Can Ozempic (semaglutide) cause euglycemic diabetic ketoacidosis (DKA)?

Euglycemic DKA and Semaglutide (Ozempic)

Semaglutide (Ozempic) is not typically associated with euglycemic diabetic ketoacidosis (euDKA), unlike SGLT2 inhibitors which are well-documented to cause this potentially life-threatening condition.

Understanding Euglycemic DKA

Euglycemic DKA is characterized by:

• Metabolic acidosis
• Ketonemia/ketonuria
• Blood glucose levels <200 mg/dL (11.1 mmol/L)

Evidence on GLP-1 RAs and Euglycemic DKA

Primary Association with SGLT2 Inhibitors

The 2025 Diabetes Care guidelines clearly identify SGLT2 inhibitors as the primary medication class associated with euglycemic DKA 1. The guidelines state that "approximately 10% of people experiencing DKA present with euglycemic DKA (plasma glucose <200 mg/dL [11.1 mmol/L])" and that "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" 1.

Limited Evidence for GLP-1 RAs

There are only isolated case reports suggesting a potential association between GLP-1 receptor agonists like semaglutide and euglycemic DKA:

• A 2024 case report described euglycemic ketoacidosis in a patient without diabetes taking semaglutide for weight loss 2.
• Another recent case report documented euglycemic DKA with dulaglutide (another GLP-1 RA) 3.

However, these represent extremely rare occurrences compared to the well-established association with SGLT2 inhibitors.

FDA Labeling and Guidelines

The FDA label for semaglutide (Ozempic) specifically states that it "is not indicated for use in patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis, as it would not be effective in these settings" 4. Notably, the label does not include warnings about euglycemic DKA risk with semaglutide use.

In contrast, the American Diabetes Association guidelines explicitly warn about euglycemic DKA risk with SGLT2 inhibitors, noting that "risk factors for DKA in individuals with type 2 diabetes treated with SGLT2 inhibitors include very-low-carbohydrate diets and prolonged fasting, dehydration, excessive alcohol intake, and the presence of autoimmunity" 1.

Risk Factors and Mechanisms

If a patient on semaglutide develops euglycemic DKA, consider these potential contributing factors:

1. Concurrent SGLT2 inhibitor use (primary risk factor)
2. Severe caloric restriction or fasting
3. Acute illness
4. Dehydration
5. Alcohol consumption
6. Underlying autoimmune diabetes (LADA)

Clinical Implications

For clinicians managing patients on semaglutide:

• Monitor for symptoms of DKA (nausea, vomiting, abdominal pain, fatigue) even when glucose levels are normal or only mildly elevated
• Consider checking ketones in symptomatic patients regardless of glucose levels
• Be particularly vigilant in patients using both GLP-1 RAs and SGLT2 inhibitors
• Educate patients about the importance of adequate caloric intake and hydration

Management of Suspected Euglycemic DKA

If euglycemic DKA is suspected in a patient taking semaglutide:

1. Discontinue semaglutide
2. Administer IV fluids with dextrose
3. Start insulin infusion
4. Monitor electrolytes and acid-base status
5. Investigate for precipitating factors

Conclusion

While there are isolated case reports of euglycemic DKA with GLP-1 RAs like semaglutide, this association is extremely rare compared to the well-established risk with SGLT2 inhibitors. Clinicians should be aware of this potential but uncommon adverse effect, particularly in patients with multiple risk factors or those using combination therapy with SGLT2 inhibitors.