In a patient taking a sodium‑glucose co‑transporter‑2 (SGLT2) inhibitor who is found to have ketonuria, how should I evaluate and manage it?

Evaluation and Management of Ketonuria in Patients Taking SGLT2 Inhibitors

When ketonuria is detected in a patient on an SGLT2 inhibitor, immediately assess for diabetic ketoacidosis (DKA) or euglycemic DKA by checking serum ketones (beta-hydroxybutyrate), venous blood gas, anion gap, and bicarbonate—regardless of the blood glucose level—because SGLT2 inhibitors can cause life-threatening ketoacidosis even with glucose levels below 250 mg/dL or as low as 127 mg/dL. 1, 2, 3, 4

Immediate Diagnostic Workup

When ketonuria is found, obtain the following tests urgently:

• Serum beta-hydroxybutyrate (most specific ketone marker; levels >3.0 mmol/L indicate significant ketosis) 1
• Venous blood gas to assess pH (DKA threshold: pH <7.3) 1
• Serum bicarbonate (typically <18 mmol/L in DKA, but can be as low as 5 mmol/L) 4, 5
• Anion gap (elevated >12-14 in ketoacidosis) 3, 4, 5
• Blood glucose (may be normal or only mildly elevated; euglycemic DKA can occur with glucose <250 mg/dL) 1, 2, 3

Risk Stratification: High-Risk Clinical Scenarios

Withhold the SGLT2 inhibitor immediately if any of these precipitating factors are present: 1, 2, 6

• Prolonged fasting or surgery (withhold at least 3 days before major surgery if possible) 2
• Critical medical illness or acute febrile illness 1, 2
• Severe dehydration or volume depletion 2, 6
• Very low carbohydrate or ketogenic diet 4, 6, 5
• Recent insulin dose reduction or missed insulin doses 2, 6
• Excessive alcohol intake 2, 6
• Extensive exercise 6

Clinical Presentation: Key Symptoms to Assess

Patients with SGLT2 inhibitor-associated ketoacidosis typically present with: 3, 4, 6

• Nausea, vomiting, and abdominal pain 2, 3, 4
• Generalized weakness and malaise 2, 3, 4
• Dyspnea or shortness of breath 2, 4
• Dehydration 2, 3, 6

Critical pitfall: Patients may be falsely reassured by normal or near-normal home glucose readings, delaying diagnosis. 3, 6

Management Algorithm Based on Ketone Levels

If Beta-Hydroxybutyrate >3.0 mmol/L AND pH <7.3:

• Diagnose DKA and discontinue SGLT2 inhibitor immediately 2, 6
• Initiate standard DKA protocol with insulin infusion and intravenous fluids 2, 4, 6
• Add glucose-containing IV fluids even if blood glucose is normal to prevent hypoglycemia and suppress ketogenesis 1, 2
• Monitor for resolution of ketoacidosis before considering restarting SGLT2 inhibitor 2
• Note: Glucosuria may persist for 3 days after discontinuation (and up to 2 weeks in some cases), which can prolong ketoacidosis 2, 7

If Beta-Hydroxybutyrate 1.5-3.0 mmol/L with Normal pH:

• Temporarily withhold SGLT2 inhibitor 1
• Ensure adequate hydration with glucose-containing fluids 1
• Address precipitating factors (resume normal diet, avoid fasting) 6
• Monitor ketones and clinical status closely 6
• Resume SGLT2 inhibitor only when patient is clinically stable, ketones have normalized, and oral intake has resumed 2

If Trace Ketonuria with Beta-Hydroxybutyrate <1.5 mmol/L:

• Continue SGLT2 inhibitor if no precipitating factors are present 1
• Educate patient on sick day rules and when to withhold medication 1
• Ensure adequate carbohydrate intake and hydration 6

Patient Education and Prevention

All patients on SGLT2 inhibitors must be counseled on: 2, 6

• Signs and symptoms of ketoacidosis (nausea, vomiting, abdominal pain, weakness, dyspnea) 2, 3
• Instructions to discontinue SGLT2 inhibitor and seek immediate medical attention if these symptoms occur 2, 6
• Sick day rules: withhold medication during acute illness, prolonged fasting, or surgery 1, 2
• Avoid very low carbohydrate or ketogenic diets while on SGLT2 inhibitors 4, 6, 5
• Never reduce or omit insulin doses without medical supervision 2, 6

Special Populations

Patients with type 1 diabetes: SGLT2 inhibitors are not indicated and markedly increase DKA risk. 2

Patients with pancreatic disorders: History of pancreatitis or pancreatic surgery increases ketoacidosis risk. 2

Patients without diabetes: Euglycemic ketoacidosis can occur even in non-diabetic patients taking SGLT2 inhibitors for heart failure or CKD; maintain high clinical suspicion. 1

Common Pitfalls to Avoid

• Do not dismiss symptoms based on normal glucose levels—euglycemic DKA is a hallmark of SGLT2 inhibitor-associated ketoacidosis. 1, 3, 6
• Do not rely on urine ketones alone—serum beta-hydroxybutyrate is more specific and quantitative. 1
• Do not provide inadequate glucose supplementation during DKA treatment—this can prolong hypoglycemia and ketosis. 4, 7
• Do not restart SGLT2 inhibitor until ketoacidosis has fully resolved and precipitating factors have been addressed. 2