What causes euglycemic ketoacidosis?

Causes of Euglycemic Diabetic Ketoacidosis

Euglycemic diabetic ketoacidosis (euglycemic DKA) is caused by insulin deficiency in the presence of factors that maintain relatively normal blood glucose levels (<200-250 mg/dL), most commonly SGLT2 inhibitor use, reduced food intake, pregnancy, alcohol consumption, and liver failure. 1

Primary Pathophysiologic Mechanism

Euglycemic DKA requires absolute or relative insulin deficiency combined with conditions that prevent hyperglycemia from developing. 2 The fundamental mechanism involves:

• Insulin deficiency leading to unrestrained lipolysis and hepatic ketone production (β-hydroxybutyrate and acetoacetate), resulting in metabolic acidosis 1
• Concurrent factors that maintain euglycemia despite ongoing ketogenesis 1

Major Causative Factors

SGLT2 Inhibitors (Most Common in Modern Practice)

SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin, sotagliflozin) are now the leading cause of euglycemic DKA, particularly as their use expands beyond diabetes to heart failure and chronic kidney disease. 1

The mechanism involves multiple pathways: 1

• Reduction in insulin doses due to improved glycemic control
• Increased glucagon levels leading to enhanced lipolysis and ketone production
• Decreased renal clearance of ketones
• Increased susceptibility during periods of reduced oral intake or acute illness

Risk is present in both diabetic and non-diabetic patients taking SGLT2 inhibitors, with non-diabetic patients on these medications for heart failure being particularly vulnerable when they experience decreased oral intake, fasting, or acute illness. 3

Reduced Caloric Intake and Starvation States

Prolonged fasting, acute illness with poor oral intake, or ketogenic/very-low-carbohydrate diets are major precipitants. 1, 4

• Ketogenic diets create severe carbohydrate restriction that promotes ketogenesis while limiting glucose availability 4
• Perioperative fasting states, particularly when combined with SGLT2 inhibitor use, create high-risk scenarios 3
• Acute illness with nausea, vomiting, or inability to eat triggers starvation ketosis 5

Pregnancy

Pregnancy, particularly in patients with type 1 diabetes, carries significant risk for euglycemic DKA (glucose <200 mg/dL). 1 Up to 2% of pregnancies with pregestational diabetes are complicated by DKA, and pregnant individuals may present with euglycemia due to:

• Lower renal threshold for glucose during pregnancy
• Accelerated starvation physiology
• Mixed acid-base disturbances, especially with hyperemesis 1

Alcohol Use

Heavy alcohol consumption or alcohol abuse promotes euglycemic DKA through: 1, 6

• Impaired gluconeogenesis leading to relative hypoglycemia
• Enhanced ketogenesis from alcohol metabolism
• Often combined with reduced food intake

Chronic Liver Disease

Liver failure or chronic liver disease impairs hepatic glucose production while ketogenesis continues, maintaining lower glucose levels despite ongoing ketoacidosis. 1, 6

Insulin Pump Failure or Insulin Omission

Mechanical failure of insulin pumps or intentional insulin omission in patients with established diabetes creates absolute insulin deficiency. 5 When combined with recent insulin administration or residual insulin effect, glucose levels may remain relatively normal while ketoacidosis develops.

Pancreatic Disorders

Conditions suggesting insulin deficiency including: 7

• Type 1 diabetes or latent autoimmune diabetes in adults (LADA) 8
• History of pancreatitis or pancreatic surgery
• Any cause of pancreatic insulin deficiency

Clinical Context and Risk Factors

The American Diabetes Association identifies key risk factors that predispose to euglycemic DKA: 1

• Absolute insulin deficiency (type 1 diabetes, LADA)
• SGLT2 inhibitor therapy
• Acute febrile illness
• Reduced caloric intake due to illness or surgery
• Dehydration
• Excessive alcohol intake
• Presence of autoimmunity in patients thought to have type 2 diabetes 8

Critical Clinical Pitfall

The most dangerous aspect of euglycemic DKA is delayed recognition and treatment because normal or near-normal glucose levels (<200-250 mg/dL) mislead clinicians into overlooking the diagnosis. 7, 5 Blood glucose levels as low as 75-86 mg/dL have been reported in SGLT2 inhibitor-associated cases. 8

Check blood or urine ketones in any ill diabetic patient regardless of blood glucose level, particularly those on SGLT2 inhibitors, pregnant patients, or those with reduced oral intake. 1, 5