Can Dapagliflozin Cause DKA in Patients Without Diabetes?
Yes, dapagliflozin can cause diabetic ketoacidosis (DKA), including euglycemic ketoacidosis, in patients without diabetes, though this is rare. This serious, life-threatening complication has been documented in non-diabetic patients taking SGLT2 inhibitors for heart failure and chronic kidney disease 1.
Understanding the Risk
The FDA drug label explicitly warns that SGLT2 inhibitors, including dapagliflozin, increase susceptibility to ketoacidosis regardless of diabetes status 1. While the risk is highest in type 1 diabetes (where dapagliflozin is contraindicated), type 2 diabetes, and pancreatic disorders, ketoacidosis can occur in non-diabetic patients when precipitating factors are present 2.
Mechanism in Non-Diabetic Patients
Even without diabetes, dapagliflozin creates a baseline state of mild ketonemia through:
- Increased glucagon levels leading to lipolysis and ketone production
- Decreased renal clearance of ketones
- Relative insulin deficiency in stress states 2, 3
When combined with precipitating factors, this baseline ketonemia can rapidly progress to life-threatening ketoacidosis while blood glucose remains normal (euglycemic DKA) 3.
Critical Precipitating Factors
The following situations dramatically increase DKA risk in non-diabetic patients on dapagliflozin:
- Reduced oral intake (most common trigger in non-diabetic cases) 3
- Acute illness or infection 1
- Surgery or prolonged fasting 4, 5, 6
- Volume depletion 1
- Ketogenic diet or carbohydrate restriction 1
- Alcohol abuse 1
Clinical Presentation
Maintain high suspicion for ketoacidosis in any patient on dapagliflozin presenting with:
- Nausea, vomiting, abdominal pain
- Generalized malaise, fatigue
- Shortness of breath
- Signs of dehydration and severe metabolic acidosis 1
Critical diagnostic point: Blood glucose may be below 250 mg/dL (often normal) in euglycemic DKA, making diagnosis challenging 2, 1. Always check ketones (blood or urine) regardless of glucose level when metabolic acidosis is suspected 1.
Evidence from Non-Diabetic Patients
Recent case reports document euglycemic ketoacidosis in non-diabetic patients on dapagliflozin for heart failure 7, 3. A systematic review identified six cases in non-diabetic patients, with decreased oral intake being the common precipitating factor in five of six cases 3. Notably, ketoacidosis can occur up to 8-11 days after stopping dapagliflozin, with persistent glucosuria and ketonuria 5.
Risk Mitigation Strategy
Pre-operative Management
Withhold dapagliflozin for at least 3 days before major surgery or procedures with prolonged fasting 1. Recent perioperative guidelines recommend stopping SGLT2 inhibitors >2 days pre-operatively to prevent DKA 4. Data suggest that omitting the drug >2 days pre-operatively significantly reduces DKA risk 4.
High-Risk Clinical Situations
Temporarily discontinue dapagliflozin when patients:
- Cannot maintain adequate oral intake
- Develop acute illness with vomiting/diarrhea
- Require prolonged fasting
- Experience significant volume depletion 1
Resume only when the patient is clinically stable and has resumed oral intake 1.
Patient Education
Educate all patients (diabetic and non-diabetic) on:
- Signs and symptoms of ketoacidosis
- Instruction to immediately discontinue dapagliflozin and seek emergency care if symptoms develop
- Sick day protocol: stop the medication during illness, maintain hydration, and seek early medical attention 8, 1
Monitoring Recommendations
For non-diabetic patients on dapagliflozin:
- Consider ketone monitoring in high-risk situations (illness, surgery, fasting) 8, 1
- Assess for ketoacidosis regardless of blood glucose level in patients with signs of metabolic acidosis 1
- Monitor closely in post-operative period, as risk is higher after surgery than elective procedures 4, 6
Treatment Approach
If ketoacidosis is suspected:
- Immediately discontinue dapagliflozin 1
- Check blood or urine ketones and arterial blood gas
- Initiate DKA protocol with IV fluids and insulin therapy 5, 6
- Monitor for resolution before considering restarting (if appropriate) 1
Important Caveats
- While large cardiovascular and heart failure trials (DAPA-HF, EMPEROR-Reduced) showed low rates of ketoacidosis in non-diabetic patients, these trials excluded high-risk individuals and may not reflect real-world risk 9, 2, 9
- The absolute risk remains low but not zero in non-diabetic patients 3
- Persistent glucosuria can last >6 days and up to 2 weeks after stopping dapagliflozin, potentially prolonging ketoacidosis risk 1, 5
Bottom line: While dapagliflozin provides significant cardiovascular and renal benefits in non-diabetic patients with heart failure and CKD 9, clinicians must remain vigilant for ketoacidosis, particularly during periods of physiologic stress, reduced oral intake, or surgery. The key is recognizing that normal blood glucose does not exclude ketoacidosis in patients on SGLT2 inhibitors.