Is Dapagliflozin (Forxiga) safe to prescribe to a patient with ketonuria?

Dapagliflozin Should Not Be Prescribed to Patients with Ketonuria

Dapagliflozin should not be prescribed to patients with existing ketonuria due to the significantly increased risk of euglycemic diabetic ketoacidosis (euDKA), which can be life-threatening. 1, 2

Understanding the Risk of Ketoacidosis with Dapagliflozin

• Dapagliflozin and other SGLT2 inhibitors can cause ketoacidosis, which may present with normal or only slightly elevated blood glucose levels (euglycemic DKA) 2
• Ketonuria is a warning sign that a patient is already producing excess ketones, making them particularly vulnerable to developing full ketoacidosis if started on an SGLT2 inhibitor 1
• The FDA drug label explicitly warns that precipitating conditions for ketoacidosis include "under-insulinization, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse" 2
• Existing ketonuria indicates that the patient already has one of these risk factors present 1

Mechanism of SGLT2 Inhibitor-Associated Ketoacidosis

• SGLT2 inhibitors like dapagliflozin cause volume depletion and increase stress hormones, which can trigger ketone production 1
• When combined with other factors that increase ketone production (which are already present in a patient with ketonuria), the risk of developing euglycemic DKA increases substantially 1, 2
• Ketoacidosis associated with SGLT2 inhibitors can persist much longer than expected based on the drug's half-life, with cases reporting persistent ketonuria for up to 11 days after discontinuation 3, 4

Evidence of Prolonged Risk

• Case reports document euglycemic DKA occurring even 8 days after the last dose of dapagliflozin, with persistent glucosuria and ketonuria for 11 days after discontinuation 3
• Another case report showed that ketonemia and glucosuria persisted well beyond the expected effect of dapagliflozin (reported half-life of 12.9 hours), requiring insulin drip treatment for several days 4
• The European spontaneous reporting system has documented 2,406 cases of ketoacidosis events with dapagliflozin, with diabetic ketoacidosis (55.39%), ketoacidosis (18.67%), and euglycemic diabetic ketoacidosis (11.61%) being the most common 5

Proper Management Approach

• For patients with existing ketonuria, the underlying cause should be addressed first before considering an SGLT2 inhibitor 1
• Alternative glucose-lowering agents that don't increase ketone production should be used in these patients 1
• If the internist prescribed dapagliflozin to a patient with ketonuria, this was likely an error that could put the patient at significant risk 2, 3
• The American Diabetes Association and KDIGO consensus emphasizes the importance of monitoring for ketosis in patients taking SGLT2 inhibitors, suggesting that existing ketosis is a contraindication 6, 1

Recommendations for Safe Use of SGLT2 Inhibitors

• SGLT2 inhibitors should be withheld during illness, prolonged fasting, or surgery 6
• Patients should be educated about the signs and symptoms of ketoacidosis (nausea, vomiting, abdominal pain, tiredness, trouble breathing) 2
• If dapagliflozin is eventually considered (after resolution of ketonuria), implement strict monitoring protocols including blood or urine ketone testing 1
• Sick day protocols should include instructions to hold SGLT2 inhibitor medication during illness 6

Conclusion

The internist's decision to prescribe dapagliflozin to a patient with ketonuria was not appropriate based on current evidence and guidelines. Ketonuria is a warning sign of increased ketone production, and adding an SGLT2 inhibitor significantly increases the risk of developing potentially life-threatening euglycemic diabetic ketoacidosis.