosis (euDKA), a potentially life-threatening complication that can occur even with normal blood glucose levels 1, 2.
• The FDA label warns that ketoacidosis associated with empagliflozin may present with blood glucose levels less than 250 mg/dL, making diagnosis challenging 2.
• Case series have documented euDKA occurring in cardiac surgery patients who discontinued SGLT2 inhibitors only 1-2 days preoperatively, demonstrating that shorter discontinuation periods are insufficient 3.

Metformin Component

• Stop metformin the night before surgery (approximately 12-24 hours preoperatively) for patients with normal renal function 4, 1, 5.
• This timing allows adequate drug clearance given metformin's plasma half-life of 6.2 hours 1, 5.
• The American College of Cardiology and other major guideline societies support this approach 1, 5.

Rationale for These Recommendations

Risk of Euglycemic DKA from Empagliflozin

• Surgery creates a perfect storm for euDKA: reduced caloric intake, insulin deficiency states, metabolic stress, and dehydration 2, 3.
• The FDA specifically warns to "consider monitoring for ketoacidosis and temporarily discontinuing JARDIANCE in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery)" 2.
• Patients present with nonspecific symptoms (nausea, vomiting, tachypnea, abdominal pain) that can be mistaken for routine postoperative findings, delaying diagnosis 3.

Risk of Lactic Acidosis from Metformin

• Metformin-associated lactic acidosis (MALA) occurs in 2-9 cases per 100,000 patients/year but carries a 30-50% mortality rate 4, 5, 6.
• Surgery increases MALA risk through hemodynamic instability, tissue hypoperfusion, acute kidney injury, and volume depletion 5, 6.
• Risk factors include renal impairment (eGFR <60 mL/min), severe heart failure (LVEF <30%), dehydration, and concomitant use of ACE inhibitors, ARBs, or NSAIDs 4, 1.

Practical Management Algorithm

Preoperative Phase (3-4 Days Before Surgery)

• Stop empagliflozin 3-4 days before surgery 1.
• Check baseline renal function (eGFR) and assess volume status 1, 5.
• Stop metformin the night before surgery 4, 1, 5.
• Consider reducing basal insulin by 25% the evening before surgery 1.
• Ensure adequate hydration 5, 6.

For Emergency Surgery

• If surgery cannot be delayed, proceed without stopping medications but alert the surgical and anesthesia teams 5, 2.
• Monitor lactate levels and renal function closely 6.
• Ensure aggressive fluid resuscitation with balanced crystalloids 6.
• Monitor for signs of euDKA (check serum and urine ketones if metabolic acidosis develops) 3.

Intraoperative Management

• Use basal-bolus insulin coverage perioperatively rather than reactive sliding scale alone 1.
• Maintain mean arterial pressure ≥65 mmHg 6.
• Monitor for signs of tissue hypoperfusion 6.

Postoperative Resumption

• Do not restart either component until at least 48 hours after surgery 1, 5.
• Before restarting metformin, confirm: eGFR ≥60 mL/min/1.73m², patient eating/drinking normally, no ongoing hemodynamic instability 1, 5, 6.
• Do not restart empagliflozin until the patient is clinically stable and has resumed a normal diet 1.
• Monitor for signs of MALA (unexplained metabolic acidosis, elevated lactate) 5, 6.

Critical Pitfalls to Avoid

• Do not stop medications too close to surgery: The 1-2 day discontinuation period documented in euDKA case reports was insufficient 3.
• Do not assume normal glucose rules out ketoacidosis: Euglycemic DKA can occur with glucose <250 mg/dL or even <140 mg/dL 2, 3.
• Do not restart metformin at 48 hours if the patient has dehydration, ongoing vasopressor requirement, acute heart failure, sepsis, or respiratory insufficiency, even if renal function appears normal 1.
• Do not restart empagliflozin before the patient has resumed normal oral intake and is clinically stable 1.

Special Considerations for High-Risk Patients

• Patients with baseline renal impairment (eGFR 30-60 mL/min) require more conservative management and closer monitoring 5.
• Elderly patients (>65 years) taking high doses of metformin are at increased risk for MALA 4.
• Major abdominal surgery carries higher risk for both complications due to greater hemodynamic instability 6.