sodium - glucose cotransporter 2 ( sglt2 ) inhibitors are oral hypoglycemic agents that augment the urinary excretion of glucose , thereby regulating glycemic control and promoting weight loss ( 1 ) .
sglt2 inhibitors have an insulin - independent mechanism of action , which is being explored in patients with type 1 diabetes ( 2 ) .
the incidence of diabetic ketoacidosis in patients treated with sglt2 inhibitors is rare ( 4,5 ) .
recently , the us food and drug administration issued a drug safety communication that sglt2 inhibitors may lead to ketoacidosis with mild to moderate glucose elevation ( euglycemic diabetic ketoacidosis ) ( 6 ) .
however , only a few cases of euglycemic diabetic ketoacidosis with persistent diuresis after the discontinuation of sglt2 inhibitors have been reported .
we herein report a case of euglycemic diabetic ketoacidosis with persistent diuresis in a diabetic patient undergoing treatment with an sglt2 inhibitor , canagliflozin .
a 27-year - old woman of asian descent from north america was admitted to our hospital for the treatment of euglycemic diabetic ketoacidosis .
she had been taking oral antidiabetic drugs ( gliclazide 300 mg , metformin 3,000 mg , and sitagliptin 150 mg per day ) , but her glycemic control was poor .
three months prior to admission , she started taking canagliflozin ( 300 mg / day ) . during that time , she lost 3 kg and her urinary frequency increased .
two days before admission , she experienced dizziness , and the following day , she developed upper abdominal pain .
on the day of admission , she visited the emergency department with complaints of thirst and malaise .
she did not smoke or drink alcohol , and she followed carbohydrate restriction for weight loss . on examination ,
the patient 's blood pressure was 145/103 mmhg , her heart rate was 123 beats / min , and her temperature was 36.2. her weight , height , and body mass index were 63 kg , 150 cm , and 28 kg / m , respectively .
the other neurological and general examination results were normal . a urinalysis detected ketone bodies , while an arterial blood gas analysis showed high anion gap metabolic acidosis and a normal lactate level .
her biochemistry results revealed electrolyte disturbance and mild hyperglycemia ( 240 mg / dl ) .
in addition , her hba1c level was 9.9% , and her fasting serum c - peptide level was < 0.1 ng / ml ( reference range , 0.61 - 2.09 ng / ml ) ; this finding indicated the severe impairment of insulin secretion .
taken together , these findings were compatible with a diagnosis of type 1 diabetes mellitus and diabetic ketoacidosis without hyperglycemia .
cpr : c - peptide immunoreactivity , gad : glutamic acid decarboxylase , hba1c : glycated hemoglobin , pco2 : partial pressure of carbon dioxide , po2 : partial pressure of oxygen 
  the patient was initially administered isotonic saline and a continuous insulin infusion with the discontinuation of all oral antidiabetic agents .
an hour after the administration of saline and the insulin infusion , her glucose level decreased to < 200 mg / dl ; thus , an infusion 5% dextrose was initiated . on the following day ,
her venous blood ph level still showed acidemia , despite a normal glucose level , and her urine output was > 5,000 ml / day .
, oral food intake was initiated and the continuous insulin infusion was switched to multiple daily injections of insulin . at this point ,
however , we prohibited ad libitum water intake . on day 4 of treatment , her venous blood ph level recovered , and her urinary output peaked ( figure ) . we could not measure the urinary output after the fifth day of treatment due to the discontinuation of urinary catheterization and the patient 's menstruation . on the eighth day of treatment , she was discharged but the nocturnal urination had not resolved .
the course of osmotic diuresis in a patient with euglycemic diabetic ketoacidosis who was treated with canagliflozin . on the second day of treatment
, the patient s urine output increased to over 5,000 ml in the absence of hyperglycemia . on the third day of treatment , oral food intake
was initiated , and the patient s urine output increased to over 9,000 ml . at this point ,
cvii : continuous intravenous insulin infusion , egfr : estimated glomerular filtration rate , fpg : fasting plasma glucose , mdi : multiple daily injections of insulin , na : not available , u - glucose : urinary glucose , u - osm : urine osmolality , serum na : serum sodium , u - na : urinary sodium
second , euglycemic diabetic ketoacidosis can accompany persistent diuresis after the administration of sglt2 inhibitors is discontinued . to our knowledge , this is the first report of euglycemic diabetic ketoacidosis with persistent diuresis during treatment with an sglt2 inhibitor .
euglycemic diabetic ketoacidosis is defined as a blood glucose level of < 300 mg / dl , and a plasma bicarbonate level 10 meq / l ( 7 ) . in a previous study of patients with type 2 diabetes ,
the incidence of diabetic ketoacidosis in patients treated with canagliflozin was more than twice as high as that in patients treated with antidiabetic drugs without canagliflozin ( 8) .
only a few case reports have described the characteristics of euglycemic diabetic ketoacidosis due to the administration of sglt2 inhibitors .
the possible causative factors for euglycemic diabetic ketoacidosis due to the administration of sglt2 inhibitors include an insulin dose reduction , alcohol intake , and a low insulin secretion capability .
gastroparesis and a low - carbohydrate diet also can trigger euglycemic diabetic ketoacidosis , especially among diabetic patients who do not use insulin ( 9 - 12 ) .
the time from the first dose of an sglt2 inhibitor to the onset of euglycemic diabetic ketoacidosis has been reported to range from 2 to 13 days in diabetic patients who do not use insulin ( 9,11,12 ) . in the present case ,
there are several possible reasons for the patient 's development of euglycemic diabetic ketoacidosis , including her low adherence to treatment , the relatively acute autoimmune destruction of  cells , and her extreme carbohydrate restriction .
this patient experienced euglycemic diabetic ketoacidosis with persistent diuresis via glycosuria , even after the discontinuation of the sglt2 inhibitor .
the possible mechanisms of this pathology are as follows : ( 1 ) her estimated glomerular filtration rate might have been increasing in association with early type 1 diabetes , thereby promoting glycosuria ; ( 2 ) exogenous insulin may have augmented the effect of sglt2 inhibition on glycosuria ( 13 ) ; and ( 3 ) canagliflozin delays the reversibility of sglt2 inhibition in comparison to its short half - life ( 10 - 13 hours ) . in a previous case ,
burr et al . reported that their patient had persistent glycosuria in the absence of hyperglycemia for 11 days after the discontinuation of an sglt2 inhibitor ( 11 ) .
the correction of hypovolemia is important for the treatment of diabetic ketoacidosis ( 3 ) . in the present case ,
the patient received 3,650 ml of fluid in 12 hours of fluid therapy , which was reasonable from the point of view of treating diabetic ketoacidosis .
after the second day of admission , fluid therapy was administered according to her urine volume .
thus , the volume of fluid that the patient received was appropriate for her clinical course . however , we did not rule out central diabetes insipidus .
previous studies have reported cases of central diabetes insipidus during diabetic ketoacidosis ( 14,15 ) . in our case ,
thus , it remains unclear whether canagliflozin induced the patient 's osmotic diuresis or masked central diabetes insipidus .
the insulin - independent actions of sglt2 inhibitors are associated with short - term tolerability and the enhancement of urinary glucose excretion in patients with type 1 diabetes ( 2 ) . on the other hand
, off - label use of sglt2 inhibitors in patients with type 1 diabetes sometimes leads to euglycemic diabetic ketoacidosis ( 6,9 ) .
in addition , sglt2 inhibitor - treated type 2 diabetes patients who develop euglycemic diabetic ketoacidosis are often misdiagnosed as having autoimmune diabetes ( 8) . the possible pathophysiologic characteristics of euglycemic diabetic ketoacidosis due to sglt2 inhibitors are as follows : ( 1 ) the urinary glucose excretion of patients with euglycemic diabetic ketoacidosis due to the administration of sglt2 inhibitors is more prominent than that in patients with diabetic ketoacidosis ( 13 ) ; ( 2 ) sglt2 inhibitors inhibit the transportation of glucose into  cells , thereby enhancing the release of glucagon , resulting in ketogenesis ; and ( 3 ) sglt2 inhibitors may augment the renal tubular reabsorption of ketone bodies ( 1 ) . in the present case ,
the patient 's intake of canagliflozin , the restriction of carbohydrates , and low insulin secretion capability led to euglycemic diabetic ketoacidosis .
clinicians should therefore be cautious when prescribing sglt2 inhibitors to diabetic patients who restrict their intake of carbohydrates or who display insufficient insulin secretion . in conclusion , the diuresis of the present patient with euglycemic diabetic ketoacidosis persisted , even after the administration of the sglt2 inhibitor was discontinued .
the findings of this case emphasize that euglycemic diabetic ketoacidosis should be considered in sglt2 inhibitor - treated patients who develop nausea or fatigue .
furthermore , adequate hydration may enhance persistent diuresis via glycosuria in patients with euglycemic diabetic ketoacidosis who are treated with sglt2 inhibitors .
 diabetic ketoacidosis is characterized by hyperglycemia , anion - gap acidosis , and increased plasma ketones . after the resolution of hyperglycemia , 
 persistent diuresis is rare . 
 we herein report the case of a 27-year - old asian woman with type 2 diabetes who was treated with a sodium - glucose cotransporter 2 ( sglt2 ) inhibitor ( canagliflozin ) who developed euglycemic diabetic ketoacidosis and persistent diuresis in the absence of hyperglycemia . 
 physicians should consider euglycemic diabetic ketoacidosis in the differential diagnosis of patients treated with sglt2 inhibitors . 