Can the onset of euglycemic diabetic ketoacidosis (DKA) be delayed in patients with type 2 diabetes mellitus taking Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors?

Can SGLT2 Inhibitor-Associated Euglycemic DKA Be Delayed?

Yes, the onset of euglycemic DKA can be delayed through strategic discontinuation of SGLT2 inhibitors before high-risk situations and implementation of specific preventive measures, though the risk exists on a continuum rather than having a defined threshold. 1

Evidence for Delayed Onset Through Drug Cessation

Discontinuing SGLT2 inhibitors 3 days before elective surgery or procedures (4 days for ertugliflozin) significantly reduces but does not eliminate the risk of euglycemic DKA. 1, 2 The 2025 multidisciplinary consensus statement from the Association of Anaesthetists and multiple UK societies recommends omitting SGLT2 inhibitors the day before and day of procedures, which provides a minimum 36-52 hour gap depending on timing. 1

Critical Timing Considerations

• A review of nearly 100 cases demonstrated that omitting SGLT2 inhibitors >2 days preoperatively prevented DKA occurrence in the perioperative setting. 1
• However, postoperative ketoacidosis has been reported even when patients withheld SGLT2 inhibitors for >72 hours, emphasizing that risk reduction is a continuum rather than an absolute threshold. 1
• Early cessation is associated with reduced risk of high anion gap acidosis. 1

Risk Stratification: When Delay Is Most Effective

The ability to delay or prevent euglycemic DKA depends heavily on identifying and mitigating precipitating factors:

High-Risk Situations Requiring Immediate Discontinuation

• Acute severe illness, vomiting, or dehydration mandate immediate SGLT2 inhibitor cessation. 3, 4
• Reduced caloric intake including very low-carbohydrate diets, prolonged fasting, or poor oral intake during illness. 2, 4
• Major surgical procedures, particularly those requiring extended fasting periods. 2
• Excessive alcohol consumption. 2, 4

Populations Where Prevention Is Critical

• Patients with latent autoimmune diabetes in adults (LADA), pancreatic insufficiency, or history of pancreatitis/pancreatic surgery should avoid SGLT2 inhibitors entirely. 3, 4
• Type 1 diabetes patients face substantially increased risk and require extreme caution. 4, 5
• Patients on complex insulin regimens, especially those who reduce insulin doses >20%. 4

Specific Mitigation Strategies to Delay Onset

Perioperative Protocol

The following algorithm reduces perioperative euglycemic DKA risk: 1

• Stop SGLT2 inhibitors the day before and day of procedure (minimum 36-48 hours)
• Ensure patients adhere to recommended fasting guidelines and avoid prolonged starvation
• Consider glucose-containing IV fluids in settings of unplanned or unavoidable prolonged fasting
• Maintain adequate hydration throughout the perioperative period
• Monitor capillary ketones, restarting SGLT2 inhibitors only when ketones <0.6 mmol/L and patient eating/drinking normally (typically 24-48 hours post-surgery)

Sick Day Rules for Outpatient Prevention

Written sick-day rules should be provided at pre-operative assessment and discharge: 1

• Temporarily discontinue SGLT2 inhibitors during acute illness, excessive exercise, or alcohol intake 3
• Maintain hydration and avoid prolonged fasting periods 1
• Monitor urine or blood ketones during high-risk situations 2
• Seek immediate medical attention for nausea, vomiting, abdominal pain, malaise, or dyspnea 1, 3

Special Consideration: Very Low-Energy Diets

For patients starting liver reduction diets (800-1000 calories/day) before bariatric or laparoscopic surgery, SGLT2 inhibitors must be stopped at diet commencement. 1 This very low-carbohydrate intake creates a ketogenic state that substantially increases euglycemic DKA risk.

Clinical Pitfalls in Delayed Recognition

The absence of significant hyperglycemia (glucose <200 mg/dL or even <250 mg/dL) delays recognition by both patients and providers, as traditional DKA symptoms may be absent. 2, 6, 5 This is particularly dangerous because:

• Metabolic acidosis with pH <7.3 and elevated ketones can develop rapidly despite normal glucose 2
• Nonspecific symptoms (malaise, nausea, vomiting, abdominal pain) may be attributed to other causes 1, 7
• In two of three patients in a recent case series, delayed diagnosis occurred specifically due to absence of hyperglycemia. 7

Restarting Criteria After High-Risk Period

SGLT2 inhibitors should only be restarted when ALL of the following criteria are met: 1, 3

• Patient eating and drinking normally
• Capillary ketones <0.6 mmol/L
• Clinical illness improving
• Renal function stable

Limitations of Prevention

Despite optimal timing of discontinuation and preventive measures, euglycemic DKA can still occur, particularly in emergency surgery (1.1% incidence) versus elective surgery (0.17% incidence). 1, 2 The overall perioperative risk remains elevated at 1.02 versus 0.69 per 1000 patients compared to non-users (OR 1.48,95% CI 1.02-2.15). 1

Importantly, euglycemic DKA has been documented in patients without diabetes mellitus taking SGLT2 inhibitors for heart failure or chronic kidney disease, challenging the previous assumption that sufficient endogenous insulin prevents ketosis. 1