Why does diabetic ketoacidosis (DKA) occur in some patients taking dapagliflozin (Forxiga) and not others?

Why DKA Occurs in Some Patients Taking Dapagliflozin and Not Others

Diabetic ketoacidosis with dapagliflozin occurs only in patients who have specific precipitating factors that trigger insulin deficiency or increased counterregulatory hormones, not from the drug alone. 1

The Fundamental Mechanism

Dapagliflozin does not directly cause DKA—it creates a metabolic environment that unmasks or amplifies underlying insulin deficiency when specific triggers are present. 1, 2

• DKA requires two conditions: reduced effective insulin action AND elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone) that drive lipolysis and ketone production 1
• Dapagliflozin alone cannot cause this—it merely lowers glucose by blocking renal reabsorption, which can mask the hyperglycemia that would normally alert patients and clinicians to worsening metabolic decompensation 2, 3

Specific Risk Factors That Determine Who Develops DKA

High-Risk Patient Populations

• Type 1 diabetes patients have markedly increased risk because they lack endogenous insulin production entirely—any reduction in exogenous insulin immediately triggers ketogenesis 2
• Type 2 diabetes with pancreatic disorders (history of pancreatitis or pancreatic surgery) have impaired insulin reserve and are at substantially elevated risk 2
• Patients with low C-peptide levels indicating minimal residual beta-cell function are vulnerable because they cannot compensate when insulin is reduced 1

Critical Precipitating Conditions

The following triggers explain why only certain patients develop DKA while taking dapagliflozin: 2

• Under-insulinization: Insulin dose reduction or missed insulin doses—this is the most common precipitating factor 2
• Acute febrile illness or infection: Increases counterregulatory hormones and insulin resistance 1, 2
• Reduced caloric intake or fasting: Decreases insulin secretion while maintaining glucagon elevation 2, 3
• Ketogenic diet: Directly provides substrate for ketone production 2
• Surgery or prolonged fasting for procedures: Combines stress response with reduced insulin and oral intake 2, 4
• Volume depletion: From vomiting, diarrhea, or inadequate fluid intake—amplifies the osmotic diuresis from dapagliflozin 2, 3
• Alcohol abuse: Inhibits gluconeogenesis and promotes ketogenesis 1, 2

Why Euglycemic DKA Is Particularly Dangerous

• Normal or mildly elevated glucose levels (often <250 mg/dL, sometimes even <180 mg/dL) delay recognition because clinicians don't expect DKA without marked hyperglycemia 2, 3, 5
• Dapagliflozin maintains urinary glucose excretion for 3 days after discontinuation, and case reports document glucosuria and ketonuria persisting up to 2 weeks or longer 2, 6, 4
• The drug's mechanism prevents the typical hyperglycemic warning signal by continuously excreting glucose renally, even as ketoacidosis worsens 3, 6

Clinical Algorithm: Who Will Develop DKA

Patients develop DKA on dapagliflozin when they have:

1. Baseline vulnerability: Type 1 diabetes, pancreatic disease, or very low C-peptide 2
2. PLUS a precipitating trigger: Illness, fasting, surgery, missed insulin, volume depletion, or alcohol 2, 3
3. PLUS inadequate insulin replacement: Either absolute deficiency or relative deficiency during stress 1, 2

Patients who do NOT develop DKA typically have:

• Preserved beta-cell function with adequate endogenous insulin to prevent lipolysis 1
• No precipitating stressors that increase counterregulatory hormones 1
• Maintained insulin therapy during illness or stress 2
• Adequate oral intake and hydration 2, 3

Critical Safety Measures to Prevent DKA

• Withhold dapagliflozin at least 3 days before major surgery or procedures requiring prolonged fasting to prevent postoperative ketoacidosis 7, 2
• Hold dapagliflozin during acute illness, particularly with fever, vomiting, diarrhea, or reduced oral intake 7, 2
• Maintain at least low-dose basal insulin in insulin-requiring patients even when dapagliflozin is held—complete insulin cessation dramatically increases DKA risk 7, 6
• Monitor for ketones (blood or urine) in high-risk situations regardless of blood glucose levels 2
• Educate patients to recognize DKA symptoms (nausea, vomiting, abdominal pain, dyspnea, malaise) and discontinue dapagliflozin immediately if they occur 2, 3

Common Pitfall to Avoid

The most dangerous error is assuming normal glucose excludes DKA in a patient taking dapagliflozin. 3, 5 Always check ketones and arterial blood gas in symptomatic patients regardless of glucose levels, as euglycemic DKA can be fatal if diagnosis is delayed. 2, 3