Should SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors be initiated in patients with a history of Diabetic Ketoacidosis (DKA)?

SGLT2 Inhibitors Should Not Be Initiated in Patients with History of DKA

SGLT2 inhibitors should not be initiated in patients with a history of diabetic ketoacidosis (DKA) due to significantly increased risk of recurrent DKA events. 1, 2, 3

Risk Assessment and Rationale

The decision to avoid SGLT2 inhibitors in patients with prior DKA is based on several key factors:

• The 2025 American Diabetes Association Standards of Care explicitly states: "Individuals who have experienced DKA should not be treated with SGLT inhibition." 1
• FDA drug labels for SGLT2 inhibitors like dapagliflozin and canagliflozin specifically warn about increased risk of ketoacidosis in susceptible patients 2, 3
• A history of DKA represents a significant risk factor for recurrent episodes, particularly when combined with SGLT2 inhibitor therapy

Mechanism of Risk

SGLT2 inhibitors can precipitate DKA through several mechanisms:

• Reduced insulin secretion and increased glucagon levels
• Enhanced lipolysis and ketogenesis
• Increased renal reabsorption of ketone bodies
• Reduced renal clearance of ketones

Special Considerations

Euglycemic DKA Risk

SGLT2 inhibitors are uniquely associated with euglycemic DKA, which presents additional diagnostic challenges:

• Up to one-third of patients with SGLT2 inhibitor-associated DKA present with glucose levels <200 mg/dL 1
• In one study, 71% presented with glucose levels ≤250 mg/dL 1
• This atypical presentation often leads to delayed diagnosis and treatment 4, 5

Additional Risk Factors

Patients with a history of DKA who also have any of these factors are at particularly high risk:

• Insulin deficiency (including insulin-dependent type 2 diabetes)
• Reduced oral intake or fasting states
• Acute illness
• Dehydration
• Alcohol consumption
• Very low-carbohydrate diets 1, 4, 6

Alternative Therapeutic Options

For patients with a history of DKA requiring antihyperglycemic therapy:

• GLP-1 receptor agonists are preferred alternatives, especially in patients with cardiovascular disease or high cardiovascular risk 1
• These agents provide cardiovascular and renal benefits without increasing DKA risk
• For patients with heart failure or chronic kidney disease who might otherwise benefit from SGLT2 inhibition, careful risk-benefit assessment with alternative therapies should be considered

Monitoring and Education

If, despite these recommendations, an SGLT2 inhibitor is deemed absolutely necessary in a patient with prior DKA (which is generally not recommended):

• Provide ketone monitoring tools and education on their use
• Implement strict "sick day" protocols including temporary discontinuation during illness
• Educate on signs and symptoms of DKA, including nausea, vomiting, abdominal pain, malaise, and shortness of breath 2, 3
• Ensure adequate insulin dosing is maintained

Clinical Guidance Algorithm

1. Patient presents with history of DKA and need for diabetes therapy
2. Avoid initiating SGLT2 inhibitors
3. Consider GLP-1 receptor agonist as preferred alternative
4. If cardiovascular or renal benefits are needed:
   • Optimize GLP-1 receptor agonist therapy
   • Consider additional cardioprotective medications (statins, ACEi/ARBs)
   • Maintain appropriate insulin therapy if needed

Conclusion

The risk of recurrent DKA in patients with a history of this condition who are started on SGLT2 inhibitors outweighs potential benefits. The American College of Cardiology and American Diabetes Association guidelines, along with FDA drug labeling, support avoiding these medications in this high-risk population.