What caused the polyuria in a 60‑year‑old woman with diarrhea who was on dapagliflozin (SGLT‑2 inhibitor), stopped the drug on ICU admission, was hydrated, and developed euglycaemic ketoacidosis?

Polyuria in This Clinical Context: Residual SGLT2 Inhibitor Effect and Osmotic Diuresis from Ketoacidosis

The polyuria in this patient was most likely caused by persistent glucosuria from residual dapagliflozin effect combined with osmotic diuresis from euglycemic ketoacidosis, despite stopping the medication on ICU admission.

Mechanism of SGLT2 Inhibitor-Induced Polyuria

The primary mechanism involves dapagliflozin's pharmacologic action on renal glucose handling:

• SGLT2 inhibitors block glucose resorption in the proximal renal tubules, causing obligatory glucosuria and osmotic diuresis 1.
• This osmotic effect increases urinary glucose elimination and fluid loss, though the Renin-Angiotensin-Aldosterone System is rarely activated due to sympathetic inhibition 1.
• The glucosuria persists well beyond the expected 12.9-hour half-life of dapagliflozin, with documented cases showing continued urinary glucose excretion for 8-11 days after drug cessation 2, 3.

Prolonged Drug Effect Despite Discontinuation

Critical clinical pitfall: Stopping dapagliflozin does not immediately resolve its renal effects.

• Persistent glucosuria and ketonuria have been documented up to 11 days after the last dose of dapagliflozin 2.
• One case report documented recurrent euglycemic ketoacidosis occurring 8 days after dapagliflozin cessation, with persistent urinary glucose excretion despite near-normal serum glucose levels 2.
• Another case showed ketonemia and glucosuria persisting beyond expected drug clearance, requiring prolonged insulin therapy 3.
• Even with discontinuation 5 days preoperatively (as recommended), patients remain at risk for complications including persistent osmotic diuresis 4.

Contribution of Euglycemic Ketoacidosis

The euglycemic ketoacidosis itself compounds the polyuria through additional mechanisms:

• Ketone bodies (β-hydroxybutyrate and acetoacetate) act as osmotic diuretics when filtered by the kidneys 5.
• The FDA label explicitly warns that dapagliflozin can cause life-threatening ketoacidosis that may occur even with blood glucose less than 250 mg/dL 5.
• Risk factors present in this case include: acute illness (diarrhea), volume depletion, and reduced oral intake—all precipitating factors for SGLT2 inhibitor-associated ketoacidosis 5, 6.

Hydration Paradox

The aggressive IV hydration administered in the ICU likely worsened the polyuria temporarily:

• With persistent SGLT2 inhibition, increased fluid administration provides more substrate for ongoing osmotic diuresis 1.
• The kidneys continue to excrete glucose (and associated water) despite volume repletion efforts 2, 3.
• This creates a clinical scenario where hydration is necessary but simultaneously perpetuates urinary losses 5.

Clinical Timeline and Implications

The temporal relationship is critical for understanding this case:

• Dapagliflozin was stopped on ICU admission, but its renal effects persisted 2, 3.
• The patient developed euglycemic ketoacidosis (likely precipitated by diarrhea and volume depletion) 5.
• Hydration was initiated, but polyuria continued due to: (1) residual drug effect causing glucosuria, (2) ketone-induced osmotic diuresis, and (3) the volume load itself 2, 3.

Key Distinguishing Features

This is NOT simple post-rehydration diuresis:

• The presence of euglycemic ketoacidosis indicates ongoing metabolic derangement 5.
• Persistent glucosuria despite euglycemia is pathognomonic for residual SGLT2 inhibitor effect 2, 3, 7.
• Normal physiologic response to hydration would not produce the degree of polyuria seen with combined SGLT2 inhibition and ketoacidosis 1.

Management Implications

Recognition of prolonged SGLT2 inhibitor effects is essential:

• Patients require monitoring for persistent glucosuria and ketonuria for up to 2 weeks after dapagliflozin cessation 2, 3.
• Insulin therapy may be necessary even with normal glucose levels to suppress ketogenesis 3, 4.
• The ADA/KDIGO consensus recommends continuing to monitor for complications even after drug discontinuation 8.
• Recurrent ketoacidosis can occur days after initial resolution if insulin is not maintained 2, 3.