Does sitagliptin (Januvia) cause euglycemic diabetic ketoacidosis (DKA)?

Does Sitagliptin Cause Euglycemic DKA?

Sitagliptin (Januvia) is not commonly associated with euglycemic diabetic ketoacidosis (DKA), unlike SGLT2 inhibitors which have a well-documented risk of this complication. However, there has been at least one case report linking sitagliptin to euglycemic DKA 1.

Understanding Euglycemic DKA

Euglycemic DKA is characterized by:

• Metabolic acidosis
• Ketosis
• Blood glucose levels <200 mg/dL (11.1 mmol/L)
• Same pathophysiology as classic DKA but without marked hyperglycemia

Medication Classes and Euglycemic DKA Risk

SGLT2 Inhibitors

• High Risk: Multiple guidelines identify SGLT2 inhibitors as having a well-established association with euglycemic DKA 2
• The 2025 ADA Standards of Care specifically notes: "Euglycemic DKA requires insulin deficiency and can be associated with a variety of factors including reduced food intake, pregnancy, alcohol use, liver failure, and/or SGLT2 inhibitor therapy" 2
• Risk factors include very-low-carbohydrate diets, prolonged fasting, dehydration, excessive alcohol intake, and autoimmunity 2

DPP-4 Inhibitors (including Sitagliptin)

• Low Risk: DPP-4 inhibitors like sitagliptin are generally not highlighted in guidelines as causing euglycemic DKA
• The 2024 DCRM 2.0 multispecialty recommendations do not list DKA as a risk for DPP-4 inhibitors in their medication summary table, while clearly indicating this risk for SGLT2 inhibitors 2
• However, a case report has documented euglycemic DKA in a patient taking sitagliptin who had influenza 1

GLP-1 Receptor Agonists

• Rare Risk: There have been case reports of GLP-1 receptor agonists like dulaglutide causing euglycemic DKA 3, but this is not commonly highlighted in guidelines

Clinical Implications

1. Monitoring Recommendations:

   • For patients on SGLT2 inhibitors: Regular monitoring for ketosis is recommended, especially during illness or fasting 2
   • For patients on sitagliptin: Routine ketone monitoring is not specifically recommended in guidelines, but awareness of the possibility is prudent

2. Risk Mitigation:

   • For SGLT2 inhibitors: Consider pausing during acute illness or stressors 2
   • For sitagliptin: No specific precautions regarding euglycemic DKA are mentioned in guidelines

3. Patient Education:

   • Patients should be informed about symptoms of DKA (nausea, vomiting, abdominal pain, fatigue, shortness of breath) regardless of glucose levels
   • Those on SGLT2 inhibitors require specific education about euglycemic DKA risk

Conclusion

While sitagliptin (and other DPP-4 inhibitors) are generally considered safe with respect to euglycemic DKA risk, clinicians should remain vigilant for this rare but possible complication, especially in patients with concurrent risk factors such as acute illness. The primary medication class associated with euglycemic DKA is SGLT2 inhibitors, which have a well-documented risk that is acknowledged across multiple clinical guidelines.

If a patient on sitagliptin presents with symptoms suggestive of DKA (nausea, vomiting, abdominal pain, fatigue), ketone testing should be performed regardless of blood glucose levels to rule out euglycemic DKA, particularly if other risk factors are present.