Mechanism of SGLT2 Inhibitor-Induced Intraoperative Euglycemic DKA

Pathophysiology of SGLT2i-Induced Euglycemic DKA

• SGLT2 inhibitors cause euglycemic DKA through several interconnected mechanisms, including altered insulin-glucagon ratio, leading to decreased insulin secretion and a relative increase in glucagon, creating a hormonal environment that promotes ketogenesis despite normal glucose levels 1, 2
• The American Heart Association recommends that SGLT2 inhibitors should be discontinued 3-4 days before elective surgery to prevent the potentially life-threatening complication of euglycemic diabetic ketoacidosis (euDKA), as the effects of SGLT2i persist beyond their plasma half-life, with clinical effects continuing for 3-4 days after discontinuation 3, 4, 5, 6

Clinical Presentation and Diagnostic Challenges

• Euglycemic DKA presents with blood glucose <250 mg/dL despite metabolic acidosis (pH <7.3) and elevated ketones, with normal or near-normal glucose levels, and high anion gap metabolic acidosis, decreased serum bicarbonate (<18 mEq/L), and elevated serum and urine ketones despite relatively normal glucose levels 3

Risk Factors for SGLT2i-Induced Euglycemic DKA

• Emergency surgery has a higher incidence of perioperative ketoacidosis (1.1%) versus elective surgery (0.17%) 1
• Prolonged fasting increases ketogenesis risk, and major surgical procedures trigger stronger stress responses, leading to a higher risk of euDKA 2

Prevention Strategies

• The American Diabetes Association recommends preoperative discontinuation of SGLT2i 3-4 days before elective surgery (canagliflozin, dapagliflozin, and empagliflozin ≥3 days; ertugliflozin ≥4 days) to prevent euDKA 3, 4, 5, 6
• Adequate hydration and avoiding prolonged fasting are crucial in preventing euDKA, and glucose monitoring is essential during the perioperative period 2, 6, 7
• Consider glucose-containing IV fluids in cases of unavoidable prolonged fasting to mitigate ketone generation 2

Special Considerations

• Patients with heart failure require careful risk-benefit assessment when discontinuing SGLT2i, as it may worsen heart failure 2
• Non-diabetic patients taking SGLT2i for other indications (e.g., heart failure) are at risk of euDKA, as they may not have sufficient insulin to prevent significant ketosis 1, 2
• SGLT2i should not be restarted until the patient is clinically stable and has resumed a normal diet, according to the American Heart Association 3

Perioperative Management of SGLT2 Inhibitors

Rationale for Withholding SGLT2 Inhibitors

• The American College of Cardiology/American Heart Association 2024 guidelines explicitly recommend that SGLT2 inhibitors should be withheld for 3-4 days before elective noncardiac surgery in patients with heart failure to reduce the risk of perioperative metabolic acidosis 8, 9
• Specific recommendations include stopping canagliflozin, dapagliflozin, and empagliflozin ≥3 days and ertugliflozin ≥4 days before scheduled surgery 8
• The risk of perioperative diabetic ketoacidosis (DKA) is higher in patients taking SGLT2 inhibitors compared to those not taking them (1.02 vs. 0.69 per 1000 patients) 10

Alternative Approaches and Considerations

• UK guidelines suggest a less conservative approach, recommending omission of SGLT2 inhibitors the day before and the day of a procedure 10, 11, 12
• Data suggest that cessation of SGLT2 inhibitors in people receiving them for heart failure may be associated with worsening of heart failure, creating a clinical dilemma 10

Risk Mitigation Strategies

• Maintaining adequate hydration, avoiding prolonged fasting periods, and monitoring glucose and ketone levels are important mitigations during the time of withholding SGLT2 inhibitors 10
• In settings of unavoidable prolonged fasting, consider glucose-containing intravenous fluids to mitigate ketone generation 10
• SGLT2 inhibitors should be restarted once the patient is eating and drinking normally (usually 24-48 hours after surgery) 10

Special Considerations

• Emergency surgery carries a higher risk of DKA than elective surgery (1.1% vs. 0.17%) 10
• Non-diabetic patients taking SGLT2 inhibitors for heart failure are still at risk of euglycemic DKA, as they may not have sufficient insulin to prevent significant ketosis 10
• For patients staying in hospital after surgery, consider restarting SGLT2 inhibitors once eating and drinking normally and capillary ketones are <0.6 mmol/L 10

Management of SGLT2 Inhibitors and GLP-1 Analogues Post-Orthopedic Surgery

SGLT2 Inhibitors Post-Orthopedic Surgery

• SGLT2 inhibitors should not be initiated immediately post-orthopedic surgery due to the risk of euglycemic diabetic ketoacidosis, while GLP-1 receptor agonists can be safely started once patients are eating and drinking normally 13, 14
• Postoperative ketoacidosis can occur even when patients have withheld SGLT2 inhibitors for >72 hours 13
• SGLT2 inhibitors should only be initiated once the patient is eating and drinking normally, usually 24-48 hours after surgery, and capillary ketones should be <0.6 mmol/L before initiation 13
• Ensure adequate hydration and avoid prolonged fasting periods when starting SGLT2 inhibitors 13
• Provide written sick-day rules to patients at discharge when initiating SGLT2 inhibitors 13

GLP-1 Receptor Agonists Post-Orthopedic Surgery

• GLP-1 receptor agonists can be initiated post-orthopedic surgery once the patient is eating and drinking normally 14

Special Considerations

• For patients with heart failure, cessation of SGLT2 inhibitors may be associated with worsening heart failure, and the benefits of early initiation should be carefully weighed against the risks of euglycemic DKA 13
• For patients on a very low energy/liver reduction diet post-surgery, do not initiate SGLT2 inhibitors as this diet already induces ketosis, and the combination could lead to significant ketoacidosis 13, 14

SGLT2 Inhibitors and Euglycemic Ketoacidosis in Diabetic Patients After Anesthesia

Introduction to SGLT2 Inhibitors and Euglycemic Ketoacidosis

• SGLT2 inhibitors are associated with euglycemic ketoacidosis (euDKA) in diabetic patients after anesthesia, with a distinct pathophysiologic mechanism that differs from typical diabetic ketoacidosis 15, 16, 17

Mechanism of Euglycemic Ketoacidosis

• SGLT2 inhibitors lower blood glucose concentrations while altering the insulin/glucagon ratio, creating a hormonal environment that promotes ketogenesis even when glucose levels remain normal, with surgical stress amplifying this effect 16, 17

Epidemiology and Risk Stratification

• Patients taking SGLT2 inhibitors have a significantly higher risk of perioperative DKA compared to those not taking them, with emergency surgery carrying substantially higher risk than elective procedures 16, 17
• euDKA can occur in non-diabetic patients taking SGLT2 inhibitors for heart failure or chronic kidney disease, challenging the previous assumption that adequate endogenous insulin prevents significant ketosis 16, 17

Evidence-Based Perioperative Management

• The UK multidisciplinary consensus recommends omitting SGLT2 inhibitors only the day before and day of the procedure, while the American College of Cardiology/American Heart Association 2024 guidelines recommend withholding SGLT2 inhibitors 3-4 days before elective surgery 15, 18
• The longer discontinuation period (3-4 days) is supported by evidence showing that omitting the drug >2 days preoperatively prevents DKA occurrence, and that SGLT2 inhibitor cessation reduces the risk of high anion gap acidosis 16, 17

Special Clinical Considerations

• Cessation of SGLT2 inhibitors in patients taking them for heart failure may worsen cardiac function, creating a clinical dilemma that requires careful risk-benefit assessment 16

Perioperative Management of SGLT2 Inhibitors

Standard of Care for SGLT2 Inhibitor Use

• The 2025 UK multidisciplinary consensus from the Association of Anaesthetists requires that patients be provided written sick-day rules at pre-operative assessment, including information on DKA symptoms and risk-reduction strategies 19
• Patients taking SGLT2 inhibitors have significantly higher perioperative DKA risk (1.02 vs. 0.69 per 1000 patients, OR 1.48) 20

Documenting Informed Consent Failures

• The surgical consent form should be reviewed to confirm whether SGLT2 inhibitor-associated DKA risk was disclosed 19
• Verify whether the medication history was obtained during pre-operative assessment 20
• Determine if the surgeon or anesthesiologist documented awareness of canagliflozin use 19

Establishing Standard of Care Breach

• Multiple specialty society guidelines from 2024-2025, including the American College of Cardiology and the American Diabetes Association, establish the contemporary standard of care for SGLT2 inhibitor use in the perioperative period 19, 20

Diabetic Ketoacidosis Risk with SGLT2 Inhibitors in Surgical Settings

Precipitating Conditions and Management

• The UK Multidisciplinary Consensus 2025 acknowledges that postoperative ketoacidosis can occur even when patients have withheld SGLT2 inhibitors for >72 hours, and critical mitigation strategies include ensuring patients remain well hydrated, avoiding long starvation periods, and adequate glucose and ketone monitoring 21
• The American College of Cardiology/American Heart Association 2024 Guidelines recommend discontinue SGLT2 inhibitors 3-4 days before elective surgery, specifically canagliflozin ≥3 days before scheduled surgery, to prevent euglycemic DKA 21

Perioperative Risk Mitigation

• The UK Multidisciplinary Consensus 2025 suggests that if surgery must proceed, ensure adequate hydration, avoid prolonged fasting periods, consider glucose-containing intravenous fluids in settings of unavoidable prolonged fasting to mitigate ketone generation, and monitor glucose AND ketone levels throughout the perioperative period 21
• The UK Multidisciplinary Consensus 2025 recommends that for hospitalized patients, consider restarting Invokana only once eating and drinking normally and capillary ketones are <0.6 mmol/L, typically 24-48 hours after surgery 21