Euglycemic Ketoacidosis in Two Patients Without Diabetes After Introduction of Sodium–Glucose Cotransporter 2 Inhibitor for Heart Failure With Reduced Ejection Fraction

Abstract

OBJECTIVE Ketoacidosis induced by sodium–glucose cotransporter 2 inhibitor (SGLT2i) treatment has been consistently observed in clinical practice in patients with type 2 diabetes despite minimal indication from the landmark cardiovascular outcome trials. It has been postulated that individuals without diabetes will not develop this complication due to an adequate insulin secretory capacity, which will protect against significant ketone formation. Cardiovascular outcome trials examining SGLT2i use in individuals with heart failure but not diabetes have not reported ketoacidosis. RESEARCH DESIGN AND METHODS We describe the first two case reports of severe nondiabetic ketoacidosis after initiation of an SGLT2i for the treatment of heart failure with reduced ejection fraction, and we describe the management strategies employed and implication for the pathophysiology of SGLT2i-associated ketoacidosis. RESULTS Each individual presented with ketoacidosis triggered by reduced oral nutrition intake. For both individuals, ketoacidosis resolved with intravenous glucose administration, encouragement of consumption of oral glucose-containing fluid, and minimal insulin administration. CONCLUSIONS These two cases demonstrate that SGLT2i-associated ketoacidosis is possible in individuals without diabetes.

Increasing patient awareness of ketoacidosis with gliflozins

“…However, case reports now suggest otherwise, so there is no room for complacency. 5,6 With good pre-procedural assessment and planning, those undergoing elective surgery and endoscopy will now…”

“…Given the historical association between ketoacidosis and diabetes, and as the cardiovascular and renal benefits of SGLT2 inhibitors appear to be independent of their glucose‐lowering effects, it was hoped that ketoacidosis may not occur when the drugs are given to those with heart failure or chronic kidney disease who did not also have diabetes. However, case reports now suggest otherwise, so there is no room for complacency 5,6 …”

SGLT2 Inhibitors – The New Standard of Care for Cardiovascular, Renal and Metabolic Protection in Type 2 Diabetes: A Narrative Review

“…during acute illness), major surgery and alcohol abuse [ 84 , 85 ]. Two recently reported cases of severe ketoacidosis triggered by reduced oral nutrition intake in people taking SGLT2i therapy for HF show that ketoacidosis can occur in people without T2DM and risk factors, such as dietary intake, should be considered for all indications [ 86 ]. As highlighted in the ADA/EASD guidelines, incidence of DKA is low in general and SGLT2is are associated with a small incremental increase in absolute risk [ 9 ].…”

Comment on Umapathysivam et al. Euglycemic Ketoacidosis in Two Patients Without Diabetes After Introduction of Sodium–Glucose Cotransporter 2 Inhibitor for Heart Failure With Reduced Ejection Fraction. Diabetes Care 2024;47:140–143

“…We have read the elegant case report in Diabetes Care by Umapathysivam et al. ( 1 ) with great interest. They have treated two patients for euglycemic ketoacidosis, each of whom was taking a sodium glucose cotransporter 2 inhibitor (SGLT2i) but did not have diabetes.…”

“…Despite the clear-cut direct effect of glucocorticoids on insulin secretion, the possibility that this is one of the causative factors for ketoacidosis is not discussed at all by Umapathysivam et al. ( 1 ). It is strongly recommended that clinicians comprehensively review the known pathophysiology when encountered a seemingly rare clinical phenomenon.…”