Case Report: Euglycemic diabetic ketoacidosis led by empagliflozin: A case report and literature review

Irina Balan; V Lakshmi N  Priyanka Ganapathiraju; Sudha Dirisanala; Shafaq Taj; Pratikkumar Vekaria

doi:10.12688/f1000research.127382.1

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Case Report

Case Report: Euglycemic diabetic ketoacidosis led by empagliflozin: A case report and literature review

[version 1; peer review: 1 approved, 1 not approved]

Irina Balan ¹, V Lakshmi N Priyanka Ganapathiraju², Sudha Dirisanala³, Shafaq Taj⁴, Pratikkumar Vekaria⁵

Irina Balan ¹, V Lakshmi N Priyanka Ganapathiraju², [...] Sudha Dirisanala³, Shafaq Taj⁴, Pratikkumar Vekaria⁵

PUBLISHED 07 Dec 2022

Author details Author details

¹ State University of Medicine and Pharmacy "N.Testemitanu", Chisinau, MD2025, Moldova
² Rangaraya Medical College, Kakinada, 533001, India
³ Konaseema Institute of Medical Sciences and Research Foundation, Amalapuram, 533201, India
⁴ Hackensack Palisades Medical Center, North Bergen, NJ 07047, USA
⁵ Prisma Health-Upstate, Greenville, South Carolina, SC 29605, USA

Irina Balan
Roles: Data Curation, Investigation, Resources, Writing – Original Draft Preparation, Writing – Review & Editing

V Lakshmi N Priyanka Ganapathiraju
Roles: Data Curation, Investigation, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing

Sudha Dirisanala
Roles: Investigation, Methodology, Resources, Writing – Original Draft Preparation, Writing – Review & Editing

Shafaq Taj
Roles: Data Curation, Formal Analysis, Writing – Original Draft Preparation, Writing – Review & Editing

Pratikkumar Vekaria
Roles: Conceptualization, Project Administration, Validation, Visualization, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

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 the current practice, and also help to take appropriate steps to mitigate its adverse effects and improve overall health outcomes in our patients.
Conclusions: SGLT2i are increasingly used because of their favorable effects on mortality in the chronic HF patients along with its benefits of weight loss and blood pressure reduction. A potential underdiagnosed adverse effect of SGLT2i use is diabetic ketoacidosis in a setting of normal blood glucose levels. Thus, it is reasonable to be cognizant of its side effects to prevent any untoward events in a timely manner.

Keywords

sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin, euglycemic diabetic ketoacidosis (EDKA), chronic heart failure, diabetes mellitus

Corresponding author: Irina Balan

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2022 Balan I et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Balan I, Ganapathiraju VLNP, Dirisanala S et al. Case Report: Euglycemic diabetic ketoacidosis led by empagliflozin: A case report and literature review [version 1; peer review: 1 approved, 1 not approved]. F1000Research 2022, 11:1448 (https://doi.org/10.12688/f1000research.127382.1) First published: 07 Dec 2022, 11:1448 (https://doi.org/10.12688/f1000research.127382.1) Latest published: 07 Dec 2022, 11:1448 (https://doi.org/10.12688/f1000research.127382.1)

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 10²^,³; glycosuria that changes the whole-body metabolism to mobilization and use of lipids, and stimulates the hepatic gluconeogenesis⁴; involvement in the ionic cardiomyocytes metabolism by direct inhibition of Na⁺/H⁺ exchange and increasing Ca²⁺ reuptake and activity of sarcoplasmic endoplasmic reticulum Ca²⁺-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 life-threatening 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.

Table 1. Laboratory findings on blood cell counts, blood chemistry, arterial blood gas and urine studies.

Laboratory findings, post admission	Day 1	Day 2	Day 3	Day 4
WBC	15.3		9.4
Hgb	12.4		9.7
Platelets	300		240
Sodium	137	136	138	135
Potassium	3.9	3.4	3.7	4.1
Bicarbonate	14	12	18	20
Anion gap	23	18	13	11
Blood glucose	182	119	104	128
Serum Creatinine	3.28 (Baseline ~1.6)	2.58	2.05	1.92
GFR	15 (Baseline ~27)	20	27	29
Lactic acid	1.1	0.9	1.2
Troponin-I	<0.01
HbA1C	8.2
	Arterial Blood Gas
Blood PH		7.30
PCO2		36
PO2		121
HCO3^-		17.6
base deficit/excess		-9.0
	Urine study
Leukocyte Esterase	Large
Ketone	20

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 m² and should be reviewed if the eGFR is less than 45 mL per min per 1.73 m² 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 day-to-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.

Table 2. Previously published cases of SGLT2i induced diabetic ketoacidosis.

Authors & year of publication	Age/Sex	Initial Presentation	Duration of SGLT2 Exposure	Treatment & Outcome
Chacko, B., et al., 2018¹⁵	55Y Male	Patient admitted to the intensive care unit (ICU) with severe, unexplained metabolic acidosis, tachypnea, polyuria and polydipsia. Status post elective total knee replacement six days prior to ICU admission. On oral hypoglycemic drugs with poor oral intake postoperatively. Other medical conditions include coronary artery bypass grafting, osteoarthritis, hypertension and post-traumatic stress disorder from military service. He developed worsening metabolic acidosis, polyuria, dehydration and tachypnea.	Six years (empagliflozin)	Started on sodium bicarbonate infusion along with electrolyte correction. Metabolic acidosis continued to worsen. Treatment for EDKA started with insulin and Dextrose infusion. Discontinued oral hypoglycemic drugs (empagliflozin, metformin and linagliptin). Patient improved in 24 hours. He was transitioned to subcutaneous insulin and was discharged on day seven. On follow up insulin was weaned and started him on two oral hypoglycemic drugs metformin and gliclazide which were sufficient to maintain his blood glucose.
Chacko, B., et al., 2018¹⁵	66Y Female	Patient was admitted to ICU following elective coronary artery bypass surgery. Known T2DM for several years and on oral hypoglycemic drugs: dapagliflozin, saxagliptin and metformin. Other medical problems include hypertension, carotid artery disease, anxiety disorder, obesity and breast cancer. The patient was transferred to the ICU for ventilation. She was extubated on day 0 according to local protocols. 20 hours after surgery she developed high anion gap metabolic acidosis with respiratory compensation.	Several years (dapagliflozin)	Treated with an insulin/dextrose infusion with steady improvement in her acidosis. She was intubated again due to combined effects of anxiety, new-onset atrial fibrillation, postoperative pain, atelectasis, and the respiratory compensation for worsening EDKA with weaning of the insulin/dextrose. Her acidosis was resolved with re-titration of insulin/dextrose infusion. She got improved and extubated on day two postoperatively. She was started on both short and long acting insulin and transferred to a ward for observation.
Guirguis, H., et al., 2022¹⁰	58Y Male	Patient was admitted to the emergency department (ED) with a history of two days of generalized weakness, confusion, fatigue, and slurred speech. He was diabetic and on metformin, empagliflozin, sitagliptin, and repaglinide. Patient was on a ketogenic diet and intermittent fasting for one month for weight loss and discontinued metformin and repaglinide since then.	Unknown (empagliflozin)	Patient was diagnosed with DKA and started on aggressive fluid resuscitation and intravenous insulin infusion. Recovered gradually and started on subcutaneous insulin. Patient was advised not to follow a ketogenic diet while using SGLT2i based on several case reports suggesting DKA as a rare side effect while on both SGLT2i and low carbohydrate diet.
Dull, R.B., et al., 2017¹⁶	62Y Male	Patient presented to the ED with a four-day history of dysuria, urinary frequency, fever, chills, and myalgia. He had a stomach without nausea, vomiting or abdominal pain. Known T2DM for 14 years complicated by neuropathy and on metformin and empagliflozin. Other medical problems include coronary artery disease, hypertension, hyperlipidemia, heart failure with preserved ejection fraction, cerebrovascular accident, obstructive sleep apnea, and morbid obesity.	11 months (empagliflozin)	Patient had sepsis due to pneumonia and EDKA. These acute conditions were managed with cefepime and sliding scale insulin. His blood glucose levels were never greater than 150 mg/dL and insulin was not given. He improved in 48 hours. Hospital course was uneventful. Discharged with to continue the metformin and to stop Empagliflozin.
Elshimy, G., et al., 2019¹⁷	28Y Female	Patient presented to the ED with sudden-onset abdominal pain and history of multiple episodes of non-bloody vomitus in the previous 24 hours. Known T2DM for one year and refused to start insulin. She was started on metformin and dapagliflozin two months before the presentation due to elevated hemoglobin A1C level.	Two months (dapagliflozin)	Patient was diagnosed with DKA, transferred to ICU and given two liters of normal saline. Initiated continuous insulin infusion with dextrose-containing intravenous solution. Metformin and dapagliflozin were held during her hospital stay. She improved in three days and was discharged on insulin regimen due to elevated hemoglobin A1C level. Metformin and dapagliflozin were discontinued.
Adachi, J., et al. 2017¹⁸	27Y Female	Patient was admitted to the hospital with dizziness, increased thirst, malaise and abdominal pain. Known T2DM for seven years and on gliclazide, metformin, and sitagliptin. She was started on canagliflozin three months before her admission due to her poor glycemic control. She was on a low carbohydrate diet for weight loss.	Three months (Canagliflozin)	Patient was diagnosed with DKA was started on isotonic saline and a continuous insulin infusion with the held all oral antidiabetic agents. On day three insulin infusion was switched to subcutaneous insulin. She recovered eventually and was discharged on day eight.
Miwa, M., et al., 2020¹⁹	45Y Female	Patient was presented to the clinic with increased thirst and decreased appetite for two weeks. Her glycemia level at the clinic was 580mg/dL (32.2 mmol/L) and received a single oral dose of tofogliflozin hydrate (20 mg/day). She was not known diabetic. Eventually her condition worsened with dyspnea and hyperventilation and was admitted to the emergency department. He had a history of intermittent asthma.	One dose (tofogliflozin)	Patient was diagnosed with EDKA. She was started on fluids and continuous intravenous insulin. Her acidosis got worse eventually and then intravenous insulin was titrated up to improve blood glucose levels. She completely recovered in five days and was started on diabetes mellitus treatment without SGLT2i and was discharged from the hospital after 25 days.
Lee, I.H., et al., 2020²⁰	70Y Female	Patient was presented to the ED with symptoms of generalized weakness, fever, oliguria, nausea, vomiting, and diagnosed with azotemia due to postrenal acute kidney injury. She had compression fracture of 1st lumbar vertebrae five days before presentation and was bedridden since then. Known T2DM for 40 years and was on metformin and dapagliflozin prior to admission.	Unknown (dapagliflozin)	Patient was started on ceftriaxone, IV fluids initially, but was later started on total parenteral nutrition due to diffuse paralytic ileus. Her oral antidiabetic drugs were held for a short time and again restarted once her condition got better. However, on day six her condition worsened and was diagnosed with EDKA and started on intravenous fluids, 5% Dextrose in water and KCl. Patient wasn’t started on regular insulin considering her blood glucose levels between 150-250 mg/dl. Patient improved on day eight and was discharged on day 14 with metformin and insulin. Dapagliflozin was discontinued.
Rafey, M.F., et al., 2019²¹	44Y Male	Five years (canagliflozin). Patient presented with generalized weakness, lethargy, nausea and anorexia. Status post C5-C7 cervical compression fracture six days ago. Known T2DM for five years and poorly controlled on dulaglutide and canagliflozin. History of metformin intolerance and had an insulin resistance phenotype.	Five years (canagliflozin)	The patient was diagnosed with EDKA, started on intravenous fluids resuscitation, with lower insulin dose. After four days of continuous treatment, her condition improved and discharged home with insulin glargine subcutaneous six units’ once daily and once weekly dulaglutide.
Rafey, M.F., et al., 2019²¹	59Y Female	Patient was presented with generalized weakness, dyspnoea and presyncope. Status post laparoscopic right partial nephrectomy for removal of a renal oncocytoma three days before presentation. Known T2DM for 17 years complicated by diabetic retinopathy. Other medical problems include Hypertension, obesity, polycystic ovarian syndrome, fibromyalgia and depression. History of metformin resistance and non-responder to glucagon-like peptide 1 (GLP1) agonists. She was on insulin and started on empagliflozin five months before presentation.	Five months (empagliflozin)	The patient was diagnosed with EDKA. She was started on aggressive intravenous fluid resuscitation and low-dose intravenous insulin. Her condition improved after 92 hours and was switched to subcutaneous insulin. She was discharged home on insulin regimen.
Kitahara, C., et al., 2020²²	59Y Male	Patient was presented to hospital for thoracoscopic debridement and intrathoracic lavage for the left-sided bacterial empyema. Known T2DM for 12 years and on Insulin and empagliflozin. During surgery, he was diagnosed with acidosis as per arterial blood gas analysis and blood glucose level of 162 mg/dL.	18 months (empagliflozin)	The patient was diagnosed with EDKA and started on intravenous regular insulin with dextrose 5% water infusion. His condition improved after 24 hour of the treatment. He was only treated with insulin for the next 14 days until his empyema got resolved.
Ramos, A.D., et al., 2019²³	44Y Female	Patient presented to the ED with a three days history of (h/o) weakness and labs revealed anion gap metabolic acidosis with presence of serum acetone and minimally elevated glucose.	Four weeks (canagliflozin)	Patient was diagnosed with EDKA. Treatment includes an initial bolus of IV 0.9% normal saline followed by a continuous infusion of IV insulin with 5% dextrose and withheld canagliflozin.
Turner, J., et al., 2016²⁴	62Y Female	A T2DM patient with presenting symptoms of decreased appetite, polydipsia, polyuria, and four days h/o worsening nausea, vomiting and generalized weakness.	Unknown (canagliflozin)	Fluid resuscitation with Insulin drip in the ICU to correct metabolic acidosis secondary to EDKA.
Mistry, S., et al. 2020²⁵	47Y Female	Patient presented to the ED with acute onset left arm numbness, chest pain after taking her first dose of empagliflozin a day prior. She was on a low carbohydrate diet for two months.	One day (empagliflozin)	Patient was diagnosed with EDKA. Treatment includes insulin drip and dextrose drip in ICU for five days to resolve acidosis.
Mistry, S., et al, 2020²⁵	34Y Male	A T2DM patient presented with one day h/o chest pain associated with shortness of breath. Further testing ruled out cardiac and pulmonary etiology. He had started a ketogenic diet a week prior.	Two months (canagliflozin)	Patient was diagnosed with EDKA. Treated in the ICU with insulin drip for three days and dextrose 5% water drip to resolve acidosis.
Sethi, S.M., et al., 2021²⁶	52Y Female	A T2DM and Hypothyroidism patient presented with h/o vomiting and lethargy for one day and low-grade fever with dry cough for a week. Physical exam revealed hyperemic pharynx with mildly enlarged tonsils	Two years (Dapagliflozin)	Patient was diagnosed with EDKA and initiated on insulin drip and IV hydration and later switched to basal with bolus insulin regimen (insulin glargine and insulin lispro).

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.

References

1. Genuardi MV, Mather PJ: The dawn of the four-drug era? SGLT2 inhibition in heart failure with reduced ejection fraction. Ther. Adv. Cardiovasc. Dis. 2021 Jan-Dec; 15: 175394472110026. PubMed Abstract | Publisher Full Text | Free Full Text
2. Lahnwong S, Chattipakorn SC, Chattipakorn N: Potential mechanisms responsible for cardioprotective effects of sodium–glucose co-transporter 2 inhibitors. Cardiovasc. Diabetol. 2018; 17: 101. Publisher Full Text
3. Zeng Q, Zhou Q, Liu W, et al.: Mechanisms and Perspectives of Sodium-Glucose Co-transporter 2 Inhibitors in Heart Failure. Front Cardiovasc Med. 2021 Feb 10; 8: 636152. PubMed Abstract | Publisher Full Text | Free Full Text
4. Ferrannini E, Baldi S, Frascerra S, et al.: Shift to Fatty Substrate Utilization in Response to Sodium-Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes. Diabetes. 2016 May; 65(5): 1190–1195. Epub 2016 Feb 9. PubMed Abstract | Publisher Full Text
5. Chambergo-Michilot D, Tauma-Arrué A, Loli-Guevara S: Effects and safety of SGLT2 inhibitors compared to placebo in patients with heart failure: A systematic review and meta-analysis. Int J Cardiol Heart Vasc. 2020 Dec 11; 32: 100690. PubMed Abstract | Publisher Full Text | Free Full Text
6. Ogawa W, Sakaguchi K: Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. J Diabetes Investig. 2016 Mar; 7(2): 135–138. Epub 2015 Sep 6. PubMed Abstract | Publisher Full Text | Free Full Text
7. Yu X, Zhang S, Zhang L: Newer Perspectives of Mechanisms for Euglycemic Diabetic Ketoacidosis. Int. J. Endocrinol. 2018 Oct 2; 2018: 1–8. PubMed Abstract | Publisher Full Text | Free Full Text
8. Nasa P, Chaudhary S, Shrivastava PK, et al.: Euglycemic diabetic ketoacidosis: A missed diagnosis. World J. Diabetes. 2021 May 15; 12(5): 514–523. PubMed Abstract | Publisher Full Text | Free Full Text
9. Clark A, Mohammed AS, Raut A, et al.: Prevalence and Clinical Characteristics of Adults Presenting With Sodium-Glucose Cotransporter-2 Inhibitor-Associated Diabetic Ketoacidosis at a Canadian Academic Tertiary Care Hospital. Can. J. Diabetes. 2021 Apr; 45(3): 214–219. Epub 2020 Aug 21. PubMed Abstract | Publisher Full Text
10. Guirguis H, Beroukhim Afrahimi S, Pham C: The Use of SGLT-2 Inhibitors Coupled With a Strict Low-Carbohydrate Diet: A Set-Up for Inducing Severe Diabetic Ketoacidosis. Clin Med Insights Case Rep. 2022 Apr 8; 15: 117954762210900. PubMed Abstract | Publisher Full Text | Free Full Text
11. Pereira MJ, Eriksson JW: Emerging Role of SGLT-2 Inhibitors for the Treatment of Obesity. Drugs. 2019 Feb; 79(3): 219–230. PubMed Abstract | Publisher Full Text | Free Full Text
12. Packer M, Anker SD, Butler J, et al.: EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N. Engl. J. Med. 2020 Oct 8; 383(15): 1413–1424. Epub 2020 Aug 28. PubMed Abstract | Publisher Full Text
13. Giorgino F, Vora J, Fenici P, et al.: Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk. Cardiovasc. Diabetol. 2020 Nov 22; 19(1): 196. PubMed Abstract | Publisher Full Text | Free Full Text
14. Mikhail N: Place of sodium-glucose co-transporter type 2 inhibitors for treatment of type 2 diabetes. World J. Diabetes. 2014 Dec 15; 5(6): 854–859. PubMed Abstract | Publisher Full Text | Free Full Text
15. Chacko B, Whitley M, Beckmann U, et al.: Postoperative euglycaemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitors (gliflozins): a report of two cases and review of the literature. Anaesth. Intensive Care. 2018; 46(2): 215–219. Publisher Full Text
16. Dull RB, Spangler ML, Knezevich EL, et al.: Euglycemic Diabetic Ketoacidosis Associated With Sodium-Glucose Cotransporter Type 2 Inhibitors in Patients With Type 2 Diabetes Mellitus Receiving Oral Therapy. J. Pharm. Pract. 2019; 32(2): 240–243. Publisher Full Text
17. Elshimy G, Correa R: Sudden-onset Hypoglycemia Following Fluid Replacement in a Patient with Dapagliflozin-induced Diabetic Ketoacidosis Without Prior Insulin Use: Case Report. Cureus. 2019; 11(8): e5448. Published 2019 Aug 21. Publisher Full Text
18. Adachi J, Inaba Y, Maki C: Euglycemic Diabetic Ketoacidosis with Persistent Diuresis Treated with Canagliflozin. Intern. Med. 2017; 56(2): 187–190. Publisher Full Text
19. Miwa M, Nakajima M, Kaszynski RH, et al.: Prolonged euglycemic diabetic ketoacidosis triggered by a single dose of sodium-glucose cotransporter 2 inhibitor. BMJ Case Rep. 2020; 13(10): e235969. Published 2020 Oct 7. Publisher Full Text
20. Lee IH, Ahn DJ: Dapagliflozin-associated euglycemic diabetic ketoacidosis in a patient with type 2 diabetes mellitus: A case report. Medicine (Baltimore). 2020; 99(21): e20228. Publisher Full Text
21. Rafey MF, Butt A, Coffey B, et al.: Prolonged acidosis is a feature of SGLT2i-induced euglycaemic diabetic ketoacidosis [published online ahead of print, 2019 Sep 27]. Endocrinol. Diabetes Metab. Case Rep. 2019; 2019: 19–0087. Publisher Full Text
22. Kitahara C, Morita S, Kishimoto S, et al.: Early detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes: A case report. J Diabetes Investig. 2021; 12(4): 664–667. Publisher Full Text
23. Diaz-Ramos A, Eilbert W, Marquez D: Euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitor use: a case report and review of the literature. Int. J. Emerg. Med. 2019; 12(1): 27. Published 2019 Sep 5. Publisher Full Text
24. Turner J, Begum T, Smalligan RD: Canagliflozin-Induced Diabetic Ketoacidosis: Case Report and Review of the Literature. J. Investig. Med. High Impact Case Rep. 2016; 4(3): 232470961666323. Published 2016 Aug 29. Publisher Full Text
25. Mistry S, Eschler DC: Euglycemic Diabetic Ketoacidosis Caused by SGLT2 Inhibitors and a Ketogenic Diet: A Case Series and Review of Literature. AACE Clin Case Rep. 2020; 7(1): 17–19. Published 2020 Dec 28. Publisher Full Text
26. Sethi SM, Vohra M, Ali SA: EUGLYCEMIC DIABETIC KETOACIDOSIS (EDKA) IN A PATIENT RECEIVING DAPAGLIFLOZIN. Acta Endocrinol (Buchar). 2021; 17(2): 266–269. Publisher Full Text

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VERSION 1 PUBLISHED 07 Dec 2022

Author details Author details

¹ State University of Medicine and Pharmacy "N.Testemitanu", Chisinau, MD2025, Moldova
² Rangaraya Medical College, Kakinada, 533001, India
³ Konaseema Institute of Medical Sciences and Research Foundation, Amalapuram, 533201, India
⁴ Hackensack Palisades Medical Center, North Bergen, NJ 07047, USA
⁵ Prisma Health-Upstate, Greenville, South Carolina, SC 29605, USA

Irina Balan
Roles: Data Curation, Investigation, Resources, Writing – Original Draft Preparation, Writing – Review & Editing

V Lakshmi N Priyanka Ganapathiraju
Roles: Data Curation, Investigation, Project Administration, Writing – Original Draft Preparation, Writing – Review & Editing

Sudha Dirisanala
Roles: Investigation, Methodology, Resources, Writing – Original Draft Preparation, Writing – Review & Editing

Shafaq Taj
Roles: Data Curation, Formal Analysis, Writing – Original Draft Preparation, Writing – Review & Editing

Pratikkumar Vekaria
Roles: Conceptualization, Project Administration, Validation, Visualization, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

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Published: 07 Dec 2022, 11:1448

https://doi.org/10.12688/f1000research.127382.1

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Balan I, Ganapathiraju VLNP, Dirisanala S et al. Case Report: Euglycemic diabetic ketoacidosis led by empagliflozin: A case report and literature review [version 1; peer review: 1 approved, 1 not approved]. F1000Research 2022, 11:1448 (https://doi.org/10.12688/f1000research.127382.1)

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Reviewer Report 07 Feb 2024

Fateen Ata, Hamad General Hospital, Doha, Doha, Qatar

Not Approved

https://doi.org/10.5256/f1000research.139883.r240271

The manuscript claims in the introduction that the incidence of Euglycemic Diabetic Ketoacidosis (EDKA) has risen with the use of SGLT2 inhibitors. This assertion, while technically accurate due to the expanded use of these drugs, lacks the necessary context ... Continue reading

The manuscript claims in the introduction that the incidence of Euglycemic Diabetic Ketoacidosis (EDKA) has risen with the use of SGLT2 inhibitors. This assertion, while technically accurate due to the expanded use of these drugs, lacks the necessary context to fully understand the implications. It is critical to note that despite the perceived increase, EDKA remains an exceedingly rare adverse effect. The apparent increase in the rare side effect is due to the increase in the prescription of the drug for obvious reasons. The introduction would benefit from highlighting the relative rarity of EDKA and including well-established data on the incidence of Diabetic Ketoacidosis (DKA), including EuDKA and HDKA, in the context of SGLT2 inhibitor use, along with a clinical perspective on these findings.

Furthermore, attributing DKA directly to SGLT2 inhibitor use without acknowledging the complexity of causation oversimplifies the issue. The terms used in the manuscript to describe the relationship between SGLT2 inhibitors and DKA are exaggerated and must be revised to more accurately reflect the nuanced nature of drug-related adverse effects. For example, the statement "EDKA has been found to be one of the significant and life-threatening adverse effects of SGLT2i use" could mislead readers regarding the actual clinical significance of EDKA in the context of SGLT2 inhibitor therapy. A review of recent, larger cohort studies would illustrate that the incidence of EDKA, while non-negligible, is relatively low. Acknowledging the risk without overstating its significance is crucial to maintaining a balanced view of the drug's overall efficacy and safety profile.

To improve the manuscript's accuracy and objectivity, I recommend a major revision that addresses these concerns. Specifically, the authors should revise the language to present a more balanced and data-driven discussion of the risks associated with SGLT2 inhibitors, including a clearer representation of the incidence and clinical context of EDKA. Adjusting the tone and content of the article to incorporate these suggestions will greatly enhance its value to the scientific community and clinical practice.

Is the background of the case’s history and progression described in sufficient detail?

No
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?

Partly
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?

Partly
Is the case presented with sufficient detail to be useful for other practitioners?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Endocrine system

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Reviewer Report 03 Jan 2023

Syed Nazeer Mahmood, Department of Medicine, Section of Pulmonary and Critical Care, Medstar Washington Hospital, Washington, DC, USA

Namratha Meda, Department of Medicine, MedStar Washington Hospital Center, Washington, DC, USA

Approved

https://doi.org/10.5256/f1000research.139883.r158062

SGLT2 inhibitors are a class of medication that can be used to treat heart failure in people with and without diabetes. It is important to be aware of the possible side effects of these medications, including the rare possibility of ... Continue reading

SGLT2 inhibitors are a class of medication that can be used to treat heart failure in people with and without diabetes. It is important to be aware of the possible side effects of these medications, including the rare possibility of developing euglycemic diabetic ketoacidosis (EDKA).

The authors report a case where the patient developed EDKA while on empagliflozin, a type of SGLT2 inhibitor. The report includes details on the signs and symptoms of the condition, relevant laboratory test results, and the treatment and outcome of the case with sufficient detail in a manner in which the teaching points can be extrapolated to general practice. The report also includes a review of other cases in the literature where SGLT2 inhibitors presented with similar complications. The case highlights a side effect of this class of medication that healthcare practitioners must be aware of.

Suggested changes pertinent to each section:

Abstract:

Would remove "reasonable" from the last sentence in the conclusion section. Can replace it with "important".

Introduction:

Change “converted in ketones” to “converted into ketones”.
The current mechanism suggested as per the quoted reference – 7 is: Decreased carbohydrate intake causes insulinopenia and increased glucagon. Increased glucagon/insulin ratio further promotes lipolysis and ketogenesis.
Please change the ratio to reflect increased glucagon/insulin instead of “insulin/glucagon”.

Case Presentation:

Please add units for all the lab values in the table as well.
As there are a few differentials here, it may be beneficial to edit the case report to reflect what was considered first and how things were ruled out before reporting that EDKA was the eventual diagnosis.

Discussion:

Please maintain consistency with regarding acronyms for the trials quoted, if you were to mention the acronym for each trial in parenthesis, please do so for the EMPA-REG OUTCOME and CANVAS-R trials as well.
It may be useful to mention that all of these case reports have been in patients with a known history of DM, given that this class of drug is now approved to be used in patients without a history of DM for cardioprotective benefits in HF, it might be beneficial to know that this side effect is likely to occur in the DM population.

Conclusions:

Would change "implicated" to "SGLTis are not only used in … ".
The conclusion goes on to emphasize the threat of EDKA although data in the non-diabetic population is limited. It may be useful to keep that open-ended and the need for further studies in that particular population.

Is the background of the case’s history and progression described in sufficient detail?

Yes
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?

Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?

Yes
Is the case presented with sufficient detail to be useful for other practitioners?

Yes

Competing Interests: I was a co-author with Irina Balan on a meta-analysis that is being considered for publication at this time. This project included multiple co-authors from various institutions and I have not directly interacted with Dr. Balan nor do I know Dr. Balan personally. The manuscript we worked on was edited independently with each co-author in charge of a separate section. The current article was not discussed with me prior to my receiving an invitation to review it and I have not had any contact with Dr. Balan about this manuscript. Additionally, this review was primarily performed by a resident physician (Namratha Meda) and I supervised her in this process without influencing any constructive or critical review points. Therefore, while I have worked with Dr. Balan in the past (indirectly), I feel like we have provided an objective and unbiased review.

Reviewer Expertise: Internal Medicine

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Version 1

VERSION 1 PUBLISHED 07 Dec 2022

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Version 1 07 Dec 22	read	read

Syed Nazeer Mahmood, Medstar Washington Hospital, Washington, USA

Namratha Meda, MedStar Washington Hospital Center, Washington, USA
Fateen Ata, Hamad General Hospital, Doha, Qatar

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Reviewer Report

7 Views

07 Feb 2024 | for Version 1

Fateen Ata, Hamad General Hospital, Doha, Doha, Qatar

7 Views Cite this report Responses(0)

Not Approved

The manuscript claims in the introduction that the incidence of Euglycemic Diabetic Ketoacidosis (EDKA) has risen with the use of SGLT2 inhibitors. This assertion, while technically accurate due to the expanded use of these drugs, lacks the necessary context to fully understand the implications. It is critical to note that despite the perceived increase, EDKA remains an exceedingly rare adverse effect. The apparent increase in the rare side effect is due to the increase in the prescription of the drug for obvious reasons. The introduction would benefit from highlighting the relative rarity of EDKA and including well-established data on the incidence of Diabetic Ketoacidosis (DKA), including EuDKA and HDKA, in the context of SGLT2 inhibitor use, along with a clinical perspective on these findings.

Furthermore, attributing DKA directly to SGLT2 inhibitor use without acknowledging the complexity of causation oversimplifies the issue. The terms used in the manuscript to describe the relationship between SGLT2 inhibitors and DKA are exaggerated and must be revised to more accurately reflect the nuanced nature of drug-related adverse effects. For example, the statement "EDKA has been found to be one of the significant and life-threatening adverse effects of SGLT2i use" could mislead readers regarding the actual clinical significance of EDKA in the context of SGLT2 inhibitor therapy. A review of recent, larger cohort studies would illustrate that the incidence of EDKA, while non-negligible, is relatively low. Acknowledging the risk without overstating its significance is crucial to maintaining a balanced view of the drug's overall efficacy and safety profile.

To improve the manuscript's accuracy and objectivity, I recommend a major revision that addresses these concerns. Specifically, the authors should revise the language to present a more balanced and data-driven discussion of the risks associated with SGLT2 inhibitors, including a clearer representation of the incidence and clinical context of EDKA. Adjusting the tone and content of the article to incorporate these suggestions will greatly enhance its value to the scientific community and clinical practice.

Is the background of the case’s history and progression described in sufficient detail?

No
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?

Partly
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?

Partly
Is the case presented with sufficient detail to be useful for other practitioners?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Endocrine system

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

Respond to this report

Responses (0)

Back to all reports

Reviewer Report

13 Views

03 Jan 2023 | for Version 1

Syed Nazeer Mahmood, Department of Medicine, Section of Pulmonary and Critical Care, Medstar Washington Hospital, Washington, DC, USA

Namratha Meda, Department of Medicine, MedStar Washington Hospital Center, Washington, DC, USA

13 Views Cite this report Responses(0)

Approved

SGLT2 inhibitors are a class of medication that can be used to treat heart failure in people with and without diabetes. It is important to be aware of the possible side effects of these medications, including the rare possibility of developing euglycemic diabetic ketoacidosis (EDKA).

The authors report a case where the patient developed EDKA while on empagliflozin, a type of SGLT2 inhibitor. The report includes details on the signs and symptoms of the condition, relevant laboratory test results, and the treatment and outcome of the case with sufficient detail in a manner in which the teaching points can be extrapolated to general practice. The report also includes a review of other cases in the literature where SGLT2 inhibitors presented with similar complications. The case highlights a side effect of this class of medication that healthcare practitioners must be aware of.

Suggested changes pertinent to each section:

Abstract:

Would remove "reasonable" from the last sentence in the conclusion section. Can replace it with "important".

Introduction:

Change “converted in ketones” to “converted into ketones”.
The current mechanism suggested as per the quoted reference – 7 is: Decreased carbohydrate intake causes insulinopenia and increased glucagon. Increased glucagon/insulin ratio further promotes lipolysis and ketogenesis.
Please change the ratio to reflect increased glucagon/insulin instead of “insulin/glucagon”.

Case Presentation:

Please add units for all the lab values in the table as well.
As there are a few differentials here, it may be beneficial to edit the case report to reflect what was considered first and how things were ruled out before reporting that EDKA was the eventual diagnosis.

Discussion:

Please maintain consistency with regarding acronyms for the trials quoted, if you were to mention the acronym for each trial in parenthesis, please do so for the EMPA-REG OUTCOME and CANVAS-R trials as well.
It may be useful to mention that all of these case reports have been in patients with a known history of DM, given that this class of drug is now approved to be used in patients without a history of DM for cardioprotective benefits in HF, it might be beneficial to know that this side effect is likely to occur in the DM population.

Conclusions:

Would change "implicated" to "SGLTis are not only used in … ".
The conclusion goes on to emphasize the threat of EDKA although data in the non-diabetic population is limited. It may be useful to keep that open-ended and the need for further studies in that particular population.

Is the background of the case’s history and progression described in sufficient detail?

Yes
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?

Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?

Yes
Is the case presented with sufficient detail to be useful for other practitioners?

Yes

Competing Interests

I was a co-author with Irina Balan on a meta-analysis that is being considered for publication at this time. This project included multiple co-authors from various institutions and I have not directly interacted with Dr. Balan nor do I know Dr. Balan personally. The manuscript we worked on was edited independently with each co-author in charge of a separate section. The current article was not discussed with me prior to my receiving an invitation to review it and I have not had any contact with Dr. Balan about this manuscript. Additionally, this review was primarily performed by a resident physician (Namratha Meda) and I supervised her in this process without influencing any constructive or critical review points. Therefore, while I have worked with Dr. Balan in the past (indirectly), I feel like we have provided an objective and unbiased review.

Reviewer Expertise

Internal Medicine

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (0)

[1] 1. Genuardi MV, Mather PJ: The dawn of the four-drug era? SGLT2 inhibition in heart failure with reduced ejection fraction. Ther. Adv. Cardiovasc. Dis. 2021 Jan-Dec; 15: 175394472110026. PubMed Abstract | Publisher Full Text | Free Full Text

[2] 2. Lahnwong S, Chattipakorn SC, Chattipakorn N: Potential mechanisms responsible for cardioprotective effects of sodium–glucose co-transporter 2 inhibitors. Cardiovasc. Diabetol. 2018; 17: 101. Publisher Full Text

[3] 3. Zeng Q, Zhou Q, Liu W, et al.: Mechanisms and Perspectives of Sodium-Glucose Co-transporter 2 Inhibitors in Heart Failure. Front Cardiovasc Med. 2021 Feb 10; 8: 636152. PubMed Abstract | Publisher Full Text | Free Full Text

[4] 4. Ferrannini E, Baldi S, Frascerra S, et al.: Shift to Fatty Substrate Utilization in Response to Sodium-Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes. Diabetes. 2016 May; 65(5): 1190–1195. Epub 2016 Feb 9. PubMed Abstract | Publisher Full Text

[5] 5. Chambergo-Michilot D, Tauma-Arrué A, Loli-Guevara S: Effects and safety of SGLT2 inhibitors compared to placebo in patients with heart failure: A systematic review and meta-analysis. Int J Cardiol Heart Vasc. 2020 Dec 11; 32: 100690. PubMed Abstract | Publisher Full Text | Free Full Text

[6] 6. Ogawa W, Sakaguchi K: Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. J Diabetes Investig. 2016 Mar; 7(2): 135–138. Epub 2015 Sep 6. PubMed Abstract | Publisher Full Text | Free Full Text

[7] 7. Yu X, Zhang S, Zhang L: Newer Perspectives of Mechanisms for Euglycemic Diabetic Ketoacidosis. Int. J. Endocrinol. 2018 Oct 2; 2018: 1–8. PubMed Abstract | Publisher Full Text | Free Full Text

[8] 8. Nasa P, Chaudhary S, Shrivastava PK, et al.: Euglycemic diabetic ketoacidosis: A missed diagnosis. World J. Diabetes. 2021 May 15; 12(5): 514–523. PubMed Abstract | Publisher Full Text | Free Full Text

[9] 9. Clark A, Mohammed AS, Raut A, et al.: Prevalence and Clinical Characteristics of Adults Presenting With Sodium-Glucose Cotransporter-2 Inhibitor-Associated Diabetic Ketoacidosis at a Canadian Academic Tertiary Care Hospital. Can. J. Diabetes. 2021 Apr; 45(3): 214–219. Epub 2020 Aug 21. PubMed Abstract | Publisher Full Text

[10] 10. Guirguis H, Beroukhim Afrahimi S, Pham C: The Use of SGLT-2 Inhibitors Coupled With a Strict Low-Carbohydrate Diet: A Set-Up for Inducing Severe Diabetic Ketoacidosis. Clin Med Insights Case Rep. 2022 Apr 8; 15: 117954762210900. PubMed Abstract | Publisher Full Text | Free Full Text

[11] 11. Pereira MJ, Eriksson JW: Emerging Role of SGLT-2 Inhibitors for the Treatment of Obesity. Drugs. 2019 Feb; 79(3): 219–230. PubMed Abstract | Publisher Full Text | Free Full Text

[12] 12. Packer M, Anker SD, Butler J, et al.: EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N. Engl. J. Med. 2020 Oct 8; 383(15): 1413–1424. Epub 2020 Aug 28. PubMed Abstract | Publisher Full Text

[13] 13. Giorgino F, Vora J, Fenici P, et al.: Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk. Cardiovasc. Diabetol. 2020 Nov 22; 19(1): 196. PubMed Abstract | Publisher Full Text | Free Full Text

[14] 14. Mikhail N: Place of sodium-glucose co-transporter type 2 inhibitors for treatment of type 2 diabetes. World J. Diabetes. 2014 Dec 15; 5(6): 854–859. PubMed Abstract | Publisher Full Text | Free Full Text

[15] 15. Chacko B, Whitley M, Beckmann U, et al.: Postoperative euglycaemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitors (gliflozins): a report of two cases and review of the literature. Anaesth. Intensive Care. 2018; 46(2): 215–219. Publisher Full Text

[16] 16. Dull RB, Spangler ML, Knezevich EL, et al.: Euglycemic Diabetic Ketoacidosis Associated With Sodium-Glucose Cotransporter Type 2 Inhibitors in Patients With Type 2 Diabetes Mellitus Receiving Oral Therapy. J. Pharm. Pract. 2019; 32(2): 240–243. Publisher Full Text

[17] 17. Elshimy G, Correa R: Sudden-onset Hypoglycemia Following Fluid Replacement in a Patient with Dapagliflozin-induced Diabetic Ketoacidosis Without Prior Insulin Use: Case Report. Cureus. 2019; 11(8): e5448. Published 2019 Aug 21. Publisher Full Text

[18] 18. Adachi J, Inaba Y, Maki C: Euglycemic Diabetic Ketoacidosis with Persistent Diuresis Treated with Canagliflozin. Intern. Med. 2017; 56(2): 187–190. Publisher Full Text

[19] 19. Miwa M, Nakajima M, Kaszynski RH, et al.: Prolonged euglycemic diabetic ketoacidosis triggered by a single dose of sodium-glucose cotransporter 2 inhibitor. BMJ Case Rep. 2020; 13(10): e235969. Published 2020 Oct 7. Publisher Full Text

[20] 20. Lee IH, Ahn DJ: Dapagliflozin-associated euglycemic diabetic ketoacidosis in a patient with type 2 diabetes mellitus: A case report. Medicine (Baltimore). 2020; 99(21): e20228. Publisher Full Text

[21] 21. Rafey MF, Butt A, Coffey B, et al.: Prolonged acidosis is a feature of SGLT2i-induced euglycaemic diabetic ketoacidosis [published online ahead of print, 2019 Sep 27]. Endocrinol. Diabetes Metab. Case Rep. 2019; 2019: 19–0087. Publisher Full Text

[22] 22. Kitahara C, Morita S, Kishimoto S, et al.: Early detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes: A case report. J Diabetes Investig. 2021; 12(4): 664–667. Publisher Full Text

[23] 23. Diaz-Ramos A, Eilbert W, Marquez D: Euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitor use: a case report and review of the literature. Int. J. Emerg. Med. 2019; 12(1): 27. Published 2019 Sep 5. Publisher Full Text

[24] 24. Turner J, Begum T, Smalligan RD: Canagliflozin-Induced Diabetic Ketoacidosis: Case Report and Review of the Literature. J. Investig. Med. High Impact Case Rep. 2016; 4(3): 232470961666323. Published 2016 Aug 29. Publisher Full Text

[25] 25. Mistry S, Eschler DC: Euglycemic Diabetic Ketoacidosis Caused by SGLT2 Inhibitors and a Ketogenic Diet: A Case Series and Review of Literature. AACE Clin Case Rep. 2020; 7(1): 17–19. Published 2020 Dec 28. Publisher Full Text

[26] 26. Sethi SM, Vohra M, Ali SA: EUGLYCEMIC DIABETIC KETOACIDOSIS (EDKA) IN A PATIENT RECEIVING DAPAGLIFLOZIN. Acta Endocrinol (Buchar). 2021; 17(2): 266–269. Publisher Full Text

Case Report: Euglycemic diabetic ketoacidosis led by empagliflozin: A case report and literature review

Abstract

Keywords

Introduction

Case presentation

Table 1. Laboratory findings on blood cell counts, blood chemistry, arterial blood gas and urine studies.

Discussion

Table 2. Previously published cases of SGLT2i induced diabetic ketoacidosis.

Conclusions

Key points

Consent

Data availability

References

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