# SGLT2 Inhibitor Associated Ketoacidosis

Suspect ketoacidosis—not merely gastrointestinal illness or postoperative stress—in any SGLT2 inhibitor user with nausea, vomiting, abdominal pain, dyspnea, or malaise, regardless of glucose. Confirm with beta-hydroxybutyrate and acid-base testing, stop the drug, and treat as diabetic ketoacidosis with early carbohydrate replacement.

**Clinical question:** How should physicians recognize, confirm, treat, and prevent ketoacidosis associated with SGLT2 inhibitor therapy?

Updated: 2026-09-15T18:29:23.938627+00:00

## What matters in practice
- Normal or modestly elevated glucose does not exclude DKA in an SGLT2 inhibitor user; obtain serum or capillary beta-hydroxybutyrate and venous blood gas when compatible symptoms or high-risk circumstances are present. [3][11][13][19]
- DKA is supported by beta-hydroxybutyrate at least 3.0 mmol/L plus metabolic acidosis; a prior diabetes diagnosis satisfies the glycemic diagnostic criterion even when presenting glucose is below 200 mg/dL. [13]
- Immediately stop the SGLT2 inhibitor when ketoacidosis is suspected or diagnosed, identify insulin deficiency and the precipitating illness, and initiate DKA-directed intravenous fluids, insulin, electrolyte management, and carbohydrate replacement. [1][11][18]
- Insulin omission or reduction, acute illness, fasting or reduced caloric intake, surgery, volume depletion, ketogenic diets, and excess alcohol are key preventable precipitants. [1][11][17][24]
- SGLT2 inhibitors are not approved for glycemic control in type 1 diabetes; DKA risk is substantially higher in type 1 diabetes and insulin-deficient type 2 diabetes than in typical type 2 diabetes. [1][18][24]

## When to suspect SGLT2 inhibitor-associated ketoacidosis

Glucose concentration should not determine whether a ketone and acid-base evaluation is ordered.

Evaluate immediately for ketoacidosis in a patient taking an SGLT2 inhibitor who has nausea, vomiting, abdominal pain, generalized malaise, dyspnea, dehydration, or otherwise unexplained high-anion-gap metabolic acidosis. FDA labeling identifies under-insulinization, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse as precipitants; symptoms may occur with glucose below the conventional DKA range. [1][2][11]

Euglycemic DKA is generally defined by ketosis and metabolic acidosis with glucose below 250 mg/dL. In the current global-consensus framework, DKA requires diabetes history or glucose at least 200 mg/dL, beta-hydroxybutyrate at least 3.0 mmol/L or urine ketones at least 2+ early in presentation, and metabolic acidosis. Thus, a patient with known diabetes, glucose 135 mg/dL, beta-hydroxybutyrate 4.5 mmol/L, and low bicarbonate meets the diagnostic framework despite no hyperglycemia. [13][19][21]

Treat perioperative fasting, inability to eat, severe intercurrent illness, or missed basal insulin as a diagnostic escalation trigger rather than reassurance from a normal glucose value. Postoperative presentations may be mistaken for routine surgical recovery; early serum beta-hydroxybutyrate testing is specifically emphasized in cardiac surgical patients receiving SGLT2 inhibitors. [7][15]
- Do not reduce or omit insulin solely because glucose is normal in an ill SGLT2 inhibitor user; under-insulinization is a labeled precipitant. [1]
- Consider occult insulin deficiency in apparent type 2 diabetes with recurrent ketosis, prior pancreatic disease or pancreatic surgery, or insulin dependence; pancreatic disorders are FDA-recognized ketoacidosis risk factors. [1]
- Include ketoacidosis in patients receiving an SGLT2 inhibitor for heart failure even without diabetes when reduced intake or other catabolic stress is present; ketoacidosis has been reported in this setting. [22]

*Clinical patterns that should prompt immediate ketone and acid-base testing in an SGLT2 inhibitor user. [1][11][13][17]*

| Presentation or exposure | Why it changes the differential | Immediate action |
| --- | --- | --- |
| Nausea, vomiting, abdominal pain, malaise, or dyspnea with glucose <250 mg/dL | Compatible with euglycemic DKA; glucose can be misleadingly low because of glucosuria. [11][19][21] | Obtain beta-hydroxybutyrate, basic metabolic panel, and venous blood gas without waiting for hyperglycemia. [3][13] |
| Insulin dose reduction, missed insulin, pump or infusion-set malfunction | Relative or absolute insulin deficiency is a major precipitant; pump users have added risk from delivery failure. [1][11][17] | Verify insulin delivery and evaluate for DKA; do not use glucose alone to judge insulin adequacy. [1][13] |
| Fasting, ketogenic or very-low-carbohydrate diet, poor oral intake, or excess alcohol | These exposures increase ketosis risk and can produce normal or low glucose. [1][17][24] | Hold the SGLT2 inhibitor and measure beta-hydroxybutyrate and acid-base status if symptomatic. [11][18] |
| Surgery or acute febrile illness with dehydration | Surgical stress, reduced intake, and volume depletion are labeled precipitants; postoperative euDKA may mimic common postoperative problems. [1][7][15] | Assess volume status, ketones, bicarbonate, pH, and the surgical or infectious precipitant. [1][13] |

## Confirm ketoacidosis and separate it from other high-gap states

Use direct beta-hydroxybutyrate measurement and acid-base testing rather than urine ketones alone.

Order serum or capillary beta-hydroxybutyrate, basic metabolic panel with calculated anion gap, venous blood gas, glucose, creatinine, and urinalysis in the initial evaluation. Beta-hydroxybutyrate at least 3.0 mmol/L supports DKA; an anion gap above 12 mEq/L is typical, but vomiting, renal bicarbonate loss, and mixed acid-base disorders can obscure the expected gap or pH. [3][13]

Direct beta-hydroxybutyrate is preferred to nitroprusside urine ketones for diagnosis and response assessment because urine testing does not directly measure beta-hydroxybutyrate and may be falsely positive with sulfhydryl drugs such as captopril or with valproic acid. A urine ketone result of 2+ or greater is an acceptable early diagnostic surrogate if beta-hydroxybutyrate is not immediately available. [3][13]

Venous pH is appropriate for serial monitoring and is usually approximately 0.03 units lower than arterial pH. A pH below 7.30 or bicarbonate below 18 mEq/L with ketonemia establishes clinically important ketoacidosis in euglycemic DKA descriptions; the global-consensus DKA approach requires metabolic acidosis in addition to ketosis. [3][13][19]
- Measure lactate when evaluating a high-anion-gap acidosis; a normal lactate should not deter DKA treatment when ketonemia and acidosis are present. [22]
- Check blood urea nitrogen and creatinine because both may rise with dehydration and are needed to characterize volume depletion and renal function. [3]
- Search for the precipitant concurrently: insulin omission, infection or febrile illness, perioperative fasting, alcohol exposure, caloric restriction, dehydration, or pancreatic disease. [1][11]

### Diagnostic interpretation

A high beta-hydroxybutyrate concentration with low bicarbonate or acidemia in an SGLT2 inhibitor user should be managed as DKA even if glucose is normal. Conversely, ketosis without metabolic acidosis requires reassessment of caloric deprivation, alcohol-associated ketosis, evolving DKA, and insulin adequacy, with repeat clinical and biochemical evaluation if symptoms persist. Alcoholic ketoacidosis is a key alternative cause of high-gap acidosis with normal or low glucose. [13]

*Diagnostic thresholds and test limitations for suspected SGLT2 inhibitor-associated ketoacidosis. [3][13][19][20]*

| Test | Actionable result | Interpretation and pitfall |
| --- | --- | --- |
| Serum or capillary beta-hydroxybutyrate | ≥3.0 mmol/L. [13] | Supports DKA when metabolic acidosis is present; preferred over urine nitroprusside testing. [3][13] |
| Venous or arterial pH | <7.30 indicates acidemia consistent with DKA. [19][20] | Use venous pH for serial monitoring; it is usually about 0.03 lower than arterial pH. [3] |
| Serum bicarbonate | <18 mEq/L supports euglycemic DKA descriptions. [19] | Vomiting or other mixed disorders may make pH or anion-gap patterns atypical. [13][20] |
| Anion gap | >12 mEq/L is typical in DKA. [13] | A nonmarked gap does not exclude ketoacidosis when vomiting or renal bicarbonate losses coexist. [13] |
| Urine ketones | ≥2+ can support early DKA. [13] | Not preferred for monitoring; captopril and valproic acid can yield false-positive nitroprusside results. [3] |
| Glucose | <250 mg/dL does not exclude DKA. [19][21] | A prior diabetes history fulfills the glycemic criterion in the global-consensus DKA framework regardless of current glucose. [13] |

## Immediate management after ketoacidosis is suspected or confirmed

Stop the SGLT2 inhibitor and manage the metabolic emergency while correcting the trigger.

Discontinue the SGLT2 inhibitor immediately when ketoacidosis is diagnosed; FDA labeling instructs clinicians to assess for ketoacidosis regardless of glucose and discontinue dapagliflozin if suspected. Begin DKA-directed management with intravenous fluid resuscitation, insulin, electrolyte management, and carbohydrate replacement rather than withholding insulin because glucose is normal. [1][18]

Euglycemic presentations require special attention to carbohydrate replacement: insulin is needed to suppress ketogenesis, while dextrose-containing intravenous fluid may be needed to permit continued insulin administration without hypoglycemia. In a reported postoperative euDKA case, treatment with intravenous insulin added to 5% glucose-saline plus potassium, fluids, and nutritional support was associated with resolution of acidosis. [7][18]

Identify and reverse the driver in parallel with metabolic treatment: restore reliable insulin delivery after omission or pump failure, address infection or acute illness, correct volume depletion, and re-establish caloric intake when feasible. Do not restart the SGLT2 inhibitor during the acute event; any later reconsideration requires reassessment of the precipitant, insulin reserve, and recurrence risk. [1][11][18]
- Use serial venous pH, bicarbonate, anion gap, beta-hydroxybutyrate, glucose, potassium, and renal function to follow resolution and treatment safety. [3][13]
- Escalate monitoring intensity for severe acidemia, persistent vomiting, hemodynamic instability, altered mental status, or inability to maintain safe insulin and carbohydrate administration; DKA is life-threatening and may require inpatient critical-care capability. [1][18][19]
- Do not substitute urine ketone clearance for beta-hydroxybutyrate and acid-base improvement when following response. [3]

### Medication disposition after recovery

The immediate disposition is to stop the implicated SGLT2 inhibitor. Long-term re-initiation is not automatic: patients with recurrent ketoacidosis, missed insulin doses, low-carbohydrate or ketogenic dietary patterns, excessive alcohol intake, or difficult-to-correct insulin deficiency have persistent risk factors that should alter the benefit-risk assessment. [1][11][17][24]

*Acute management priorities in SGLT2 inhibitor-associated ketoacidosis. [1][3][7][18]*

| Priority | Specific action | Treatment endpoint or reason |
| --- | --- | --- |
| Remove the exposure | Stop the SGLT2 inhibitor immediately. [1][18] | Continued exposure may perpetuate glucosuria and obscure recognition of ketoacidosis. [1][21] |
| Suppress ketogenesis | Use intravenous insulin as part of DKA management; provide carbohydrate replacement when needed to continue insulin safely in euglycemia. [7][18] | Normal glucose does not correct insulin-deficient ketogenesis. [11][18] |
| Restore circulating volume and electrolytes | Provide intravenous fluids and manage potassium and other electrolyte abnormalities during insulin treatment. [7][18] | Volume depletion is a recognized precipitant and treatment-related electrolyte shifts require monitoring. [1][3] |
| Track resolution | Follow beta-hydroxybutyrate, venous pH, bicarbonate, anion gap, glucose, potassium, and renal function. [3][13] | Resolution requires improvement of ketosis and acidosis, not glucose normalization alone. [3][13] |
| Correct the trigger | Treat illness, restore nutrition, correct dehydration, and resolve insulin omission or delivery failure. [1][11][17] | Recurrence prevention depends on eliminating the precipitating condition. [11] |

## Prevent ketoacidosis during illness, fasting, and surgery

Risk mitigation centers on temporarily withholding therapy during catabolic stress and avoiding under-insulinization.

Before initiating an SGLT2 inhibitor, identify high-risk phenotypes: type 1 diabetes, insulin-deficient type 2 diabetes, prior or recurrent DKA, meal skipping, ketogenic or very-low-carbohydrate diets, excessive alcohol intake, and insulin pump use. SGLT2 inhibitors are not approved for glycemic control in type 1 diabetes, where estimated DKA incidence is approximately 4% and risk is reported as 5- to 17-fold higher than in untreated type 1 diabetes. [1][17][24]

For patients receiving SGLT2 inhibitors, temporarily withhold therapy during reduced caloric intake, dehydration, acute febrile illness, major illness, or other situations likely to cause ketosis. Reinforce that insulin should not be omitted or inappropriately reduced during sick days; if compatible symptoms develop, the next action is ketone and acid-base testing rather than home glucose-based reassurance. [1][11][18]

For planned surgery, a 3- to 4-day preoperative interruption is recommended in perioperative reports to reduce euDKA risk. Clinical decisions in patients prescribed SGLT2 inhibitors for heart failure require individualized risk-benefit assessment because perioperative interruption may adversely affect cardiovascular risk, but ketoacidosis risk rises with fasting and surgical stress. [7][9][15]
- Ask specifically about ketogenic diets, prolonged fasting, skipped meals, alcohol exposure, and insulin changes before prescribing and at preoperative medication review. [1][17][24]
- In a patient using an insulin pump, assess for pump or infusion-set malfunction whenever ketosis develops. [17]
- Document the SGLT2 inhibitor indication—diabetes, heart failure, or kidney disease—when making perioperative interruption decisions, because the tradeoff differs by indication. [9][22]

### Risk communication that changes behavior

Counsel patients that nausea, vomiting, abdominal pain, unusual fatigue, or shortness of breath during illness or fasting warrants urgent assessment for ketoacidosis even when fingerstick glucose is not elevated. This message is particularly important because SGLT2 inhibitor-associated DKA may present with glucose below 14 mmol/L (252 mg/dL) and can be missed if clinicians or patients use hyperglycemia as the sole trigger for evaluation. [11][19][21]

*High-risk situations and prevention actions for patients receiving SGLT2 inhibitors. [1][7][11][17][24]*

| Situation | Risk mechanism or discriminator | Prevention action |
| --- | --- | --- |
| Type 1 diabetes or insulin-deficient diabetes | Higher DKA risk; SGLT2 inhibitors are not approved for glycemic control in type 1 diabetes. [1][24] | Avoid use for type 1 diabetes glycemic control and maintain adequate insulin delivery. [1][18] |
| Acute illness, fever, dehydration, or poor intake | Catabolic stress, volume depletion, and reduced caloric intake are recognized precipitants. [1][11] | Temporarily withhold the SGLT2 inhibitor; assess ketones and acid-base status if symptomatic. [11][18] |
| Ketogenic diet, prolonged fasting, or skipped meals | Promotes ketosis and complicates interpretation of ketone elevation. [1][17][24] | Avoid SGLT inhibitor therapy with a ketogenic diet; withhold during fasting or poor intake. [17] |
| Planned surgery | Fasting and surgical stress increase perioperative euDKA risk. [1][15] | Interrupt therapy 3-4 days before surgery according to perioperative reports; reassess postoperative intake and metabolic status before resumption. [7] |
| Insulin pump therapy or recent insulin reduction | Pump malfunction and under-insulinization can precipitate DKA. [1][17] | Verify pump function and avoid inappropriate insulin dose reduction. [1][11] |

## Common questions

### Can an SGLT2 inhibitor user have ketoacidosis with glucose below 200 mg/dL?

Yes. In the global-consensus diagnostic framework, a prior diabetes diagnosis satisfies the glycemic criterion irrespective of presenting glucose; beta-hydroxybutyrate at least 3.0 mmol/L plus metabolic acidosis supports DKA. [13]

### What is the preferred ketone test in suspected SGLT2 inhibitor-associated ketoacidosis?

Use serum or capillary beta-hydroxybutyrate when available. It is preferred to urine nitroprusside testing for diagnosis and monitoring because urine testing does not directly measure beta-hydroxybutyrate and can be falsely positive with captopril or valproic acid. [3]

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## Editorial note

Prepared from cited clinical literature using Astra's research workflow. Verify recommendations against current guidance and patient-specific factors.