Euglycemic Diabetic Ketoacidosis With Prolonged Glucosuria Associated With the Sodium-Glucose Cotransporter-2 Canagliflozin

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve glycemic control by a reversible inhibition of the sodium-glucose cotransporters in the renal proximal tubules resulting in increased urinary glucose. This unique mechanism, independent of insulin secretion and beta cell function, has made this class of medication desirable in patients with type 2 diabetes. However in May 2015, the US Food and Drug Administration issued a safety warning pertaining to the development of diabetic ketoacidosis (DKA) with the use of SGLT2 inhibitors. DKA associated with SGLT2 inhibitors frequently develops in the absence of hyperglycemia, which makes the diagnosis more challenging. Due to the reversible inhibition of SGLT2 by this class of medication, a quick recovery of glucosuria after cessation of medication is expected. In this article, we present a case of a 50-year-old woman with type 2 diabetes who developed euglycemic DKA after initiating therapy with canagliflozin. This case of DKA associated with SGLT2 inhibitor use was unique due to her hypoglycemic presentation and persistent glucosuria. SGLT2 inhibitors such as canagliflozin may predispose patients not only to diabetic ketoacidosis but also to prolonged glucosuria.

Prolonged glucosuria and relapse of diabetic ketoacidosis related to SGLT2‐inhibitor therapy

“…Two more recent studies designed to identify risk factors for developing SGLT2i‐associated DKA also reported hospital stay characteristics, though the focus was on precipitating events which lead to DKA rather than inpatient course, and duration of glucosuria was not reported. Case reports have suggested that despite half‐lives of 10‐19 hours (depending on the agent), the glucosuric effects of SGLT2i can persist up to 9 days . In our cohort of 11 patients, six had elevated urinary glucose concentrations for 3‐10 days despite cessation of the medication upon admission, and three of those had DKA relapse during their admission.…”

A Case of Euglycemic Diabetic Ketoacidosis due to Canagliflozin Complicated by Takotsubo Cardiomyopathy

“…SGLT 2 inhibition should disappear 2 to 3 days after discontinuation of canagliflozin as its half-life is dose dependent, 10.6 and 13.1 hours for 100 mg and 300 mg of canagliflozin respectively [4]. Along with favorable effects on blood pressure and body weight, Canagliflozin causes sustained reduction of HbA1C [5].…”

“…Search of the FDA Adverse Event Reporting System (FAERS) database identified 73 cases of ketoacidosis in patients with type 1 or type 2 diabetes treated with SGLT 2 inhibitors from March 2013 to May 2015 [8]. DKA associated with SGLT 2 inhibitors usually does not have elevated blood glucose level due to persistent excretion of glucose in urine [4]. Euglycemic DKA is defined by anion gap metabolic acidosis (PH <7.3 and serum bicarbonate <18 mEq/L), presence of ketones in blood or urine and blood glucose <200 mg/dl [9].…”

Protracted glycosuria after discontinuation of sodium‐glucose cotransporter 2 inhibitors: Implications for weekly dosing and extended risk of euglycemic diabetes ketoacidosis

“…However, Kelmenson et al reported one case of euglycemic DKA with prolonged glycosuria associated with the use of high‐dose canagliflozin. Unfortunately, absolute urine glucose values were never recorded, but the authors described glucosuria 9 days after discontinuation of the drug.…”