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

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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." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/11-1448", "name": "Case Report: Euglycemic diabetic ketoacidosis led by empagliflozin:..." } } ] } Home Browse Case Report: Euglycemic diabetic ketoacidosis led by empagliflozin:... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article 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 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ 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 https://orcid.org/0000-0001-6688-2534 1 , V Lakshmi N Priyanka Ganapathiraju 2 , Sudha Dirisanala 3 , Shafaq Taj 4 , Pratikkumar Vekaria https://orcid.org/0000-0002-2379-5980 5 Irina Balan https://orcid.org/0000-0001-6688-2534 1 , V Lakshmi N Priyanka Ganapathiraju 2 , [...] Sudha Dirisanala 3 , Shafaq Taj 4 , Pratikkumar Vekaria https://orcid.org/0000-0002-2379-5980 5 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 DETAILS 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. READ ALL READ LESS Keywords sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin, euglycemic diabetic ketoacidosis (EDKA), chronic heart failure, diabetes mellitus Corresponding Author(s) Irina Balan ( [email protected] ) Close 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 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 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 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 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. , 2018 15 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. , 2018 15 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. , 2022 10 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. , 2017 16 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. , 2019 17 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. 2017 18 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. , 2020 19 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. , 2020 20 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. , 2019 21 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. , 2019 21 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. , 2020 22 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. , 2019 23 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. , 2016 24 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. 2020 25 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, 2020 25 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. , 2021 26 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. 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Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 07 Dec 2022 ADD YOUR COMMENT Comment 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. Article Versions (1) version 1 Published: 07 Dec 2022, 11:1448 https://doi.org/10.12688/f1000research.127382.1 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. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article 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 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 07 Dec 2022 Views 0 Cite How to cite this report: Ata F. Reviewer Report For: 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/10.5256/f1000research.139883.r240271 ) The direct URL for this report is: https://f1000research.com/articles/11-1448/v1#referee-response-240271 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 07 Feb 2024 Fateen Ata , Hamad General Hospital, Doha, Doha, Qatar Not Approved VIEWS 0 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 READ ALL 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. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Ata F. Reviewer Report For: 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/10.5256/f1000research.139883.r240271 ) The direct URL for this report is: https://f1000research.com/articles/11-1448/v1#referee-response-240271 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Mahmood SN and Meda N. Reviewer Report For: 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/10.5256/f1000research.139883.r158062 ) The direct URL for this report is: https://f1000research.com/articles/11-1448/v1#referee-response-158062 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details 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 VIEWS 0 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 READ ALL 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. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Mahmood SN and Meda N. Reviewer Report For: 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/10.5256/f1000research.139883.r158062 ) The direct URL for this report is: https://f1000research.com/articles/11-1448/v1#referee-response-158062 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 07 Dec 2022 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 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 Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Ata F. This is an open access peer review report 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. 07 Feb 2024 | for Version 1 Fateen Ata , Hamad General Hospital, Doha, Doha, Qatar 0 Views copyright © 2024 Ata F. This is an open access peer review report 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. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions 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. reply Respond to this report Responses (0) Ata F. Peer Review Report For: 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/10.5256/f1000research.139883.r240271) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/11-1448/v1#referee-response-240271 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2023 Mahmood S et al. This is an open access peer review report 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. 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 0 Views copyright © 2023 Mahmood S et al. This is an open access peer review report 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. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions 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. reply Respond to this report Responses (0) Mahmood SN and Meda N. Peer Review Report For: 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/10.5256/f1000research.139883.r158062) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. 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