Mechanism of SGLT2 Inhibitor-Induced Intraoperative Euglycemic DKA
SGLT2 inhibitors should be discontinued 3-4 days before elective surgery to prevent the potentially life-threatening complication of euglycemic diabetic ketoacidosis (euDKA). 1
Pathophysiology of SGLT2i-Induced Euglycemic DKA
SGLT2 inhibitors cause euglycemic DKA through several interconnected mechanisms:
Altered insulin-glucagon ratio: SGLT2i lower blood glucose by inhibiting renal glucose reabsorption, causing glycosuria. This reduction in blood glucose leads to decreased insulin secretion and a relative increase in glucagon, creating a hormonal environment that promotes ketogenesis despite normal glucose levels 1
Persistent pharmacodynamic effects: The effects of SGLT2i persist beyond their plasma half-life, with clinical effects continuing for 3-4 days after discontinuation. This explains why euDKA can occur even when the medication is stopped 48-72 hours before surgery 2, 3, 4
Surgical stress response: Surgery triggers counterregulatory hormones (catecholamines, cortisol, glucagon) that further drive ketone production. When combined with the SGLT2i-induced predisposition to ketosis, this creates ideal conditions for euDKA development 1, 2
Fasting and reduced carbohydrate intake: Perioperative fasting exacerbates ketone production in patients on SGLT2i by further reducing insulin levels and promoting lipolysis and ketogenesis 1, 5
Clinical Presentation and Diagnostic Challenges
Normal or near-normal glucose levels: Unlike traditional DKA where hyperglycemia is prominent, euDKA presents with blood glucose <250 mg/dL despite metabolic acidosis (pH <7.3) and elevated ketones 1, 2
Nonspecific symptoms: Postoperative nausea, vomiting, and tachypnea can be mistaken for common post-surgical complaints, delaying diagnosis 2, 6
Metabolic derangements: High anion gap metabolic acidosis, decreased serum bicarbonate (<18 mEq/L), and elevated serum and urine ketones despite relatively normal glucose levels 1, 4
Risk Factors for SGLT2i-Induced Euglycemic DKA
Emergency surgery: Higher incidence of perioperative ketoacidosis in emergency (1.1%) versus elective surgery (0.17%) 1
Insufficient discontinuation time: Cases have been reported even when SGLT2i were discontinued 48-72 hours before surgery 3, 4
Prolonged fasting: Extended periods without caloric intake increase ketogenesis risk 1, 5
Major surgical procedures: More invasive surgeries trigger stronger stress responses 2, 3
Prevention Strategies
Preoperative discontinuation: Stop SGLT2i 3-4 days before elective surgery (canagliflozin, dapagliflozin, and empagliflozin ≥3 days; ertugliflozin ≥4 days) 1
Adequate hydration: Ensure patients remain well-hydrated during the perioperative period 1
Avoid prolonged fasting: Adhere to recommended fasting guidelines and avoid unnecessarily extended starvation periods 1
Glucose monitoring: Regular blood glucose checks during the perioperative period 1
Consider glucose-containing IV fluids: In cases of unavoidable prolonged fasting, glucose-containing fluids may help mitigate ketone generation 1
Management of Suspected Euglycemic DKA
High index of suspicion: Consider euDKA in any recent SGLT2i user with unexplained acidosis, even with normal glucose levels 2, 6
Laboratory assessment: Check serum and urine ketones, blood gas analysis, and anion gap when euDKA is suspected 2, 4
Treatment: Insulin and dextrose infusions to suppress ketogenesis while maintaining normoglycemia 2, 6
Special Considerations
Patients with heart failure: Discontinuing SGLT2i may worsen heart failure, requiring careful risk-benefit assessment 1
Non-diabetic patients: Recent evidence shows euDKA can occur in non-diabetic patients taking SGLT2i for other indications (e.g., heart failure), as they may not have sufficient insulin to prevent significant ketosis 1
Resumption of therapy: SGLT2i should not be restarted until the patient is clinically stable and has resumed a normal diet 1