Euglycemic ketoacidosis following a single dose of empagliflozin

ABSTRACT Sodium-glucose co-transporter 2 (SGLT-2) inhibitors have recently joined the therapeutic armamentarium for the treatment of diabetes mellitus. SGLT-2 inhibitors, as monotherapy or in combination with other medications, have a favorable effect on hemoglobin A1C concentrations. However, a growing number of reports have described ketoacidosis as a complication following prolonged SGLT-2 inhibitor therapy. We report a case of SGLT-2 inhibitor associated ketoacidosis in a patient following a single first dose of empagliflozin.


Introduction
The World Health Organization reports that the prevalence of diabetes mellitus (DM) for adults over 18 years of age has increased from 4.7% to 8.5% over the past three decades [1] and is continuously trending upwards. Approximately 9.3% of the population of the U.S.A. has DM, and 37% are pre-diabetic [2], with a projected prevalence of DM between 1 in 3-5 adults by the year 2050 [3]. DM not only affects the major organs of the body at a cellular level but also affects the macro and microvasculature of vital organs throughout the body, potentially leading to vascular, cerebral, retinal, cardiovascular, and renal complications [2]. While a number of treatment options have been proposed over the decades for the treatment of DM, diet and consistent physical exercise remain the first line strategy [1,2]. Several treatment modalities have emerged in recent years [4][5][6]. The U.S. Food and Drug Administration (FDA) approved empagliflozin in August 2014 as an adjunct to diet and physical exercise to assist in attaining optimal glycemic control [7].
Although not recommended for patients with type 1 DM, sodium-glucose co-transporter 2 (SGLT-2) inhibitors appear to be useful in the treatment of type 2 DM [8]. SGLT-2 inhibitor treatment may occur either as monotherapy or in addition to conventional treatment with insulin, sulfonylureas, or metformin [9][10][11]. With the exception of mild side effects of nausea, vomiting, abdominal pain, and lethargy, SGLT-2 inhibitors have thus far been generally well tolerated by diabetic patients.
Between March 2013 and May 2015, the FDA Adverse Event Reporting System (AERS) received 73 reports of acidosis associated with SGLT-2 inhibitor use. Nearly all of these cases required emergency department visits for the treatment of ketoacidosis, and all reported cases of ketoacidosis occurred in patients on stable, regular doses of SGLT-2 inhibitors usually over a period of weeks to months [8].
We report a case of ketoacidosis following a single first dose of empagliflozin.

Case report
A 25-year-old male presented to the emergency department with complaints of diffuse body cramping, lightheadedness, and sweating for four hours. He had been feeling tired and generally unwell for the previous two weeks. Eight weeks before presentation, he started metformin 500 mg twice daily for newly diagnosed DM with a dose increase to 1000 mg twice daily four weeks before presentation. His primary care provider added empagliflozin (10 mg daily) as a combination therapy with metformin to help achieve glycemic control. The patient indicated that he had only begun the empagliflozin the day prior to his ED presentation and had only used one dose of the drug prior to presentation. He denied any current alcohol or illicit drug use.
On presentation, he was awake, alert, and oriented to person, time, place, and situation. He appeared to be weak and diaphoretic. The initial vital signs were temperature 97.4 degree F, blood pressure 127/64 mm Hg, pulse 88 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 100% on room air. The physical examination was otherwise unremarkable, and an initial electrocardiogram was normal.
Treatment commenced with intravenous normal saline followed by insulin infusion at 0.5 units/hour and 5% dextrose in normal saline (D5NS) infusion. The anion gap declined from 30 mEq/L to 15 mEq/L over a period of 24 hours. The intravenous insulin was converted to the subcutaneous administration of long acting insulin. The patient continued to improve and was discharged from the hospital after 76 hours on both short-and long-acting insulin and with follow up by the Endocrinology service. The patient received strict instructions to avoid empagliflozin or other SGLT-2 inhibitor class drugs.

Discussion
Empagliflozin is a member of the SGLT-2 inhibitor class of medications that was approved for the treatment of DM on 1 August 2014 [7]. The mechanism of action for SGLT-2 inhibitors blocks SGLT-2 transporter at proximal renal tubules [12][13][14]. This results in decreased absorption of glucose and sodium with resultant glucosuria. This drug appears to be generally safe and well tolerated [10][11][12] with associated reductions in HbA1C in diabetic patients [10]. Further benefits reported by the FDA include reduction of cardiovascular mortality in adults with DM II [15]. However, reports of ketoacidosis soon followed FDA approval [8,16,17]. Most cases have involved euglycemic ketoacidosis in patients taking canagliflozin 300 mg [17,18] and empagliflozin 25 mg [19].
The pathophysiology of euglycemic ketoacidosis associated with SGLT-2 inhibitor appears to involve decreased insulin production and increased glucagon production. These in turn result in lipolysis with increased fatty acid production and the subsequent oxidation of free fatty acids with ketone body formation [17][18][19][20]. The mainstay of treatment includes intravenous fluid and insulin administration to increase uptake of glucose by peripheral tissues as well as to decrease gluconeogenesis and ketogenesis, thus closing the anion gap.
The risk of ketoacidosis with empagliflozin appears to be dose-dependent [16]. In this case, we report the presentation of euglycemic ketoacidosis after a single 10 mg dose of empagliflozin.
We used the Naranjo score to determine the probability that empagliflozin caused ketoacidosis in this case [21]. The calculated Naranjo score is 7 based upon previous conclusive reports on ketoacidosis secondary to SGLT-2 inhibitors (+1); the adverse event appeared after a single dose of empagliflozin (+2) and improved after the drug was discontinued (+1); no other alternate causes of the event were identified (+2) and laboratory investigations were consistent with euglycemic ketoacidosis (+1). According to the Naranjo adverse drug reaction probability scale, a score between 5 and 8 indicates that the untoward reaction was "probably due to the drug" [21]. We concluded that metformin associated lactic acidosis (MALA) was unlikely since the patient had minimally elevated lactate compared to the typically high lactate concentration in MALA [22]. The physiologic effects of empagliflozin on insulin, glucagon, and free fatty acid production after acute use of empagliflozin [19] likely explains the sudden onset of ketoacidosis after a single dose.

Conclusion
We report a case of ketoacidosis following a single dose of empagliflozin (10 mg). Clinicians prescribing empagliflozin must maintain a high level of suspicion for ketoacidosis and educate patients on the need to seek emergency medical attention for symptoms consistent with that entity. Future research should clarify the risk factors that may predispose diabetic patients to empagliflozin-associated ketoacidosis.