What causes diabetic ketoacidosis (DKA) in hospitalized patients on Farxiga (dapagliflozin)?

Causes of DKA in Hospitalized Patients on Farxiga (Dapagliflozin)

Farxiga (dapagliflozin) causes DKA in hospitalized patients through a unique mechanism that promotes ketone production even with normal or near-normal blood glucose levels (euglycemic DKA), particularly when combined with precipitating factors such as acute illness, reduced oral intake, surgery, or volume depletion.

Mechanism of SGLT2 Inhibitor-Induced DKA

• Dapagliflozin inhibits renal glucose reabsorption, causing persistent glucosuria that lowers blood glucose while simultaneously triggering a metabolic state that favors ketone production 1
• This creates a paradoxical situation where patients develop ketoacidosis despite blood glucose levels often below 250 mg/dL—the typical threshold for DKA recognition 1, 2
• The medication's effects on glucose and ketone metabolism can persist far beyond its reported 12.9-hour half-life, with documented cases showing persistent ketonemia and glucosuria 8-11 days after the last dose 3, 4

Primary Precipitating Factors in Hospitalized Patients

Acute Illness and Infection

• Infection is the most common precipitating factor for DKA in general, and this risk is amplified in patients taking SGLT2 inhibitors 5, 6
• Any acute illness (pneumonia, urinary tract infection, sepsis) can trigger the cascade toward ketoacidosis in patients on dapagliflozin 2, 7

Reduced Oral Intake and Fasting States

• Patients who cannot eat or drink as usual, skip meals, or have reduced carbohydrate intake are at particularly high risk 1, 8
• Volume depletion from vomiting, diarrhea, or inadequate fluid intake significantly increases DKA risk 1, 2
• Ketogenic diets or diets high in fat and low in carbohydrates further elevate risk 1

Surgical Procedures

• Surgery is a critical risk factor, yet dapagliflozin is often not discontinued appropriately before procedures 3
• The American Diabetes Association recommends discontinuing SGLT2 inhibitors 3-4 days before any planned surgery to prevent euglycemic DKA 9, 6
• Post-operative states with reduced oral intake and physiologic stress create a perfect storm for DKA development 3

Insulin Deficiency or Reduction

• Taking less than the usual amount of insulin, missing insulin doses, or having underlying insulin deficiency (including unrecognized type 1 diabetes or pancreatic insufficiency) increases risk 1, 7
• Patients with type 2 diabetes who have significant beta-cell dysfunction are at higher risk 1

Volume Depletion States

• Dehydration from any cause (diuretics, poor oral intake, gastrointestinal losses) is a major precipitating factor 1, 2
• Patients taking blood pressure medications, especially diuretics, or those on low-salt diets are at increased risk 1
• Elderly patients (≥65 years) are particularly vulnerable to volume depletion 1

High-Risk Clinical Scenarios in Hospitalized Patients

• Critical illness requiring hospitalization should prompt immediate discontinuation of dapagliflozin 2
• Patients with acute pancreatitis (especially from hypertriglyceridemia) are at elevated risk 8
• Those with acute kidney injury or baseline renal impairment face compounded risk 3
• Alcohol consumption in hospitalized patients can precipitate ketoacidosis 1

Key Clinical Pitfalls to Avoid

Delayed Recognition Due to Normal Glucose

• The most dangerous pitfall is failing to suspect DKA because blood glucose is below 250 mg/dL 1, 2
• Clinicians must maintain high suspicion for ketoacidosis in any patient on dapagliflozin who presents with nausea, vomiting, abdominal pain, or altered mental status, regardless of glucose level 1, 2
• Ketone testing (urine or blood) should be performed liberally in symptomatic patients on SGLT2 inhibitors 1, 2

Failure to Discontinue Medication Appropriately

• Dapagliflozin should be stopped immediately upon hospital admission for acute illness, not continued during hospitalization 2, 7
• The medication must be discontinued 3-4 days (some experts recommend up to 1 week) before elective procedures 9, 6, 4
• Effects persist much longer than the drug's half-life would predict, with cases showing metabolic effects 8-11 days after cessation 3, 4

Inadequate Treatment Duration

• Persistent ketonemia can occur even after initial DKA resolution, requiring prolonged insulin therapy 3, 4
• Basal insulin may be necessary to prevent recurrent ketoacidosis even after the acute episode resolves 4
• Premature discontinuation of insulin therapy before complete ketone clearance can lead to DKA relapse 3, 4

Monitoring and Prevention Strategies

• Check ketones (blood beta-hydroxybutyrate preferred) in any hospitalized patient on dapagliflozin who develops symptoms, even with normal glucose 6, 1
• Discontinue dapagliflozin immediately upon hospital admission for acute illness, surgery, or when oral intake is compromised 2, 7
• Initiate basal insulin if ketones are positive, even if blood glucose is normal 4
• Monitor for persistent glucosuria and ketonuria, which indicate ongoing drug effect 3, 4
• Educate patients before discharge about stopping the medication during illness and seeking immediate medical attention for symptoms of ketoacidosis 2, 7