What is the risk of euglycemic diabetic ketoacidosis (euDKA) with Semaglutide (GLP-1 receptor agonist) use?

Risk of Euglycemic Diabetic Ketoacidosis with Semaglutide Use

Semaglutide itself has a low risk of euglycemic diabetic ketoacidosis (euDKA) compared to SGLT2 inhibitors, but rare cases have been reported in recent literature.

Understanding Euglycemic DKA Risk with GLP-1 Receptor Agonists

Euglycemic diabetic ketoacidosis (euDKA) is characterized by metabolic acidosis and ketonemia without significant hyperglycemia (blood glucose <250 mg/dL). While this condition is well-established as a risk with SGLT2 inhibitors, the risk profile with GLP-1 receptor agonists like semaglutide is different:

Evidence on Semaglutide and euDKA

• Recent case reports have documented euDKA occurring with GLP-1 receptor agonists including semaglutide 1 and dulaglutide 2
• A 2025 case report described euDKA in a patient without diabetes who was taking semaglutide for weight loss for 7 months 1
• Another 2025 case report documented euDKA in a patient on both semaglutide and empagliflozin, though the SGLT2 inhibitor was likely the primary contributor 3

Risk Comparison

• SGLT2 inhibitors have a well-documented and higher risk of euDKA, with multiple case reports and warnings in guidelines 4, 5
• The American Diabetes Association guidelines (2020-2022) extensively discuss cardiovascular benefits of semaglutide but do not specifically mention euDKA risk with GLP-1 receptor agonists 6
• The risk appears to be substantially lower with GLP-1 receptor agonists compared to SGLT2 inhibitors

Risk Factors and Mechanisms

When euDKA occurs with semaglutide, it appears to involve:

1. Reduced caloric intake: GLP-1 receptor agonists significantly reduce appetite, which can lead to reduced carbohydrate consumption
2. Dehydration: Gastrointestinal side effects (nausea, vomiting, diarrhea) can contribute to dehydration
3. Precipitating factors: Illness, surgery, or other stressors may trigger euDKA in susceptible individuals
4. Combination therapy: Risk may be higher when semaglutide is used alongside SGLT2 inhibitors 3

Clinical Implications and Management

Monitoring Recommendations

• Monitor for symptoms of euDKA in patients on semaglutide, especially during illness, surgery, or periods of reduced oral intake
• Be alert to non-specific symptoms like fatigue, nausea, vomiting, abdominal pain, and weakness
• Consider checking ketones in symptomatic patients even with normal glucose levels

Management of Suspected euDKA

• Prompt administration of intravenous fluids (dextrose-containing if glucose is not elevated)
• Insulin therapy to suppress ketogenesis
• Electrolyte replacement, particularly potassium
• Temporary discontinuation of semaglutide until resolution

Conclusion

While the cardiovascular benefits of semaglutide are well-established in multiple large trials 6, 7, the risk of euDKA appears to be rare but present. Clinicians should be aware of this potential complication, particularly in patients with risk factors or those using combination therapy with SGLT2 inhibitors.

The risk-benefit profile still strongly favors semaglutide use in appropriate patients, but vigilance for this rare complication is warranted.