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 >>
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 >>
Sglt2 Inhibitors And Diabetic Ketoacidosis: What's Behind The Fda Warning
With commentary by Yehuda Handelsman, MD, FACP, FACE, FNLA, an endocrinologist in private practice in Tarzana, CA, Medical Director and Principal Investigator of the Metabolic Institute of America and President of the American College of Endocrinology People with diabetes who take blood sugar-lowering drugs called SGLT2 inhibitors were recently warned by the U.S. Food and Drug Administration (FDA) that they should watch for signs of a life-threatening condition called diabetic ketoacidosis. canagliflozin (Invokana) dapagliflozin (Farxiga) empagliflozin (Jardiance) as well as the combination pills: canagliflozin plus metformin (Invokamet) dapagliflozin plus metformin extended-release (Xigduo XR) empagliflozin plus linagliptin (Glyxambi). “Diabetic ketoacidosis (DKA) can be deadly,” says Amy Hess-Fischl, MS, RD, LDN, BC-ADM, CDE, an advanced practice dietitian at the University of Chicago Kovler Diabetes Center and a member of EndocrineWeb’s advisory board. “DKA is usually more of a concern for people with type 1 diabetes, but this warning is for people with type 2 diabetes who are taking the SGLT2 inhibitors, as well as people with type 1 diabetes who take these medications off label. DKA — dangerously high acid levels in the bloodstream — happens when your body breaks down fat instead of glucose for energy, releasing acidic compounds called ketones. Early symptoms include thirst, frequent urination and sweet, fruity breath, Hess-Fischl says. You may feel tired and confused, and develop nausea, stomach pain, vomiting and difficulty breathing. “If you notice symptoms, call your doctor immediately. But if you’re vomiting, can’t catch your breath or are concerned, go to the emergency room,” she says. Putting the Risk in Perspective The FDA warning, relea Continue reading >>
Get Unlimited Access On Medscape.
You’ve become the New York Times and the Wall Street Journal of medicine. A must-read every morning. ” 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 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 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 >>
In Brief: Ketoacidosis With Sglt2 Inhibitors
The FDA has warned that use of an SGLT2 (sodium-glucose co-transporter 2) inhibitor for treatment of type 2 diabetes may lead to ketoacidosis.1 Three SGLT2 inhibitors, canagliflozin (Invokana, Invokamet), dapagliflozin (Farxiga, Xigduo XR), and empagliflozin (Jardiance, Glyxambi), are approved for treatment of type 2 diabetes in the US. Between March 2013 and June 2014, 20 cases of ketoacidosis requiring emergency room visits or hospitalization were reported in patients who had recently started taking an SGLT2 inhibitor; the median time to onset of symptoms after initiation of therapy was 2 weeks (range 1-175 days). SGLT2 inhibitors decrease renal glucose reabsorption and increase urinary glucose excretion, resulting in a reduction in blood glucose levels. The mechanism by which these drugs could cause ketoacidosis has not been established. Diabetic ketoacidosis (DKA) occurs primarily in patients with type 1 diabetes; it is characterized by elevated blood glucose levels (usually ≥250 mg/dL), a high anion gap, glucosuria, and ketonuria.2 Unlike typical cases of DKA, most ketoacidosis cases associated with SGLT2 inhibitors have occurred in patients with type 2 diabetes, and in some patients glucose levels were <200 mg/dL. Only half of the 20 cases were associated with a recognizable DKA-precipitating factor, such as infection, reduced caloric intake, or reduced insulin dose. Other factors that may contribute to the development of high anion gap metabolic acidosis, such as hypovolemia, hypoxemia, reduced oral intake, acute renal impairment, and a history of alcohol use, were identified in some patients.1 Continue reading >>
Ketosis And Diabetic Ketoacidosis In Response To Sglt2 Inhibitors: Basic Mechanisms And Therapeutic Perspectives.
Abstract Inhibitors of the sodium-glucose cotransporter SGLT2 are a new class of antihyperglycemic drugs that have been approved for the treatment of type 2 diabetes mellitus (T2DM). These drugs inhibit glucose reabsorption in the proximal tubules of the kidney thereby enhancing glucosuria and lowering blood glucose levels. Additional consequences and benefits include a reduction in body weight, uric acid levels, and blood pressure. Moreover, SGLT2 inhibition can have protective effects on the kidney and cardiovascular system in patients with T2DM and high cardiovascular risk. However, a potential side effect that has been reported with SGLT2 inhibitors in patients with T2DM and particularly during off-label use in patients with type 1 diabetes is diabetic ketoacidosis. The US Food and Drug Administration recently warned that SGLT2 inhibitors may result in euglycemic ketoacidosis. Here, we review the basic metabolism of ketone bodies, the triggers of diabetic ketoacidosis, and potential mechanisms by which SGLT2 inhibitors may facilitate the development of ketosis or ketoacidosis. This provides the rationale for measures to lower the risk. We discuss the role of the kidney and potential links to renal gluconeogenesis and uric acid handling. Moreover, we outline potential beneficial effects of modestly elevated ketone body levels on organ function that may have therapeutic relevance for the observed beneficial effects of SGLT2 inhibitors on the kidney and cardiovascular system. KEYWORDS: diabetic ketoacidosis; ketogenesis; ketone body reabsorption; ketosis; kidney; sodium glucose cotransporter Continue reading >>
Sglt2 Inhibitors Double The Risk For Diabetic Ketoacidosis
SGLT2 Inhibitors Double the Risk for Diabetic Ketoacidosis The risk of developing diabetic ketoacidosis (DKA) among type 2 diabetes patients initiating a sodiumglucose cotransporter 2 (SGLT2) inhibitor medication is about double that seen among patients starting a dipeptidyl peptidase-4 (DPP-4) inhibitor, but the overall risk is still low, new research suggests. Findings from the largest study conducted to date to investigate the issue were published as a research letter in the June 8 issue of the New England Journal of Medicine by Michael Fralick, MD, and colleagues at the Brigham and Women's Hospital, Boston, Massachusetts. "We found a doubling in the risk of DKA, which sounds frightening, but the absolute risk is quite small.I still think this is a very good class of medications and for certain patients will continue to be. Now we just have a little more information to add to the discussion when the risks and benefits are being considered," Dr Fralick told Medscape Medical News. He estimates that between 5 and 8 patients per 1000 initiating SGLT2 inhibitors will develop DKA. And he advisesthat patients be strictly monitored for signs of DKA after starting on SGLT2 inhibitors, noting, "This is something that can happen relatively quickly, so that's why I think it's important right after patients are started on these drugs that they're closely monitored and the clinician considers ordering bloodwork." But overall, Dr Fralick, a general internist, supports use of the SGLT2 inhibitor class for selected patients with type 2 diabetes, given the recent results from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study showing reduction in cardiovascular deaths, as well as renal protection , with empagliflozin (Ja Continue reading >>
Sglt2 Inhibitors May Predispose To Ketoacidosis.
J Clin Endocrinol Metab. 2015 Aug;100(8):2849-52. doi: 10.1210/jc.2015-1884. Epub 2015 Jun 18. 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; and Division of Diabetes, Endocrinology, and Nutrition (S.I.T.), Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201. 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 diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis. Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism. SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic -cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies Continue reading >>
Euglycemic Diabetic Ketoacidosis Induced By Sglt2 Inhibitors: Possible Mechanism And Contributing Factors
Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors Kazuhiko Sakaguchi - Kobe University It is possible that SGLT2 inhibitors trigger euglycemic diabetic ketoacidosis in some patients. Possible mechanism of euglycemic DKA induced by SGLT2 inhibitors is illustrated. 2018 Digital Science & Research Solutions, Inc. All Rights Reserved | About us Privacy policy Legal terms VPAT Citation Count is the number of times that this paper has been cited by other published papers in the database. The Altmetric Attention Score is a weighted count of all of the online attention Altmetric have found for an individual research output. This includes mentions in public policy documents and references in Wikipedia, the mainstream news, social networks, blogs and more. More detail on the weightings of each source and how they contribute to the attention score is available here . The Relative Citation Ratio (RCR) indicates the relative citation performance of an article when comparing its citation rate to that of other articles in its area of research. A value of more than 1.0 shows a citation rate above average. The articles area of research is defined by the articles that have been cited alongside it. The RCR is normalized to 1.0 for all articles. The Field Citation Ratio (FCR) is an article-level metric that indicates the relative citation performance of an article, when compared to similarly-aged articles in its subject area. A value of more than 1.0 indicates higher than average citation, when defined by FoR Subject Code, publishing year and age. The FCR is calculated for articles published in 2000 and later. The recent citations value is the number of citations that were received in the last two years. It is currently reset at the 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 >>
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 >>
