What does ketonuria indicate and how should it be evaluated and managed in cases of prolonged fasting, uncontrolled diabetes mellitus, and patients taking sodium‑glucose cotransporter‑2 inhibitors?

Ketonuria: Clinical Significance and Management

Ketonuria indicates increased ketone body production from fat metabolism and requires immediate evaluation with blood β-hydroxybutyrate measurement—not reliance on urine testing alone—to distinguish benign physiologic ketosis from life-threatening diabetic ketoacidosis, particularly in patients taking SGLT2 inhibitors where euglycemic DKA can occur with normal glucose levels. 1

What Ketonuria Indicates

Physiologic vs. Pathologic States

• Benign physiologic ketosis occurs in up to 30% of first morning urine specimens from pregnant women, during starvation/prolonged fasting, and after hypoglycemia 1
• Pathologic ketoacidosis presents with ketonuria in diabetic ketoacidosis (DKA), alcoholic ketoacidosis, and SGLT2 inhibitor-associated euglycemic DKA 1
• Critical distinction: Positive urine ketones in a diabetic patient with typical symptoms and hyperglycemia suggests impending or established DKA 1

SGLT2 Inhibitor Context

• SGLT2 inhibitors increase DKA risk in type 2 diabetes (0.6–4.9 events per 1,000 patient-years) with a relative risk of 2.46 compared to placebo 1, 2
• Euglycemic DKA (glucose <200-250 mg/dL) is the hallmark presentation with SGLT2 inhibitors, where ketonuria occurs despite relatively normal glucose 1, 3, 2
• Patients on SGLT2 inhibitors should check urine or blood ketones at any sign of illness, even with normal glucose levels 1, 2

Critical Limitation of Urine Ketone Testing

Why Urine Testing Is Inadequate

• Urine ketone tests using nitroprusside only detect acetoacetate, not β-hydroxybutyrate (the predominant ketone in DKA) 1
• During active DKA, β-hydroxybutyrate predominates in blood; as DKA resolves, it converts to acetoacetate, which then appears in urine 4
• This creates a dangerous lag: urine ketones may be increasing even as DKA is resolving, or may be negative despite severe ketonemia 1, 5
• 73% of elevated plasma β-hydroxybutyrate measurements in poorly controlled diabetics showed no ketonuria 5

The Gold Standard

Blood β-hydroxybutyrate measurement should be used for diagnosis of DKA and may be used for monitoring during treatment. 1

Evaluation Algorithm by Clinical Context

1. Prolonged Fasting (Non-Diabetic)

• Expected finding: Mild ketonuria is physiologic and benign 1
• Action required: None if patient is otherwise well
• Red flags: If accompanied by nausea, vomiting, or abdominal pain, measure blood β-hydroxybutyrate to exclude pathologic ketoacidosis 1

2. Uncontrolled Diabetes Mellitus

Immediate evaluation required:

• Measure blood glucose simultaneously 1
• If glucose >200 mg/dL with ketonuria: Obtain blood β-hydroxybutyrate, venous blood gas for pH and anion gap 1
• DKA diagnosis requires all three: hyperglycemia, increased blood ketones/β-hydroxybutyrate, and acidosis with increased anion gap 1
• Do not rely on urine ketone determinations alone for DKA diagnosis 1

Management approach:

• If β-hydroxybutyrate elevated but patient hemodynamically stable, cognitively intact, tolerating oral fluids: May treat mild DKA outpatient with frequent monitoring, noncaloric hydration, and subcutaneous insulin 1
• Seek immediate medical attention if unable to tolerate oral hydration, glucose not improving with insulin, altered mental status, or worsening illness 1
• Never stop basal insulin even if not eating—this is a critical precipitant of DKA 1

3. Patients Taking SGLT2 Inhibitors

High-risk scenario requiring heightened vigilance:

When to Check Ketones 1, 2

• Any sign of illness (nausea, vomiting, abdominal pain, weakness)
• Prolonged fasting or very-low-carbohydrate diet
• Dehydration or reduced oral intake
• Even with normal glucose levels 1, 3, 2

Perioperative Management 1

• Stop SGLT2 inhibitors the day before and day of procedure (minimum 36-48 hour gap) 1
• Some cases of postoperative ketoacidosis occur even after >72 hours of withholding, emphasizing risk is a continuum 1, 6
• Avoid prolonged fasting; consider glucose-containing IV fluids if unavoidable prolonged fasting 1
• For very-low-energy/liver reduction diets: Stop SGLT2 inhibitors at diet commencement 1
• Restart only when eating/drinking normally AND capillary ketones <0.6 mmol/L 1

Sick Day Rules 1, 2

• Temporarily discontinue SGLT2 inhibitors during acute illness, dehydration, or prolonged fasting 2
• Maintain hydration 1
• Monitor blood glucose and ketones frequently 2
• Provide written sick-day guidance at discharge 1

Common Pitfalls to Avoid

Testing Errors

• Never use nitroprusside-based blood ketone tests to monitor DKA treatment—acetoacetate and acetone may increase as β-hydroxybutyrate falls during successful therapy 1
• Do not dismiss DKA possibility based solely on glucose <250 mg/dL in SGLT2 inhibitor users 3, 2
• Negative urine ketones do not exclude significant ketonemia 5

Management Errors

• Avoid >20% reduction in insulin dose when initiating SGLT2 inhibitors 2
• Do not continue SGLT2 inhibitors during very-low-carbohydrate diets or prolonged fasting 1, 2
• Never hold basal insulin in diabetic patients even if not eating 1

Special Populations

• Pregnant women: Up to 30% have physiologic ketonuria in first morning specimens; however, pregnant individuals with diabetes are at risk for euglycemic DKA and should seek immediate care for any concerning symptoms 1
• Alcoholic ketoacidosis: Positive urine ketones without hyperglycemia (may have hypoglycemia) 1
• Type 1 diabetes patients on SGLT2 inhibitors (off-label): Substantially higher DKA risk than type 2 diabetes 1

When to Hospitalize

Immediate inpatient evaluation required for: 1

• Suspected hyperosmolar hyperglycemic state (HHS)—always associated with greater volume depletion
• Inability to tolerate oral hydration
• Altered mental status
• Blood glucose not improving with subcutaneous insulin
• Any signs of worsening illness despite outpatient management