Case Report: Euglycemic diabetic ketoacidosis led by empagliflozin: A case report and literature review [version 1; peer review: awaiting peer review]

Introduction: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new class of medications that have been approved for the treatment of heart failure (HF) in patients with and without type-2 diabetes mellitus. It is important to be aware of the likely side effects of SGLT2i for their optimal use and enhanced patient safety. One such rare but potential side effect is the development of euglycemic diabetic ketoacidosis (EDKA). Objective: We present a case report of EDKA, in a patient who was started on empagliflozin – one of the SGLT2i – highlighting its presenting signs and symptoms, pertinent laboratory findings, differential diagnosis, treatment and outcome. To strengthen our findings and hypothesis, we conducted a literature review of other cases that used SGLT2i and found similar complications. This case report with review can help recognize the serious, potentially life-threatening complications of the new class of medication SGLT2i that has been incorporated into


Introduction
Based on the most recent Center for Disease Control and Prevention (CDC) report, approximately 6.2 million adults in the United States have chronic heart failure (HF) with a mortality rate of 13.4%, regardless of the major cardioprotective effects of the notable pharmacological HF agents (https://www.cdc.gov/heartdisease). 1 In May 2020, the US Food and Drug Administration (FDA) implemented a new approach by approving the use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the treatment of HF with reduced ejection fraction in patients with or without type-2 diabetes mellitus (T2DM) (https://www.fda.gov/news-events).
Multiple studies revealed the complex direct cardiac effects of SGLT2i, including anti-inflammatory properties by reducing the macrophage infiltration, the activity of C-reactive protein (CRP) or enhancing the messenger RNA of interleukin 10 2,3 ; glycosuria that changes the whole-body metabolism to mobilization and use of lipids, and stimulates the hepatic gluconeogenesis 4 ; involvement in the ionic cardiomyocytes metabolism by direct inhibition of Na + /H + exchange and increasing Ca 2+ reuptake and activity of sarcoplasmic endoplasmic reticulum Ca 2+ -ATPase (SERCA2a), therefore improving the left ventricular diastolic dysfunction. 2 The cardiorenal protective effects involve the enhancement of sodium concentration in the distal macula and reduction of intraglomerular hypertension and hyperfiltration, resulting in 40-50% decrease of the estimated glomerular filtration rate (eGFR) decline. 3,5 Considering the limited information currently available regarding the severe side effects of the SGLT2i, the cause of numerous cases of diabetic ketoacidosis (DKA) could not be directly related to this relatively new pharmacological group. 6 Certainly, not every patient using SGLT2i has a high risk of developing euglycemic DKA (EDKA), although the potential mechanisms comprise the increase of glycosuria and reduction of serum insulin, subsequently inducing the lipolysis and production of free fatty acids that could be converted in ketones by the hepatic β-oxidation. 6 The precipitating factors induced by decreased carbohydrates intake, considered a euglycemic status, are increased insulin/ glucagon ratio and insulinopenia that would activate the ketogenesis. 7 We have also provided data on previously published case reports/case series, management, and overall outcomes to provide a comprehensive view of potential side effects (EDKA) and their management. We searched the material for this case report and literature review through Google Scholar and PubMed.
EDKA is frequently a delayed diagnosis due to relatively lower glycaemia; however, ketoacidosis could become lifethreatening in case of prolonged fasting, bariatric surgery, gastroparesis or hepatopathy. 8 The incidence of EDKA has increased since the introduction of SGLT2i used in the treatment of chronic heart failure and we aim to provide a complex presentation of a series of cases, including our own case.

Case presentation
A 53-year-old Caucasian female with a past medical history of uncontrolled diabetes mellitus on long-term insulin, hypertension and chronic kidney disease stage-4 (CKD-4) presented in August 2021 with a chief complaint of dizziness followed by a fall. The patient reported that she was feeling dizzy after standing up for two to three days. The patient fell a day before coming to the hospital, but she didn't endorse loss of consciousness or head trauma. The patient went to the urgent care for the evaluation. She stated that urgent care did some work-up, but she didn't get any definitive answers from them, and she decided to come to the emergency room (ER) as her dizziness continued. The patient reported that she went to her nephrologist two weeks prior to coming to the ER and she was started on empagliflozin along with her chronic insulin regimen for better blood glucose control. The patient told us that her diabetes was poorly controlled.
The patient's vitals, pertinent laboratory and imaging findings on admission were as under: Vitals: Temperature 98.7 degrees Fahrenheit (oral), pulse rate 112 per minute, blood pressure 149/64 mmHg, oxygen saturation 100% on room air. Furthermore, chest x-ray showed no evidence of acute cardiopulmonary abnormalities. The patient had sinus tachycardia without any acute ST segment/T-wave changes on the electrocardiogram (ECG). The patient was diagnosed with euglycemic diabetic ketoacidosis (EDKA) in the setting of recently started empagliflozin, urinary tract infection (UTI) and acute kidney injury. The patient was also in sepsis on admission, but lactic acid was within normal limits. Alcohol and starvation related anion gap (AG) metabolic acidosis were ruled out given no history of alcohol use and no recent significant changes in diet or body weight. Blood and urine cultures were collected in the ER. Further details regarding the patient's laboratory findings and progress are presented in Table 1. The patient was given intravenous (IV) fluid bolus and started on ceftriaxone in the ER. She was initially admitted to the medical ward, but later she was transferred to the intensive care unit (ICU) and was started on IV insulin drip along with bicarbonate-dextrose 5% in water (D5W) drip.
Gradually, the patient's bicarbonate levels improved, and the anionic gap was closed. The patient also improved clinically, and she was able to tolerate an oral diet. She was transitioned to basal plus bolus insulin regimen from the insulin drip. Blood and urine cultures came back unremarkable after 72 hours. The patient's renal function also improved, and serum creatinine was 1.55 on the day of discharge. She was advised to stop taking empagliflozin as it was the potential cause of developing UTI and EDKA in this case. She was provided follow-up with a primary care physician for further diabetes management.

Discussion
SGLT2i are relatively new non-insulin and oral hypoglycemic agents that cause glycosuria by inhibiting the glucose reabsorption in proximal renal tubules. 9 In addition to better glycemic control and cardioprotective effects, there are other metabolic benefits, including improvement of lipids, insulin resistance, nonalcoholic steatohepatitis, and weight associated with the use of SGLT2i. 6 SGLT2i has been a drug of choice for patients with comorbidities like hypertension and obesity because of their favorable effects on the blood pressure and weight/body mass index. 10 There is an average 1.5-2 kg weight loss compared to placebo, and a clinically notable reduction by approximately 2.5-5.0 mm Hg and 1-2 mm Hg for systolic and diastolic blood pressure respectively. 11,12 The EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients) study showed a 38% relative risk reduction in deaths from cardiovascular (CV) causes in patients receiving empagliflozin in comparison to placebo, and a CANVAS-R (CANagliflozin cardiovascular Assessment Study-Renal) program demonstrated that canagliflozin had a lower risk of cardiovascular events than those who received placebo. 10 The data from randomized controlled CV outcome trials with all SGLT2i showed multiple cardiovascular benefits like a 30% reduction in hospital admission for HF and a reduction in deaths due to heart failure or arrhythmia. 13 The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial showed a 26% reduction in worsening of heart failure with reduced ejection fraction (HFrEF) or cardiovascular death, with a median duration of follow-up of 1.5 years. 12 The studies using large databases from multiple countries have reassured us that these benefits can be reproduced in routine clinical practice. 12  SGLT2i shows glycemic control efficacy and a meta-analysis of 58 studies with eight different SGLT2i showed a reduction in mean HbA1c by 0.61% when used as add-on therapy compared to placebo. 14 All SGLT2i can be initiated if the estimated glomerular filtration rate (eGFR) is more than 60 mL per min per 1.73 m 2 and should be reviewed if the eGFR is less than 45 mL per min per 1.73 m 2 because of a diminished glucose lowering effect. 12 Renal disorders are common in T2DM, with approximately 50% of patients developing some degree of renal impairment and an increasing prevalence of both conditions over time. 13 Recent trials with SGLT2i suggested their potential to reduce the rates of end stage renal disease (ESRD) and acute kidney injury (AKI). 13 Multiple renal risk markers like eGFR, urinary albumin: creatinine ratio (UACR), and serum uric acid levels have been used as risk measurements together with hard outcomes like ESRD or renal death in five major CV outcome trials, thus indicating that SGLT2i could prevent the development and/or delay the worsening of CKD in people with T2DM at any level of renal risk. 13 Analyses on CV outcome trials have shown that there may be fewer AKI events in patients on SGLT2i compared to placebo. 13 Considering the above-mentioned beneficial effects of SGLT2i, the use of these medications has been increasing in dayto-day practice by the providers in all clinical settings. Thus, it is reasonable to be cognizant of its side effects at the same time to prevent any untoward events in a timely manner. A potentially underdiagnosed adverse effect of SGLT2i use is diabetic ketoacidosis with a reported incidence of less than 0.2% in type 2 and 9.4% in type 1 diabetic patients. 9 We collected data on 16 recently published case reports showing development of diabetes ketoacidosis with and without euglycemia in the patients started on SGLT2i.
In order to support our hypothesis, we combined our case report with an extensive literature review that can help promote evidence-based practice in the real world to improve the health of patients and community. To summarize, all case reports mentioned below in Table 2 endorse the findings of our case presentation, specifically SGLT2i-related side effects. We also tried to collect information on the duration of SGLT2i exposure before the development of EDKA and found the range of 1 dose to six years which suggests an uncertain latent time before the patient can develop EDKA. We can construe that overall management is almost the same in all case reports which include treatment with insulin drip, intravenous hydration, and cessation of SGLT2i.
The limitations of our case report and literature review include limited availability of data on laboratory parameters and pre-existing systematic conditions that could have contributed to the induction of DKA. There is limited data on the duration of drug usage in correlation with the incidence of euglycemic DKA. We only included case reports found on the PubMed database and written in English which may lead to missing case reports in other languages.

Conclusions
The use of SGLT2i has increased significantly in recent times. SGLTi are not only implicated in the treatment of diabetes, but also in the management of chronic HF, hypertension and CKD. As SGLT2i has been approved for use in these multiple disease conditions, regardless of patients' diabetes status, it is thus imperative for the clinical providers to equip themselves with the knowledge of possible side effects of SGLT2i. EDKA has been found to be one of the significant and life-threatening adverse effects of SGLT2i use. Therefore, it is crucial for physicians to monitor patients who use this medication for signs and symptoms of DKA in the setup of normal glucose levels. This will facilitate early diagnosis, obviate hospitalizations and associated patient morbidity, and thus expedite effective patient management and their disposition.

Key points
• The use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been on the rise for the treatment of various disease conditions including chronic heart failure, blood pressure and weight loss with or without concomitant diabetes mellitus.
• It is imperative to be aware of potential life-threatening complications of SGLT2i such as euglycemic diabetic ketoacidosis.
• Physicians should closely monitor patients who use this class medications for signs and symptoms of diabetic ketoacidosis (DKA) in the setting of normal glucose levels to improve patient safety and health outcomes.

Consent
Written informed consent for publication of their clinical details was obtained from the patient.

Data availability
All data underlying the results are available as part of the article and no additional source data are required.