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Prolonged Ketosis In A Patient With Euglycemic Diabetic Ketoacidosis Secondary To Dapagliflozin
Sodium-glucose cotransporter 2 inhibitors (SGLT2) are the newest class of oral agents to receive US Food and Drug Administration (FDA) approval for the treatment of type 2 diabetes (T2DM). SGLT2 inhibitors currently approved by the FDA include canagliflozin, dapagliflozin, and empagliflozin as well as various combination drugs (Table 1). The enthusiasm this class of drugs has been greeted with stems from the benefits associated with SGLT2 inhibitors. They include decrease in A1c by 0.5% to 1%, reduction in insulin doses, modest weight loss, and improved systolic and diastolic blood pressure.1 In addition, the EMPA-REG OUTCOME trial showed a reduction in all-cause and cardiovascular mortality with empagliflozin.2 Also, a post hoc analysis of a study on dapagliflozin in type 2 diabetics with moderate renal impairment showed improved albuminuria and delayed progression to severe renal failure.3 The popularity of SGLT2 inhibitors is understandable considering the paucity of oral diabetic drugs that promote both weight loss and reduction of insulin needs. Endocrinologists and internists alike have increasingly prescribed this class of drugs as to avoid initiation of insulin or escalation of insulin doses. With more patients using SGLT2 inhibitors, reports of euglycemic diabetic ketoacidosis (euDKA) have emerged. While DKA can be expected with off-label use of SGLT2 inhibitors in patients with T1DM, it has also occurred in T2DM patients. Thus, the FDA posted a drug safety communication on DKA in 2015.4 Greater understanding of how to safely use this newest tool in our arsenal against diabetes is essential. A 50-year-old African American female with T2DM since the age of 35 presented with 10 days of constipation and fatigue, as well as reduced oral intake for 3 days prior to a Continue reading >>
Euglycemic Diabetic Ketoacidosis: A Review
Euglycemic Diabetic Ketoacidosis: A Review Author(s): Anar Modi , Department of Endocrinology, Diabetes & Metabolism, Cooper University Hospital, Camden, New Jersey, United States Abhinav Agrawal* , Department of Medicine, Monmouth Medical Center, 300 Second Avenue, Long Branch, New Jersey, United States Farah Morgan . Department of Endocrinology, Diabetes & Metabolism, Cooper University Hospital, Camden, New Jersey, United States Introduction: Diabetic ketoacidosis (DKA) is one of the most serious complications of diabetes.It is characterised by the triad of hyperglycemia (blood sugar >250 mg/dl), metabolic acidosis(arterial pH <7.3 and serum bicarbonate <18 mEq/L) and ketosis. Rarely these patients can present withblood glucose (BG) levels of less than 200 mg/dl, which is defined as euglycemic DKA. The possibleetiology of euglycemic DKA includes the recent use of insulin, decreased caloric intake, heavy alcoholconsumption, chronic liver disease and glycogen storage disorders. DKA in pregnancy has also beenreported to present with euglycemia. The recent use of sodium glucose cotransporter 2 (SGLT2) inhibitorshas shed light on another possible mechanism of euglycemic DKA. Clinicians may also be misledby the presence of pseudonormoglycemia. Conclusion: Euglycemic DKA thus poses a challenge to physicians, as patients presenting with normalBG levels in ketoacidosis may be overlooked, leading to a delay in appropriate management strategies.In this article, we review all the possible etiologies and the associated pathophysiology of patients presentingwith euglycemic DKA. We also discuss the approach to diagnosis and management of suchpatients. Despite euglycemia, ketoacidosis in diabetic patients remains a medical emergency and mustbe treated in a quick and appropriate mann Continue reading >>
Euglycemic Diabetic Ketoacidosis With Sglt2 Inhibitors In Lean Type 2 Diabetes
Mi-kyung KIM Abstract We experienced a case of euglycemic diabetic ketoacidosis after adding SGLT2 inhibitor to current medications in type 2 diabetes. She was 57 years old and DM duration was 3 years. She had low body mass index (< 18 mg/m2) which may mean relative insulin deficiency state. Her ketone body levels and fasting serum glucagon levels were higher with SGLT2 inhibitors and decreased after stopping them. Their DKA were improved by stopping SGLT2 inhibitors, hydration with insulin treatment. Key words Type 2 diabetes, Euglycemic diabetic ketoacidosis Introduction Sodium-glucose cotransporter 2 (SGLT2) inhibitors are novel anti-hyperglycemic agents showed surprisingly significant reductions in cardiovascular mortality and all-cause mortality [1]. While the exact mechanisms why SGLT2 inhibitors dramatically improved CV outcome are not clear, one of explanations for them is that they lower not only glucose but also weight and blood pressure [2]. In terms of weight loss, SGLT2 inhibitors produce weight loss of ∼2–3 kg, secondary to the 280–320 kcal/day loss because 70-80 g of glucose is excreted in the urine [3,4]. Since type 2 diabetes are usually more obese than non-diabetes, SGLT2 inhibitors may be the first medication after metformin for obese diabetic patients. But, weight loss could be a concern for patients with low body weight after SGLT2 inhibitors treatment. We recently experienced a case of euglycemic diabetic ketoacidosis with SGLT2 inhibitors in lean type 2 diabetes. Case reports A 57-year-old woman was diagnosed with diabetes at the age of 54 years. Her height was 163 cm, body weight was 47 kg and body mass index was 17.7 kg/m2. She had family history of diabetes. She did not have history of diabetic ketoacidosis. She received glimepiride (4 mg Continue reading >>
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 >>
(pdf) Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, And Preventable Safety Concern With Sglt2 Inhibitors
Diabetes Care 2015;38:16381642 |DOI: 10.2337/dc15-1380 potential triggering factors such as inter- of all of the three approved SGLT2 inhib- itors (canagliozin, dapagliozin, and em- pagliozin) to evaluate the risk of DKA in for the mention that all cases were seri- ous and some required hospitalisation. Al- that in this issue of Diabetes Care there tected during the relatively short clinical DKA is an overt serious clinical condition terestingly, the large clinical development tients, bore no clear signal of DKA. Erondu et al. (3), representing Janssen, the man- ufacturer of canagliozin, report a rela- 12 on canagliozin and 3 still blinded in rospective analysis of 17,596 participants 0.8, and 0.2 per 1,000 patient-years with canagliozin 100 mg, canagliozin 300 mg, lished) gures that are even lower than the tients exposed to dapagliozin in the ran- dapaglioz in or placebo, the total number Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche, Pisa, Italy Corresponding author: Julio Rosenstock, [email protected] 2015 by the American Diabe tes Association. Readers may use this article as long as the wor k is properly cited, the use is educational and no t for prot, See accompanying articles, pp. 1680 and 1687. 1638 Diabetes Care Volume 38, September 2015 In a retrospective analysis of randomized phase 2 and 3 empagliozin trials (.13,000 T2D participants), there were eight events greater incidence of DKA, but 6 out of the diagnosis was correct, most of the patients were on insulin treatment and were part of T2D stage with signicant b-cell failure. lot studies in T1D have reported improve- less glucose variability, weight loss, and have disseminated initial favorable expe- hi Continue reading >>
Euglycemic Diabetic Ketoacidosis Sometimes Seen With Sglt2 Inhibitors
Craig Cocchio, PharmD, BCPS, is an Emergency Medicine Clinical Pharmacist at Trinity Mother Frances Hospital in Tyler, Texas. Follow on Twitter @iEMPharmD and on his blog at empharmd.blogspot.com Diabetic ketoacidosis (DKA) in patients with presenting serum blood glucose <200 mg/dL isn’t common. More often, it’s seen in patients with type 1 diabetes in conjunction with starvation and acute illness.1 It’s difficult to determine an incidence of euglycemic DKA (euDKA) among all DKA cases in the literature, given the migration of the serum glucose cutoff from ≤300 mg/dL to ≤200 mg/dL. The best estimation based on an analysis of case reports suggests an incidence anywhere between 0.8% and 7.5%.1 However, the sodium-glucose cotransporter-2 (SGLT2) inhibitors canagliflozin, dapagliflozin, and empagliflozin can apparently induce this once-rare form of DKA.2,3 SGLT2 inhibitors are a class of oral hypoglycemic drugs indicated only for type 2 diabetes. Their novel mechanism of action prevents glucose reabsorption from the proximal renal tubules, resulting in increased glucosuria and decreasing plasma glucose. SGLT2 inhibitors lower serum glucose and HBA1C levels, and even produce weight loss. However, the increased glucose concentration in the bladder is a terrific incubation environment for fungi and bacteria, so much so that the FDA stuck a post-marketing warning on the drug class for the increased risk of serious urinary tract infections and urosepsis, in addition to euglycemic DKA. The proposed mechanism suggests that while SGLT2 inhibitors lower serum glucose, they also reduce insulin secretion from pancreatic beta cells in a negative feedback fashion. The lower serum insulin coupled with lower serum glucose consequently shifts energy metabolism to antilipolytic act Continue reading >>
Euglycemic Diabetic Ketoacidosis: A Potential Complication Of Treatment With Sodiumglucose Cotransporter 2 Inhibition
Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With SodiumGlucose Cotransporter 2 Inhibition We are experimenting with display styles that make it easier to read articles in PMC. The ePub format uses eBook readers, which have several "ease of reading" features already built in. The ePub format is best viewed in the iBooks reader. You may notice problems with the display of certain parts of an article in other eReaders. Generating an ePub file may take a long time, please be patient. Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With SodiumGlucose Cotransporter 2 Inhibition Anne L. Peters, Elizabeth O. Buschur, [...], and Irl B. Hirsch Sodiumglucose cotransporter 2 (SGLT-2) inhibitors are the most recently approved antihyperglycemic medications. We sought to describe their association with euglycemic diabetic ketoacidosis (euDKA) in hopes that it will enhance recognition of this potentially life-threatening complication. Cases identified incidentally are described. We identified 13 episodes of SGLT-2 inhibitorassociated euDKA or ketosis in nine individuals, seven with type 1 diabetes and two with type 2 diabetes, from various practices across the U.S. The absence of significant hyperglycemia in these patients delayed recognition of the emergent nature of the problem by patients and providers. SGLT-2 inhibitors seem to be associated with euglycemic DKA and ketosis, perhaps as a consequence of their noninsulin-dependent glucose clearance, hyperglucagonemia, and volume depletion. Patients with type 1 or type 2 diabetes who experience nausea, vomiting, or malaise or develop a metabolic acidosis in the setting of SGLT-2 inhibitor therapy should be promptly evaluated for the presence of urine and/or serum ketones. SGLT-2 inhi Continue reading >>
Euglycemic Diabetic Ketoacidosis Associated With Sglt2 Inhibitor Use In Non-type 1 Diabetes Mellitus
Euglycemic Diabetic Ketoacidosis Associated with SGLT2 Inhibitor Use in Non-Type 1 Diabetes Mellitus Automated Event-Based System for the Prevention of Post-Bariatric Hypoglycemia Using a Mini-Dose of a Stable Glucagon Formulation Continue reading >>
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 >>
Euglycemic Diabetic Ketoacidosis: A Potential Complication Of Treatment With Sodiumglucose Cotransporter 2 Inhibition
Objective Sodiumglucose cotransporter 2 (SGLT-2) inhibitors are the most recently approved antihyperglycemic medications. We sought to describe their association with euglycemic diabetic ketoacidosis (euDKA) in hopes that it will enhance recognition of this potentially life-threatening complication. Research Design and Methods Cases identified incidentally are described. Results We identified 13 episodes of SGLT-2 inhibitorassociated euDKA or ketosis in nine individuals, seven with type 1 diabetes and two with type 2 diabetes, from various practices across the U.S. The absence of significant hyperglycemia in these patients delayed recognition of the emergent nature of the problem by patients and providers. Conclusions SGLT-2 inhibitors seem to be associated with euglycemic DKA and ketosis, perhaps as a consequence of their noninsulin-dependent glucose clearance, hyperglucagonemia, and volume depletion. Patients with type 1 or type 2 diabetes who experience nausea, vomiting, or malaise or develop a metabolic acidosis in the setting of SGLT-2 inhibitor therapy should be promptly evaluated for the presence of urine and/or serum ketones. SGLT-2 inhibitors should only be used with great caution, extensive counseling, and close monitoring in the setting of type 1 diabetes. Sodiumglucose cotransporter 2 (SGLT-2) inhibitors are the newest class of antihyperglycemic medications, first marketed in 2013 for the treatment of type 2 diabetes.[ 1 ] Limited studies suggest that SGLT-2 inhibitors may be effective in addressing many of the unmet needs of people with type 1 diabetes, including improving average glycemia, while reducing glycemic variability and postprandial hyperglycemia, without increasing hypoglycemia, as well as promoting weight loss while reducing insulin doses.[ 28 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 >>
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 >>
Sglt2 Inhibitors May Predispose To Ketoacidosis
SGLT2 Inhibitors May Predispose to Ketoacidosis Diabetes, Endocrinology, and Obesity Branch (S.I.T., J.E.B., K.I.R.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Division of Diabetes, Endocrinology, and Nutrition (S.I.T.), Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201 Address all correspondence and requests for reprints to: Simeon I. Taylor, MD, PhD, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Mail Stop 1453, 9000 Rockville Pike, Bethesda, MD 20892. Search for other works by this author on: Diabetes, Endocrinology, and Obesity Branch (S.I.T., J.E.B., K.I.R.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Search for other works by this author on: Diabetes, Endocrinology, and Obesity Branch (S.I.T., J.E.B., K.I.R.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Search for other works by this author on: The Journal of Clinical Endocrinology & Metabolism, Volume 100, Issue 8, 1 August 2015, Pages 28492852, Simeon I. Taylor, Jenny E. Blau, Kristina I. Rother; SGLT2 Inhibitors May Predispose to Ketoacidosis, The Journal of Clinical Endocrinology & Metabolism, Volume 100, Issue 8, 1 August 2015, Pages 28492852, Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of di Continue reading >>
Euglycemic Dka Secondary To Sglt2 Inhibitors
Authors: Priyanka Kailash (MS-4, Campbell University School of Osteopathic Medicine), Kevin Weaver, DO (Program Director, Lehigh Valley Health Network), and Krystle Shafer, MD (Attending Physician, York Hospital) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit) A 35-year-old male with a past medical history of type 2 diabetes arrives at the Emergency Department (ED) with altered mental status, nausea, vomiting, and diffuse abdominal pain that started 10 hours ago. The patient was recently started on an SGLT2 inhibitor. On examination, the patient is tachycardic (HR 126) and tachypneic (RR 25), with normal blood pressure (110/90). He is further noted to have dry mucous membranes and poor skin turgor. Blood glucose is noted to be 140 mg/dl, serum ketones 6.2 mmol/L, and arterial pH of 6.9. The patient is diagnosed with euglycemic DKA and quickly admitted to ICU for treatment. Pathogenesis of Typical DKA Two major complications from type 1 diabetes mellitus and type 2 diabetes mellitus are diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). DKA is typically seen in younger individuals, while HHS is typically seen in older patients(1). In the pathogenesis of typical DKA, the body experiences a starved state. Insulin deficiency (either through decreased production or decrease sensitivity) leads to the inactivation of GLUT4 receptors on cells. GLUT4 receptors function to help transport glucose molecules into cells so that it can be converted into energy. Without GLUT4 receptor activation, the glucose entry into cells remains shut. Thus, the cells start to experience a starved state. To compensate, the body activates an alternative energy pathway Continue reading >>
