From the Guidelines
SGLT2 inhibitors are the primary medications that can cause diabetic ketoacidosis (DKA) with almost normal blood glucose levels, with up to a third of patients presenting with glucose levels <200 mg/dL. Several medications can cause euglycemic diabetic ketoacidosis (eDKA), a condition where ketoacidosis occurs despite relatively normal blood glucose levels. The most notable culprits are sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin, as stated in the 2025 standards of care in diabetes 1. These medications work by preventing glucose reabsorption in the kidneys, leading to increased urinary glucose excretion which can lower blood glucose levels while simultaneously creating a state that promotes ketone production.
Key points to consider:
- SGLT2 inhibitors are not approved for use in people with type 1 diabetes, but can be used in people with type 2 diabetes, with an estimated incidence of DKA of 0.6–4.9 events per 1,000 person-years 1.
- Risk factors for DKA in individuals with either type 1 or type 2 diabetes treated with SGLT inhibitors include very-low-carbohydrate diets, prolonged fasting, dehydration, excessive alcohol intake, and other common precipitating factors 1.
- Patients taking SGLT2 inhibitors should be particularly vigilant about monitoring for symptoms of DKA, such as nausea, vomiting, abdominal pain, fatigue, and fruity-smelling breath, even when blood glucose readings aren't elevated, and should temporarily discontinue these medications during periods of acute illness, fasting, or surgical procedures.
- It is essential to educate at-risk individuals about the signs and symptoms of DKA and DKA mitigation and management, and to prescribe accurate tools for ketone measurement, as up to 71% of people treated with SGLT2 inhibitors who developed DKA presented with glucose levels <250 mg/dL 1.
From the Research
Medications Causing DKA with Almost Normal Blood Sugar
- SGLT-2 inhibitors, such as dapagliflozin 2, 3 and canagliflozin 4, 5, have been reported to cause diabetic ketoacidosis (DKA) with almost normal blood glucose levels.
- These medications work by increasing urinary glucose excretion, which can lead to a state of euglycemic DKA, where the blood glucose level is not significantly elevated despite the presence of ketoacidosis 5.
- The risk of DKA associated with SGLT-2 inhibitors may be increased in certain individuals, such as those with a low beta cell function reserve, excessive alcohol consumption, and a low carbohydrate diet 4.
- Patients taking SGLT-2 inhibitors who become ill should discontinue the medication, undergo ketone evaluation, and start basal insulin if ketones are positive 2.
- Emergency physicians should be aware of the potential for euglycemic DKA in patients taking SGLT-2 inhibitors, as a delay in diagnosis can be life-threatening 5, 3.
Key Findings
- A meta-analysis of randomized controlled trials found that SGLT-2 inhibitors were not associated with an increased risk of ketoacidosis as a class, but individual molecules may have different effects 6.
- Cases of prolonged DKA associated with canagliflozin have been reported, with ketonemia persisting for up to 12 days after discontinuation of the medication 4.
- Dapagliflozin has also been reported to cause euglycemic DKA, with clinical effects persisting longer than expected 2.