Canagliflozin is the Most Likely Cause
The patient's presentation is classic for SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis (DKA), directly caused by canagliflozin. The combination of severe metabolic acidosis (pH 7.18), high anion gap (23), significant ketonuria (3+), with only modest hyperglycemia (144 mg/dL) in a patient recently started on canagliflozin is pathognomonic for this condition 1.
Why Canagliflozin is the Culprit
The clinical picture perfectly matches SGLT2 inhibitor-associated DKA:
- Euglycemic presentation: Blood glucose of 144 mg/dL is far below the typical DKA threshold of >250 mg/dL, which is characteristic of SGLT2 inhibitor-associated ketoacidosis 2, 3
- Recent medication initiation: Started only 6 weeks prior, which is a high-risk period 4, 5
- Critical precipitating factor present: Her insulin dose was drastically reduced from 15 units to 5 units (a 67% reduction) just last week—far exceeding the dangerous >20% reduction threshold that precipitates DKA 4
- FDA black box warning: The canagliflozin label explicitly warns that "precipitating conditions for diabetic ketoacidosis include under-insulinization due to insulin dose reduction" 2
Mechanism of SGLT2 Inhibitor-Associated DKA
Canagliflozin creates a perfect storm for ketoacidosis through multiple pathways 1, 4:
- Promotes glucosuria independent of insulin, allowing ketoacidosis to develop without marked hyperglycemia 2, 3
- Increases glucagon secretion, driving lipolysis and ketone production 1, 4
- Causes volume depletion (up to 10% plasma volume loss), exacerbating metabolic derangement 5
- Decreases renal clearance of ketones 1
- When combined with insulin reduction, beta cell reserve becomes insufficient to suppress ketogenesis 4, 6
Why Other Options Are Unlikely
Metformin: Would cause lactic acidosis, not ketoacidosis. The patient has 3+ ketones in urine, not elevated lactate 1. Metformin-associated lactic acidosis typically occurs with severe illness or acute kidney injury, neither of which is the primary issue here 1.
Medication nonadherence: This would cause hyperglycemic DKA with glucose typically >250-300 mg/dL 1. Her glucose is only 144 mg/dL, and she's on a stable outpatient regimen 1.
Renal tubular acidosis: Would present with non-anion gap (hyperchloremic) acidosis 1. This patient has a high anion gap of 23, indicating ketoacidosis, not RTA 1.
Critical Clinical Pitfalls
The modest hyperglycemia can mislead clinicians into missing the diagnosis 1, 4, 2:
- Traditional DKA teaching emphasizes glucose >250 mg/dL, but SGLT2 inhibitors allow DKA at much lower levels 2, 3
- The deep breathing pattern (Kussmaul respirations) with severe acidosis (pH 7.18) should immediately trigger ketone assessment regardless of glucose level 2
- Symptoms of nausea, malaise, and shortness of breath are classic for SGLT2 inhibitor-associated DKA 1, 2
The recent insulin dose reduction was a critical error 4:
- Reducing insulin by >20% when initiating SGLT2 inhibitors dramatically increases DKA risk 4
- The 67% reduction (from 15 to 5 units) essentially removed the patient's protective insulin coverage 4
- This created relative insulin deficiency despite the patient having type 2 diabetes 4, 6
Management Implications
Prolonged treatment course should be anticipated 6, 7, 8:
- Glucosuria persists for 3 days after discontinuing canagliflozin, but cases lasting >6 days to 2 weeks are reported 2, 6
- Ketonaemia can persist for up to 12 days despite standard DKA therapy 6
- Individualized insulin regimens may be needed to prevent relapse into ketoacidosis while avoiding hypoglycemia 6
Standard DKA protocol should be initiated immediately 1: