Euglycemic diabetic ketoacidosis following traumatic brain injury.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels by reducing glucose reabsorption in the kidneys, which can lead to ketogenesis. Euglycemic diabetic ketoacidosis (DKA) is a rare but potentially life-threatening complication of SGLT2 inhibitors that can be triggered by trauma. However, the absence of significant hyperglycemia can delay its diagnosis and treatment, which may lead to detrimental consequences. Herein, we report a case of euglycemic DKA following traumatic brain injury in a patient with type 2 diabetes who was taking an SGLT2 inhibitor. Delayed recognition of euglycemic DKA in this case led to progressive metabolic deterioration. This report emphasizes the importance of promptly suspecting, diagnosing, and treating euglycemic DKA in patients with traumatic injuries who exhibit high anion-gap metabolic acidosis, ketonuria, and glucosuria-even if they do not have significant hyperglycemia.

Euglycemic Diabetic Ketoacidosis Caused by Alcoholic Pancreatitis and Starvation Ketosis.

Starvation ketosis and pancreatitis are uncommon and underrecognized etiologies of euglycemic diabetic ketoacidosis (DKA). Euglycemic DKA is associated commonly with pregnancy, use of insulin en route to the hospital, and use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors. A 58-year-old male with past medical history of type II diabetes mellitus and alcoholism presented with chief complaint of nausea, vomiting, and poor oral intake for several weeks. Despite extensive history of diabetes and no recent SGLT-2 inhibitor use, his labs were consistent with euglycemic DKA. His imaging and clinical history also confirmed alcoholic pancreatitis. The patient was admitted for euglycemic DKA secondary to starvation ketosis and alcoholic pancreatitis. His anion gap and beta-hydroxybutyrate rapidly cleared with initiation of the DKA protocol. This case teaches us that clinicians should consider early initiation of the DKA protocol even in the setting of euglycemia, when a patient presents with high-anion-gap metabolic acidosis, a high beta-hydroxybutyrate level, and a clinical picture of pancreatitis and starvation.

The effect of preoperative sodium-glucose cotransporter 2 inhibitors on the incidence of perioperative metabolic acidosis: A retrospective cohort study.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors are a novel class of anti-hyperglycemic agents. Although several cases of perioperative euglycemic diabetic ketoacidosis have been linked to these medications, the association remains unclear. This study aimed to examine the association between sodium-glucose cotransporter 2 inhibitor use and the incidence of perioperative metabolic acidosis with euglycemia, the surrogating outcome of perioperative euglycemic diabetic ketoacidosis. METHOD: This was a retrospective, matched cohort study, which was conducted in the intensive care unit of a tertiary care facility in Japan. We identified patients aged 20 years or older with diabetes mellitus who received pharmacologic therapy and were admitted to the intensive care unit after elective surgery between April 2014 and March 2019. We extracted the following data from the electronic medical record for matching: age, sex, surgery year, surgical site, hemoglobin A1c level, and prescription for sodium-glucose cotransporter 2 inhibitors. Eligible patients were divided into two groups, those who were prescribed sodium-glucose cotransporter 2 inhibitors (SGLT2-i group) and those who were not (control group). For each patient in the SGLT2-i group, we randomly selected four patients from the control group matched for the extracted characteristics. The primary outcome was the incidence of metabolic acidosis with an elevated anion gap and euglycemia. The secondary outcome was the lowest pH value of each patient during their ICU stay. RESULTS: A total of 155 patients were included in this study. Patients receiving sodium-glucose cotransporter 2 inhibitors had comparable characteristics to control participants; however, the proportions of patients undergoing dialysis were not similar. Metabolic acidosis with euglycemia was seen in 7/31 (22.6%) patients receiving sodium-glucose cotransporter 2 inhibitors and in 10/124 (8.1%) control patients (p = 0.047). CONCLUSIONS: This study shows that the use of sodium-glucose cotransporter 2 inhibitors is associated with a significantly higher incidence of metabolic acidosis with euglycemia. Patients receiving sodium-glucose cotransporter 2 inhibitors who are scheduled to undergo invasive surgical procedures should be closely monitored for the development of euglycemic diabetic ketoacidosis.

Euglycemic Diabetic Ketoacidosis Associated With Sodium-Glucose Cotransporter-2 Inhibitors After Cardiac Surgery: A Review of Current Literature.

There is growing evidence to support the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for type 2 diabetes mellitus (T2DM) and the management of heart failure. As such, more patients undergoing cardiac surgery are on SGLT2-inhibitor therapy. Despite the numerous benefits of SGLT2 inhibitors on cardiac health, they can be associated with an increased risk of diabetic ketoacidosis, often with normal glucose levels (euglycemic diabetic ketoacidosis or EDKA), which potentially can be detrimental in this vulnerable patient population. In this narrative review, the authors discuss 17 papers that described EDKA in perioperative cardiac surgical patients. The authors discuss suggested preventative measures and management options, with a particular emphasis on raising the clinical awareness of the care teams toward this complication. SGLT2 inhibitor-induced EDKA is a medical emergency that can be difficult to identify in the postcardiac surgical patient due to the overlap of signs and symptoms with other frequent scenarios in these patients. A reduction in SGLT2 inhibitor-associated EDKA can be mitigated by the appropriate perioperative discontinuation of the medication, clinical awareness, and early investigation to diagnose the condition, with emphasis on serum ß-hydroxybutyrate. Future quality improvement initiatives are needed to assist in reducing EDKA in patients taking SGLT2 inhibitors in the perioperative surgical setting.

Predisposing factors for the development of diabetic ketoacidosis with lower than anticipated glucose levels in type 2 diabetes patients on SGLT2-inhibitors: a review.

PURPOSE: SGLT2-inhibitors (SGLT-2i) have been linked to the risk of potential life-threatening diabetic ketoacidosis (DKA). The U.S. Food and Drug Administration and the European Medicines Agency issued warnings in 2015 and 2016 respectively on the predisposing factors to the development of DKA in individuals on an SGLT2i. New predisposing factors to DKA are still being discovered with the use of SGLT-2i. The list by FDA and EMA is yet to be updated. This article aims to provide a holistic list that includes the newer factors that have been implicated in the development of DKA. The overall aim is to guide physicians in prescribing this class of drugs for type 2 diabetes mellitus (T2D). METHOD: A search was done using PUBMED, Google Scholar, and Directory of Open Access Journals with the following words: SGLT-2 Inhibitors AND Ketoacidosis were entered. We included articles from 2000 to 2020, those in English, those involving any of the approved SGLT2i medications in T2D patients, and studies that focused on DKA linked to SGLT-2i. These articles were reviewed, and relevant data extracted and compiled. RESULTS AND CONCLUSION: The review has revealed that predisposing factors include (excess) alcohol consumption, female gender, starvation due to illness or fasting, withholding the use of SGLT2i for less than 48 h peri-operatively, and the existence of a variations in the expression of SGLT2 receptors. Patients should be advised on "sick day rules," and if a patient becomes unwell while on an SGLT2i, they should be advised to withhold the medication for the duration of the intercurrent illness.

Euglycemic diabetic ketoacidosis: Etiologies, evaluation, and management.

INTRODUCTION: Diabetic ketoacidosis is an endocrine emergency. A subset of diabetic patients may present with relative euglycemia with acidosis, known as euglycemic diabetic ketoacidosis (EDKA), which is often misdiagnosed due to a serum glucose <250 mg/dL. OBJECTIVE: This narrative review evaluates the pathogenesis, diagnosis, and management of EDKA for emergency clinicians. DISCUSSION: EDKA is comprised of serum glucose <250 mg/dL with an anion gap metabolic acidosis and ketosis. It most commonly occurs in patients with a history of low glucose states such as starvation, chronic liver disease, pregnancy, infection, and alcohol use. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, which result in increased urinary glucose excretion, are also associated with EDKA. The underlying pathophysiology involves insulin deficiency or resistance with glucagon release, poor glucose availability, ketone body production, and urinary glucose excretion. Patients typically present with nausea, vomiting, malaise, or fatigue. The physician must determine and treat the underlying etiology of EDKA. Laboratory assessment includes venous blood gas for serum pH, bicarbonate, and ketones. Management includes resuscitation with intravenous fluids, insulin, and glucose, with treatment of the underlying etiology. CONCLUSIONS: Clinician knowledge of this condition can improve the evaluation and management of patients with EDKA.

Diabetes: From Research to Clinical Practice.

The number of people living with diabetes, the number of deaths attributable to it, and the cost of treating the disease and its complications are increasing exponentially. Centuries of research led to the discovery of insulin and other drugs based on pathophysiology from "the triumvirate to ominous octet". The agonists of the glucagon-like peptide-1 (GLP-1) receptor, and the inhibitors of the sodium-glucose transport protein 2 (SGLT2) are the new drugs that improve cardiovascular outcomes and provide renal protection, and they are being used increasingly for evidence-based treatment of type 2 diabetes. Bariatric surgery, when indicated, results in excellent weight- and metabolic-control, and in many instances even remission of diabetes. Technological advances like Flash glucose monitoring, continuous subcutaneous insulin infusion (CSII), and continuous glucose monitoring (CGM) have improved glycemic control, reduced episodes of severe hypoglycemia, and improved quality of life. For the treatment of diabetic macular edema intravitreal injection of several anti-VEGF agents are being used. Numerous people living in the middle- and low-income countries cannot afford the costs of care of diabetes. Institutions like the World Health Organization, the World Bank and the International Monetary Fund should roll out plans to convince the politicians to invest more in improving the diabetes care facilities.

SGLT-2 Inhibitors in Heart Failure: Guide for Prescribing and Future Perspectives.

PURPOSE OF REVIEW: Heart failure is responsible for a significant part of diabetes-associated cardiovascular mortality and morbidity. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are novel agents approved for the treatment of diabetes mellitus; in recent clinical trials, these agents have shown a significant reduction in cardiovascular death and hospitalization secondary to heart failure. RECENT FINDINGS: Clinical trials with specific heart failure outcomes have shown the benefit of SGLT-2 inhibitors in reducing the mortality and morbidity associated with heart failure. The guidelines for the management of diabetes mellitus recommend the preferential use of SGLT-2 inhibitors in patients with a history of cardiovascular disease. SGLT-2 inhibitors are potential game changers in the treatment of heart failure. Guidelines for prescription of these agents help assess risk-benefit analysis and personalize treatment for maximal benefit.

Severe euglycemic diabetic ketoacidosis of multifactorial etiology in a type 2 diabetic patient treated with empagliflozin: case report and literature review.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a relatively novel class of oral medications for the treatment of Type 2 DM with a generally acceptable safety profile. However, these agents have been associated with rare events of a serious and potentially life-threatening complication named euglycemic diabetic ketoacidosis (euDKA). euDKA is not identical with the typical diabetic ketoacidosis, as it often presents with serious metabolic acidosis but only mild to moderate glucose and anion gap elevation. CASE PRESENTATION: We report a case of a 51-year old female with Type 2 DM treated with an SGLT-2 inhibitor, developing severe metabolic acidosis with only mild blood glucose elevation after a routine surgery. A careful evaluation of involved factors led to the diagnosis of euDKA, followed by cautious application of simple therapeutic measures that resulted in complete restoration of acidosis and glycemic control in less than 48-h. CONCLUSIONS: Euglycemic ketoacidosis is a rare but rather serious complication of SGLT-2 inhibitors use, often with a multifactorial etiology. Its atypical presentation requires a high level of awareness by physicians as early recognition of this complication can quickly and safely restore acid-base balance.

Challenges in the Diagnosis of Euglycemic Diabetic Ketoacidosis in a Patient With Multiple Sclerosis Taking a Sodium-Glucose Cotransporter 2 Inhibitor.

BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been reported to cause euglycemic diabetic ketoacidosis (eDKA), a diagnosis that may be challenging to establish in the emergency department (ED). CASE REPORT: This is a case report of missed eDKA in a 47-year-old male taking empagliflozin (a SGLT2 inhibitor) that presented to the ED with generalized weakness. His past medical history included multiple sclerosis (MS) diagnosed 4 years ago and type 2 diabetes mellitus. The patient attributed his weakness to MS. His neurologist was consulted and agreed with the plan to discharge the patient with diagnoses of asthenia and dehydration and a prescription of prednisone. The patient returned to the ED the next day with similar symptoms and was admitted to the hospital for treatment of eDKA. He was eventually treated per the hospital diabetic ketoacidosis (DKA) protocol and discharged home with instructions to discontinue empagliflozin. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The increasing utilization of SGLT2 inhibitor in patients with type 2 diabetes mellitus will inevitably lead to more cases of eDKA seen in the ED. Emergency physicians need to consider this diagnosis in patients taking these medications that present with symptoms including weakness, nausea, vomiting, abdominal pain, and dehydration. Patients taking these medications should be warned about these symptoms, especially because they may be falsely reassured by relatively low plasma glucose levels on home glucometer readings.

Inpatient Glycemic Management of the Pregnant Patient.

PURPOSE OF REVIEW: There is a rising prevalence of type 1 diabetes (T1DM), type 2 diabetes (T2DM), and gestational diabetes (GDM) in pregnancy. Reaching and maintaining glycemic targets during and after this time are important for both the health of the mother and her baby. RECENT FINDINGS: Based on recently published guidelines from various societies, we review the diagnosis of diabetes in pregnancy, types of therapies available to maintain euglycemia, important keys to management of T1DM, T2DM, and GDM, and strategies for reaching inpatient glycemic targets during the peripartum period. Care for pregnant patients with T1DM is especially challenging, and providers should be aware of the varying insulin requirements at different stages of pregnancy and how to reduce hypoglycemia and avoid diabetic ketoacidosis. Insulin sensitivity fluctuates throughout pregnancy due to physiologic changes, especially during labor and delivery and immediately post-partum. We review recommendations regarding how to manage this dynamic time and present our own institution's inpatient management protocol. Finally, we review management of diabetes post-partum, including medications, breast-feeding, and continued monitoring and screening. With the collaborative efforts of the patient and an interdisciplinary team and in-depth knowledge of the most up-to-date management principles, it is possible to achieve euglycemia during this critical time of a mother and baby's life.

Euglycemic Diabetic Ketoacidosis Secondary to Dapagliflozin Use: A Case Report.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a novel class of oral antihyperglycemic agents. They are associated with rare cases of euglycemic diabetic ketoacidosis (DKA), which presents a diagnostic challenge in the emergency department (ED) and potentially severe consequences if missed. CASE REPORT: A 53-year-old man with type 2 diabetes mellitus and a recent Roux-en-Y gastric bypass surgery presented to the ED with nausea, vomiting, and generalized abdominal pain. His medications included dapagliflozin. Work-up revealed anion-gap acidosis, which prompted us to send serum ketone levels despite a blood glucose level of 9.8 mmol/L (162 mg/dL). The patient was ultimately diagnosed with euglycemic DKA. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients on SGLT2 inhibitors may present in DKA despite having normal blood glucose levels. It is important for emergency physicians to be aware of this phenomenon in all SGLT2-inhibitor users, as a delay in the diagnosis of DKA can be life threatening.

Euglycemic Diabetic Ketoacidosis with Elevated Acetone in a Patient Taking a Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitor.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitor medications are a class of antihyperglycemic agents that increase urinary glucose excretion by interfering with the reabsorption of glucose in the proximal renal tubules. In May of 2015, the U.S. Food and Drug Administration released a warning concerning a potential increased risk of ketoacidosis and ketosis in patients taking these medications. CASE REPORT: We present a case of a 57-year-old woman with type 2 diabetes mellitus taking a combination of canagliflozin and metformin who presented with progressive altered mental status over the previous 2 days. Her work-up demonstrated a metabolic acidosis with an anion gap of 38 and a venous serum pH of 7.08. The serum glucose was 168 mg/dL. The urinalysis showed glucose > 500 mg/dL and ketones of 80 mg/dL. Further evaluation demonstrated an elevated serum osmolality of 319 mOsm/kg and an acetone concentration of 93 mg/dL. She was treated with intravenous insulin and fluids, and the metabolic abnormalities and her altered mental status resolved within 36 h. This was the first episode of diabetic ketoacidosis (DKA) for this patient. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Diabetic patients on SGLT2 inhibitor medications are at risk for ketoacidosis. Due to the renal glucose-wasting properties of these drugs, they may present with ketoacidosis with only mild elevations in serum glucose, potentially complicating the diagnosis. Acetone is one of the three main ketone bodies formed during DKA and it may be present at considerable concentrations, contributing to the serum osmolality.

Canagliflozin-associated Diabetic Ketoacidosis with Lower-than-anticipated Glucose Levels.

The Food and Drug Administration has approved the use of sodium-glucose co-transporter 2 (SGLT-2) inhibitors for use in Type II diabetics. These are a relatively new addition to the armamentaria of diabetes management. Postmarketing surveillance is a witness to several side effects, a morbid one being ketoacidosis. Herein is discussed a scenario of a Type II diabetic who presented with substantial ketoacidosis without significant hyperglycemia. The absence of the customary precipitating factors and the presence of a recent introduction of canagliflozin, a SGLT-2 inhibitor to the diabetes prescription, hinted at the causal relationship. Of note, she had never experienced diabetic ketoacidosis in the past prior to commencement of SGLT-2 inhibitor therapy. As clinicians, we need to be aware of the treatment-emergent adverse effect of this relatively new class of diabetic treatment.

Diabetic acidosis with severe fetal hypoxia in pregnancy: Narrative review and case study.

Diabetic ketoacidosis (DKA) in pregnancy could be a disastrous event with increased maternal and perinatal morbidity and mortality. DKA can occur with a normal blood glucose level, known as euglycemic DKA. It particularly affects pregnant women with type I diabetes. Here, we report the case of a 28 year-old primigravid patient, with a diagnosis of type 1 diabetes for 8 years. This patient consulted our department at 29 weeks of gestation with a previous history of headaches, vomiting and diarrhea for 9 h. Blood glucose level was 8.8 mmol/L with a ketone test positive (>15 mg/dL). Blood test showed high anion gap (17.9 mmol/L) with low serum bicarbonate rate (21 mmol/L). Systemic examination and fetal heart rate (FHR) was reassuring. The patient was subsequently discharged. She returned to the clinic 19 h later with further symptoms of nausea, polyuria-polydipsia, asthenia and a weight loss of 4 kg since the day before. Blood sugar was 14.3 mmol/L and a ketone test was strongly positive. Cardiotocography showed fetal tachycardia and repeated late decelerations. A diagnosis of DKA was made and emergency cesarean was performed for fetal distress. At delivery, pH was acidosis (pH: 7.02, lactates: 6.2). The patient was successfully treated with intravenous hydration and insulin. Neonatal evolution was favorable. Pregnant women with type I diabetes can develop euglycemic DKA. Early recognition and prompt treatment could help prevent severe maternal and fetal adverse outcomes. DKA in pregnant women can induce fetal acidosis with abnormal FHR. In this situation, a cesarean can be performed to improve neonatal outcome even inducing a premature delivery. Prolonged pregnancy can lead to irreversible neonatal brain abnormalities.

From Sweet to Sour: SGLT-2-Inhibitor-Induced Euglycemic Diabetic Ketoacidosis.

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are highly selective, effective, and generally well-tolerated antihyperglycemic agents targeting the SGLT-2 transmembrane protein. Despite being primarily registered for diabetes treatment, due to their cardiorenal protective properties, SGLT-2 inhibitors caused a paradigm shift in the treatment of other diseases on the cardiorenal spectrum, becoming a fundamental part of heart failure and chronic kidney disease management. With their rapidly increasing use, there are also increased reports of a rare, often under-recognised and potentially deadly side effect, SGLT-2-inhibitor-induced euglycemic diabetic ketoacidosis (EDKA). The primary pathophysiological process behind its multifactorial aetiology comprises glucosuria and osmotic diuresis, which produce a significant carbohydrate deficit, leading to an increase in the glucagon-insulin ratio, thus resulting in accelerated ketogenesis. Although EDKA has a similar clinical presentation as diabetic ketoacidosis (DKA), the absence of the high glucose levels typically expected for DKA and the presence of urine ketone reabsorption contribute to a significant delay in its recognition and timely diagnosis. Given the broad use of SGLT-2 inhibitors, increased awareness, early recognition, and prompt identification of precipitating factors are essential. In this narrative review, we comprehensively explore the pathophysiological mechanisms of SGLT-2-inhibitor-induced EDKA, analyse its clinical manifestation, and identify the most common triggers for its development. We also discuss EDKA management and preventive strategies.

Life-threatening coronary vasospasm in patients with type 2 diabetes with SGLT2 inhibitor-induced euglycemic ketoacidosis: a report of two consecutive cases.

Euglycemic diabetic ketoacidosis (eDKA) has emerged as an adverse event associated with sodium-glucose transporter-2 inhibitors (SGLT2i). We present two consecutive cases of SGLT2i-induced eDKA, both manifested as life-threatening coronary vasospastic angina (VSA). Case 1: A 64-year-old male overweight patient with type 2 diabetes (BMI 28.2 kg/m2), treated with dapagliflozin 5 mg daily for 6 months and a restricted diet for 2 months, experienced loss of consciousness following severe chest pain while driving, resulting in a traffic accident: plasma glucose, 163 mg/dL; urine ketones, (+++); bicarbonate (HCO3-), 13.2 mmol/L; and total ketone body, 1539 µmol/L. Coronary angiography (CAG) performed on day 5 revealed diffusely spastic coronary arteries with 90% stenosis in the right coronary artery, leading to the diagnosis of VSA in the presence of coronary atherosclerosis. Case 2: A 63-year-old male patient with type 2 diabetes (BMI 22.2 kg/m2) experienced severe chest discomfort and faintness following 2 months of chest pain while on dapagliflozin 10 mg daily for 1 year: plasma glucose, 112 mg/dL; urine ketones, (+++); HCO3-, 15.3 mmol/L; and total ketone body, 10,883 µmol/L. CAG performed on day 10 revealed no organic stenosis but diffusely spastic coronary arteries in response to coronary ergonovine infusion, confirming the diagnosis of VSA. SGLT2i has the potential to inhibit acetylcholine and butyrylcholine esterase activities, leading to reduced scavenging of acetylcholine and possible induction of coronary vasospasm. These cases highlight the association between life-threatening VSA and SGLT2i-induced eDKA.

Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitor-Related Euglycemic Diabetic Ketoacidosis: A Case Series.

Objectives: Sodium-glucose transporter-2 inhibitors (SGLT2i) are commonly used for the treatment of Type 2 Diabetes Mellitus, offering additional benefits in non-diabetic patients with conditions such as chronic kidney disease and heart failure. However, SGLT2i have been associated with an increased risk of euglycemic diabetic ketoacidosis (DKA). This case series describes three cases of patients who developed euglycemic DKA while taking SGLT2i. Key Findings: Each of the three patients with euglycemic DKA were taking SGLT2i for the treatment of diabetes and all had additional risk factors for the development of DKA. These factors included reduced oral intake, major acute illness, chronic pancreatitis, and a history of previous DKA episodes. Unfortunately, the absence of hallmark symptoms like hyperglycemia, polyuria, and polydipsia led to delayed diagnosis of euglycemic DKA in two of the three patients. Conclusion: Early recognition of risk factors and a high level of suspicion are critical in identifying euglycemic DKA in patients taking SGLT2i. Healthcare providers should conduct thorough medication reconciliation upon admission and closely monitor patients for concurrent issues, especially in cases of minimal oral intake, acute illnesses, and chronic pancreatitis. Prompt diagnosis and management of euglycemic DKA can significantly improve patient outcomes.