Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, And Preventable Safety Concern With Sglt2 Inhibitors
The Case At Hand Recently, the U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication that warns of an increased risk of diabetic ketoacidosis (DKA) with uncharacteristically mild to moderate glucose elevations (euglycemic DKA [euDKA]) associated with the use of all the approved sodium–glucose cotransporter 2 (SGLT2) inhibitors (1). This Communication was based on 20 clinical cases requiring hospitalization captured between March 2013 and June 2014 in the FDA Adverse Event Reporting System database. The scarce clinical data provided suggested that most of the DKA cases were reported in patients with type 2 diabetes (T2D), for whom this class of agents is indicated; most likely, however, they were insulin-treated patients, some with type 1 diabetes (T1D). The FDA also identified potential triggering factors such as intercurrent illness, reduced food and fluid intake, reduced insulin doses, and history of alcohol intake. The following month, at the request of the European Commission, the European Medicines Agency (EMA) announced on 12 June 2015 that the Pharmacovigilance Risk Assessment Committee has started a review of all of the three approved SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) to evaluate the risk of DKA in T2D (2). The EMA announcement claimed that as of May 2015 a total of 101 cases of DKA have been reported worldwide in EudraVigilance in T2D patients treated with SGLT2 inhibitors, with an estimated exposure over 0.5 million patient-years. No clinical details were provided except for the mention that “all cases were serious and some required hospitalisation. Although [DKA] is usually accompanied by high blood sugar levels, in a number of these reports blood sugar levels were only moderately increased” (2). Wit Continue reading >>
Euglycemic Dka: It’s Not A Myth
Background: Diabetic ketoacidosis (DKA) is traditionally defined as a triad of hyperglycemia (>250mg/dL), anion gap acidosis, and increased plasma ketones. There is another entity that providers must be aware of known as euglycemic DKA (euDKA), which is essentially DKA without the hyperglycemia (Serum glucose <200 mg/dL). Euglycemic DKA is a rare entity that mostly occurs in patients with type 1 diabetes, but can possibly occur in type 2 diabetes as well. The exact mechanism of euDKA is not entirely known, but has been associated with partial treatment of diabetes, carbohydrate food restriction, alcohol intake, and inhibition of gluconeogenesis. euDKA, can also be associated with sodium-glucose cotransporter 2 (SGLT-2) inhibitor medications. These medications first came onto the market in 2013 and are FDA approved for the treatment of type 2 diabetes, however many physicians use them off-label for type I diabetes due to their ability to improve average glucose levels, reduce glycemic variability without increasing hypoglycemia, and finally promote weight loss. Does euDKA Exist even in Patients not Using SGLT-2 Inhibitors? The short answer is YES. Munro JF et al [5] reviewed a case series of 37 episodes of euDKA in a publication from 1973. Although, dated and not robust evidence some take home messages can be derived: All but one episode was in insulin dependent diabetics Vomiting was the most frequent symptom of euDKA in 32% of patients Management in most cases consisted of: Intravenous fluids and electrolyte replacement. No deaths occurred in this case series What are the Names of the SGLT-2 Inhibitors? Ipragliflozin (Suglat) – Approved in Japan Dapagliflozin (Farxiga) – 1st SGLT2 Inhibitor Approved; Approved in US Luseogliflozin (Lusefi) – Approved in Japan Tofo Continue reading >>
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Euglycemic Diabetic Ketoacidosis: The Clinical Concern Of Sglt2 Inhibitors
Euglycemic diabetic ketoacidosis is a post market warning in patients with type 1 diabetes and type 2 diabetes treated with SGLT-2 inhibitors. We report a case of a 39-year-old obese female with presumed type 2 diabetes for seven years who presented to the emergency department with three days of nausea, vomiting, and abdominal pain. Due to previous total non-adherence with a prescribed insulin regimen, she was recently started on canagliflozin and liraglutide. The diagnosis of euDKA was missed in the initial evaluation as the blood glucose level was only 167 mg/dL. Further work up showed severe metabolic acidosis with an anion gap of 25 and positive ketones in the urine. She was treated successfully with dextrose water 5%/half normal saline and an insulin drip. As part of the work up, she tested positive for glutamic acid decarboxylase autoantibodies. Given the increasing utilization of SGLT-2 inhibitors and the fact that patients can present with near-normal glycemia, the diagnosis can be missed. Vigilance with the use of SGLT-2 inhibitors is necessary to decrease morbidity and potentially mortality particularly in patients with long-standing type 2 diabetes associated with marked β-cell insufficiency, type 1 diabetes mellitus, or latent autoimmune diabetes of adult onset. Continue reading >>
Dka That Wasn't: A Case Of Euglycemic Diabetic Ketoacidosis Due To Empagliflozin | Oxford Medical Case Reports | Oxford Academic
Sodium glucose co-transporter (SGLT-2) inhibitor is a relatively new medication used to treat diabetes. At present, the Food and Drug Administration (FDA) has only approved three medications (canagliflozin, dapagliflozin and empagliflozin) in this drug class for the management of Type 2 diabetes. In May 2015, the FDA issued a warning of ketoacidosis with use of this drug class. Risk factors for the development of ketoacidosis among patients who take SGLT-2 inhibitors include decrease carbohydrate intake/starvation, acute illness and decrease in insulin dose. When identified, immediate cessation of the medication and administration of glucose must be done, and in some instances, starting an insulin drip might be necessary. We present a case of a patient with diabetes mellitus being on empagliflozin (SGLT-2 antagonist) who was admitted for acute cholecystitis. The hospital course was complicated by euglycemic diabetic ketoacidosis after being kept nothing per orem before a contemplated cholecystectomy. The management of diabetes has evolved since its discovery in 1910. A gamut of medications has become available to address the glycemic control among diabetics especially for Type 2 diabetics. Empagliflozin is a sodium glucose co-transporter (SGLT-2) inhibitor that has been approved by the Food and Drug Administraiton (FDA) in August 2014. It has been the latest drug approved in the drug class since 2013. This case highlights a case of euglycemic ketoacidosis with the use of empagliflozin. A 61-year-old female presented to her primary care doctor with right upper quadrant abdominal pain for a day. Her onlymedical history is diabetes Type 2 maintained on empagliflozin and diet controlled hypertension. Patient used to be on the combination of metforminrepaglinide but has bee Continue reading >>
A Can't Miss Ed Diagnosis: Euglycemic Dka
The FDA has approved these three SGLT2 inhibitors for Type 2 diabetics, and at times, they are prescribed off-label for Type 1. The mechanism involves decreasingglucose reabsorption in the nephrons proximal tubule (via inhibition of the sodium-glucose linked cotransporter-2 protein). This results in increased urinary excretion of glucose that is independent of the bodys insulin secretion.1 Other potential benefits of this class of medications include:13 In 2015 the FDA issued a warning, however, that SGLT2 inhibitors may cause ketoacidosis, urinary tract infections, and urosepsis.4 Since then, multiple case reports have been published showing an association between SGLT2 inhibitors and the development of euglycemic DKA. Euglycemic DKA is an uncommon and likely under-diagnosed phenomenon, best defined as DKA with alower than expected blood glucose (less than 250 mg/dL according to the American Diabetes Association).46 Potential precipitants, in addition to SGLT2 inhibitors, include:7 EPs may delay diagnosis, given the modest glucose levels at the time of presentation. This, however, is false reassurance because DKA is not defined by an absolute blood glucose. Interestingly, patients with euglycemic DKA may have a normal mental status despite marked ketoacidosis, and vomiting seems to be a common complaint.5 Euglycemic DKA treatment is the same as traditional DKA, and includes hydration, insulin, and supportive care. Patients with euglycemic DKA may also need a dextrose infusion given the lower glucose levels. SGLT2 Inhibitors and Euglycemic DKA: Mechanism The mechanisms by which SGLT2 inhibitors cause or predispose to euglycemic DKA are unclear and likely complex. SGLT2 inhibitors may lead to a decrease in either endogenous or exogenous insulin, and an increase in gluca Continue reading >>
A Case Of Canagliflozin Induced Euglycemic Diabetic Ketoacidosis: Rare But Significant
Keywords: Canagliflozin , Dka , Euglycemic DKA , Invokana , SGLT2 Inhibitor Case Presentation: A 54 year-old woman with a past medical history of hypertension and Type 2 diabetes mellitus treated with metformin and canagliflozin presented to the hospital with lethargy and malaise. She reported that her blood glucose was stable over the past 2 weeks with fingerstick glucoses ranging from 100-130mg/ dL. She had been vomiting the day prior to presentation with decreased oral intake. She denied alcohol use. Physical exam was significant for tachycardia, tachypnea, and lethargy. Her fingerstick glucose was 245 mg/dL and labs were notable for leukocytosis to 20.91 k/uL, sodium 121mmol/L, and high anion gap metabolic acidosis with bicarbonate of 11mmol/L, blood pH of 6.9, and elevated beta-hydroxybutyrate to 9.4 mmol/L. Her HgbA1c was 8.8%. Respiratory viral panel was positive for enterovirus. She was intubated for airway protection due to worsening lethargy and admitted to the intensive care unit for euglycemic diabetic ketoacidosis (DKA). The patient was treated with dextrose-based IV fluids, insulin drip and bicarbonate drip until her anion gap closed. She was then transitioned to basal and bolus insulin and maintained on sodium bicarbonate tablets until her ketoacidosis resolved. She was discharged on basal and bolus insulin, and canagliflozin was discontinued. Discussion: Euglycemic DKA is a rare variant of DKA, classified as mildly to moderately elevated glucose levels (<250 mg/ dL) combined with metabolic acidosis (bicarbonate <18) and ketosis (1). This variant is often under-recognized due to normal glucose levels and can be triggered by heavy alcohol consumption, decreased caloric intake, severe acute illness, and the use of sodium-glucose co-transporter 2 (SGLT2) in Continue reading >>
Risk Of Diabetic Ketoacidosis After Initiation Of An Sglt2 Inhibitor
To the Editor: Inhibitors of sodium–glucose cotransporter 2 (SGLT2) decrease plasma glucose by blocking the reabsorption of glucose at the proximal tubule.1,2 Case reports have suggested that SGLT2 inhibitors may be associated with an increased risk of diabetic ketoacidosis, which led to a warning from the Food and Drug Administration (FDA) in May 2015.3,4 The objective of our study was to assess the risk of diabetic ketoacidosis after the initiation of an SGLT2 inhibitor. Using a large claims database of commercially insured patients in the United States (Truven MarketScan), we identified a cohort of adult patients (≥18 years of age) who had newly started treatment with either an SGLT2 inhibitor or a dipeptidyl peptidase-4 (DPP4) inhibitor between April 1, 2013, and December 31, 2014 (before the FDA warning). DPP4 inhibitors were chosen as the comparator medication because they are similarly used as a second-line treatment for diabetes but have no known association with diabetic ketoacidosis. We excluded patients with human immunodeficiency virus infection, end-stage renal disease, cancer, type 1 diabetes, or past diabetic ketoacidosis. Our primary outcome was hospitalization for diabetic ketoacidosis (using the primary position code of the International Classification of Diseases, Ninth Revision) within 180 days after the initiation of an SGLT2 inhibitor or a DPP4 inhibitor. We censored data for patients at the time that they discontinued the initial medication, had the outcome, lost insurance coverage, or died. We used 1:1 propensity-score matching to balance 46 characteristics of the patients and Cox regression to estimate hazard ratios and 95% confidence intervals for diabetic ketoacidosis within 180 days after treatment initiation. Predefined sensitivity analy Continue reading >>
Best Case Ever 58 Euglycemic Dka
This is EM Cases Best Case Ever 58 – Euglycemic DKA with Walter Himmel, the walking encyclopedia of emergency medicine. It’s not only run of the mill DKA, starvation and alcoholic ketoacidosis that can cause a metabolic acidosis with elevated ketones. Euglycemic DKA can be caused by the newer diabetes medications sodium-glucose co-transporter 2 inhibitors like Canagliflozin; and it’s important to recognize this tricky diagnosis early and initiate treatment for DKA despite a normal serum glucose level, because DKA can lead to serious complications like renal failure, cerebral edema, ARDS, shock, and death. Podcast production, sound design and editing by Anton Helman; Written by Anton Helman, June 2017 Euglycemic DKA can occur in any diabetic and has been reported in the literature since the 1970’s, but there has recently been a rise in incidence of euglycemic DKA associated with sodium-glucose co-transporter 2 inhibitors (SGLT-2 inhibitors, or the “zins”) such as Canagliflozin, Dapagliflozin and Empagliflozin. When to suspect euglycemic DKA Any patient with Type 1 or 2 diabetes taking SGLT-2 inhibitors who presents with nausea, vomiting, SOB or malaise or is found to have a metabolic acidosis should have blood drawn for serum ketones. Triggers of euglycemic DKA are similar to the triggers for any DKA: Alcohol use, infection and reduced oral intake. Distinguishing euglycemic DKA from alcoholic DKA Alcoholic ketoacidosis may also present with nausea, vomiting, malaise, ketones and anion gap metabolic acidosis. The key differentiating factor besides the obvious history of heavy alcohol use vs a diabetic taking an SGLT-2 inhibitor, is that patients with alcoholic ketoacidosis tend to have frankly low glucose. How is treatment of euglycemic DKA different? In addit Continue reading >>
Euglycemic Diabetic Ketoacidosis With Persistent Diuresis Treated With Canagliflozin
Diabetic ketoacidosis is characterized by hyperglycemia, anion-gap acidosis, and increased plasma ketones. After the resolution of hyperglycemia, persistent diuresis is rare. We herein report the case of a 27-year-old Asian woman with type 2 diabetes who was treated with a sodium-glucose cotransporter 2 (SGLT2) inhibitor (canagliflozin) who developed euglycemic diabetic ketoacidosis and persistent diuresis in the absence of hyperglycemia. Physicians should consider euglycemic diabetic ketoacidosis in the differential diagnosis of patients treated with SGLT2 inhibitors. Continue reading >>
Sglt2 Inhibitor Diabetes Drugs May Cause Ketoacidosis: Fda
SGLT2 Inhibitor Diabetes Drugs May Cause Ketoacidosis: FDA The US Food and Drug Administration (FDA) warned today that sodium-glucose cotransporter-2 (SGLT2) inhibitors used to treat type 2 diabetes may lead to ketoacidosis requiring hospitalization. The warning includes the SGLT2 inhibitors canagliflozin (Invokana, Johnson & Johnson), dapagliflozin (Farxiga, AstraZeneca), and empagliflozin (Jardiance, Lilly/Boehringer), as well as three combination products that include an SGLT2 inhibitor: canagliflozin plus metformin (Invokamet, Johnson & Johnson), dapagliflozin plus metformin extended release (Xigduo XR, AstraZeneca), and empagliflozin plus linagliptin (Glyxambi, Lilly/Boehringer). A search of the FDA Adverse Event Reporting System database identified 20 cases of acidosis reported as diabetic ketoacidosis (DKA), ketoacidosis, or ketosis in patients treated with SGLT2 inhibitors from March 2013 to June 6, 2014, the FDA said . Ketoacidosis is not typically observed in patients with type 2 diabetes, the FDA notes, and the DKA case presentations were "atypical in that glucose levels were only mildly elevated at less than 200 mg/dL in some reports, while patients with type 1 diabetes who have DKA typically have glucose levels greater than 250 mg/dL." Signs of ketoacidosis include difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue and sleepiness. "Healthcare professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or symptoms; discontinue SGLT2 inhibitors if acidosis is confirmed; and take appropriate measures to correct the acidosis and monitor sugar levels," the FDA advises. In Half of Cases, No Triggering Factor for DKA In all cases, a diagnosis of DKA or ketoacidosis wa Continue reading >>
Severe Ketoacidosis Associated With Canagliflozin (invokana): A Safety Concern
Case Reports in Critical Care Volume 2016 (2016), Article ID 1656182, 3 pages 1Section of Pulmonary and Critical Care Medicine, Providence Hospital and Medical Center, 16001 W 9 Mile Road, Southfield, MI 48075, USA 2Department of Internal Medicine, Providence Hospital and Medical Center, 16001 W 9 Mile Road, Southfield, MI 48075, USA Academic Editor: Kurt Lenz Copyright © 2016 Alehegn Gelaye et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Canagliflozin (Invokana) is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor that was first introduced in 2013 for the treatment of type 2 diabetes mellitus (DM). Though not FDA approved yet, its use in type 1 DM has been justified by the fact that its mechanism of action is independent of insulin secretion or action. However, some serious side effects, including severe anion gap metabolic acidosis and euglycemic diabetic ketoacidosis (DKA), have been reported. Prompt identification of the causal association and initiation of appropriate therapy should be instituted for this life threatening condition. 1. Introduction More than 5 million patients are admitted annually to intensive care units (ICUs) in the United States. A number of life threatening medical conditions, including diabetic ketoacidosis, can be associated with metabolic acidosis. Metabolic acidosis may also arise from several drugs and toxins through a variety of mechanisms. Since approval of the first-in-class drug in 2013, data have emerged suggesting that Sodium Glucose Transporter-2 (SGLT-2) inhibitors, including canagliflozin, may lead to diabetic ketoacidosis [1]. We pre Continue reading >>
Euglycemic Diabetic Ketoacidosis Due To Canagliflozin In A Patient With An Uncertain Diagnosis Of Type 2 Diabetes: A Case Report
University of Pittsburgh Medical Center, Pittsburgh, PA, USA *Corresponding Author: Bonnie B. Lu University of Pittsburgh Medical Center Pittsburgh, PA, USA Tel: +1 412-647-2345 E-mail: [email protected] Citation: Lu BB, Rivera-Lebron B, Ng J (2017) Euglycemic Diabetic Ketoacidosis Due to Canagliflozin in A Patient with an Uncertain Diagnosis of Type 2 Diabetes: A Case Report. Diabetes Case Rep 2:127. doi: 10.4172/2572-5629.1000127 Copyright: © 2017 Lu BB, 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 author and source are credited. Visit for more related articles at Diabetes Case Reports Abstract Sodium-glucose cotransport 2 (SGLT2) inhibitors are approved for use only in patients with type 2 diabetes and work by blocking glucose reabsorption in the proximal renal tubule. There is also evidence that SGLT2 inhibitors directly act on pancreatic α-cells to stimulate glucagon secretion, leading to additional ketone body production, and that SGLT2 inhibitors decrease renal clearance of ketone bodies. While the risk of euglycemic diabetic ketoacidosis (eDKA) associated with offlabel use in patients with type 1 diabetes is well known, there are currently no guidelines for SGLT2 inhibitor use in patients with diabetes of uncertain or transitioning pathology. We report a case of eDKA associated with canagliflozin in a patient with rapid progression of noninsulin dependent to insulin-dependent diabetes within the span of 2 years to illustrate the risk of eDKA when SGLT2 inhibitors are used in patients with an uncertain insulin treatment requirement in T2D. Keywords SGLT2 inhibitor; Euglycemic diabetic ketoacidosis Continue reading >>
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Euglycemic Diabetic Ketoacidosis: An Easily Missed Diagnosis
SESSION TITLE: Critical Care Student/Resident Case Report Posters I SESSION TYPE: Student/Resident Case Report Poster INTRODUCTION: A 47 year-old woman with type 1 diabetes presented with euglycemic diabetic ketoacidosis (DKA) that initially went undiagnosed. Recognition and treatment with insulin resulted in rapid resolution of her clinical condition. CASE PRESENTATION: A 47 year-old woman presented to our hospital with four days of fever, abdominal pain, diarrhea, nausea, vomiting, lethargy and malaise. She had a history of type 1 diabetes mellitus managed with an insulin pump. Her blood pressure was 88/51. She was disoriented with a diffusely tender but soft abdomen. Laboratory studies revealed blood glucose of 109 mg/dL, bicarbonate of 15 mmol/L, anion gap of 27 mmol/L, lactic acid of 2.4 mmol/L, and a bandemia of 11%. Rapid flu test was positive. She was admitted to the intensive care unit, resuscitated with intravenous fluid, and started on oseltamivir, cefepime and vancomycin. Hemodialysis was initiated soon thereafter. The patient received no insulin due to her euglycemia. Influenza A was detected by PCR on the second hospital day and antibiotics were discontinued. Her gastrointestinal symptoms improved but her mental status remained poor. Furthermore, while her lactate normalized and blood glucose remained under 120 mg/d, her anion gap persisted at 23-36 mmol/L and her bicarbonate remained low at 15-17 mmol/L. Beta hydroxybutyrate was found to be 4.88 mmol/L. An insulin infusion was started, along with dextrose 5% in water, and her mental status rapidly improved as her acidemia and anion gap normalized. DISCUSSION: Euglycemic DKA is a rare condition that can easily go undiagnosed. It has been previously described in the context of critical illness.1 The pathoge Continue reading >>
Euglycemic Diabetic Ketoacidosis With Canagliflozin: Not-so-sweet But Avoidable Complication Of Sodium-glucose Cotransporter-2 Inhibitor Use
What is known and objective: In the outpatient setting, sodium-glucose co-transporter 2 inhibitors (SGLT2i) are recognized as effective agents to optimize glycaemia and also developing robust evidence for cardiovascular (CV) and renal protection in people with type 2 diabetes, particularly those at higher risk. However, data on the safety and efficacy of these drugs in hospitalized patients remain limited. The purpose of this review is to discuss the balance between risks and benefits of SGLT2i use in the inpatient setting.Methods: PubMed, Embase and Google Scholar databases were searched to identify relevant published work. Available evidence on the mechanisms of action and the safety profile of SGLT2i in the context of their use in hospitalized individuals are summarized and discussed in this narrative review.Results and discussion: The rationale behind the use of these agents in the inpatient setting is based on the low risk of hypoglycaemia, the practical dosing scheme and the potential to decrease subsequent heart failure admission rates. In addition, data from animal studies indicate the ability of SGLT2i to ameliorate oxidative stress, suppress sympathetic activity, enhance autophagy and promote cardiac remodelling, when administered in the acute phase of CV episodes. On the other hand, these drugs have been linked to specific adverse events related to their mechanism of action, including an increased risk of euglycaemic diabetic ketoacidosis and volume depletion, which raises concerns over their usefulness in inpatients, particularly individuals with multimorbidities.What is new and conclusion: Potential benefits deriving from the use of SGLT2i in the inpatient setting cannot mitigate possible risks, at least until robust evidence on their efficacy in hospitali Continue reading >>
