Causes of Euglycemic Diabetic Ketoacidosis
Euglycemic DKA occurs when blood glucose is less than 200-250 mg/dL in the presence of ketoacidosis, and is most commonly precipitated by SGLT2 inhibitor use, insulin dose reduction, reduced caloric intake, pregnancy, and acute illness. 1, 2
SGLT2 Inhibitors - The Primary Culprit
SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) are the leading cause of euglycemic DKA in contemporary practice. 3 These medications promote urinary glucose excretion independent of insulin, allowing ketoacidosis to develop while maintaining relatively normal blood glucose levels. 4, 5
Key precipitating factors with SGLT2 inhibitors include:
- Insulin dose reduction or omission (>20% reduction) - the most critical precipitating factor 6, 7
- Reduced caloric intake - very-low-carbohydrate/ketogenic diets, prolonged fasting, or poor oral intake during illness 6, 4, 2
- Volume depletion and dehydration 6, 5
- Excessive alcohol consumption 6, 2
- Acute illness or infection 1, 6, 8
- Perioperative states - particularly procedures requiring fasting 6
The FDA drug labels for both dapagliflozin and empagliflozin explicitly warn that "ketoacidosis can happen even if your blood sugar is less than 250 mg/dL" and emphasize that patients who are sick, cannot eat or drink as usual, skip meals, follow ketogenic diets, take less insulin, drink too much alcohol, or undergo surgery are at increased risk. 4, 5
Insulin-Related Causes
Recent insulin use prior to presentation is a classic cause of euglycemic DKA, as insulin administration lowers glucose while ketoacidosis persists. 2, 9 This creates the paradoxical situation where patients have received insulin (lowering glucose) but insufficient amounts to suppress ketogenesis.
Insulin omission due to psychological problems and financial constraints is recognized as the most common cause of DKA in patients with established diabetes, and can present with euglycemia if any insulin was administered. 3, 1
Pregnancy
Up to 2% of pregnancies with pregestational diabetes are complicated by DKA, with pregnant individuals frequently presenting with euglycemic DKA. 1 The physiological changes of pregnancy - including accelerated starvation, increased insulin resistance, and altered renal glucose handling - predispose to ketoacidosis at lower glucose thresholds. 2, 9
Reduced Carbohydrate Availability
Several conditions create a relative carbohydrate deficit state:
- Decreased caloric intake - starvation, gastroparesis, persistent vomiting 10, 2, 9
- Heavy alcohol consumption - alcohol inhibits gluconeogenesis while promoting ketogenesis 2, 9
- Chronic liver disease and cirrhosis - impaired glycogen storage and gluconeogenesis 2, 9
- Glycogen storage disorders 2
Acute Illness and Stress
Infections account for approximately 50% of DKA cases overall and can precipitate euglycemic DKA when combined with other factors. 1 Other acute stressors include:
- Myocardial infarction 3
- Stroke and trauma 5
- Sepsis 9
- Pancreatitis - particularly relevant as it suggests insulin deficiency 5, 9
Medication-Induced
Beyond SGLT2 inhibitors, other medications can precipitate DKA:
- Corticosteroids - increase insulin resistance and counter-regulatory hormones 3
- Atypical antipsychotics - associated with metabolic derangements 3
High-Risk Populations
Patients with latent autoimmune diabetes in adults (LADA) misdiagnosed as type 2 diabetes face substantially elevated risk of euglycemic DKA, particularly when prescribed SGLT2 inhibitors. 6 These patients have progressive beta-cell failure similar to type 1 diabetes but are often initially treated as type 2 diabetes.
Patients with pancreatic insufficiency from any cause (history of pancreatitis, pancreatic surgery) have increased risk due to absolute or relative insulin deficiency. 6, 5
Critical Clinical Pitfall
The normal or near-normal glucose level in euglycemic DKA frequently leads to delayed diagnosis and treatment, as clinicians may not suspect ketoacidosis when glucose is below the traditional 250 mg/dL threshold. 1, 7, 10 This delay can have serious metabolic consequences and increase morbidity. 2, 9
Always check ketones (urine or blood) in patients on SGLT2 inhibitors who present with nausea, vomiting, abdominal pain, or malaise, regardless of blood glucose level. 1, 4, 5