Canagliflozin Dka

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 >>

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 >>

Three Diabetes Drugs Linked To Ketoacidosis, Fda Warns

NASHVILLE -- Three type 2 diabetes drugs -- canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) -- may lead to ketoacidosis, the FDA warned today. The sodium-glucose co-transporter-2 (SGLT2) inhibitors are designed to lower blood sugar in patients with diabetes, but the FDA is investigating a connection between the drugs and dangerously high acid levels in the blood. They are also looking at whether changes will need to be made to the prescribing information, they said in the warning, which is posted online. At least two studies presented here at the annual meeting of the American Association of Clinical Endocrinologists have found a connection between the SGLT2 inhibitors and diabetic ketoacidosis (DKA). "Healthcare professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or symptoms," the FDA said. "Discontinue SGLT2 inhibitors if acidosis is confirmed, and take appropriate measures to correct the acidosis and monitor sugar levels." The signs and symptoms listed included difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness. The FDA is issuing the warning after they searched their database of adverse event complaints, they said in an announcement. From March 2013 to June 2014 there were 20 cases of DKA reported, most of them with type 2 diabetes as the indication. Hospitalization was required in all of the cases, and the median time to onset was 2 weeks after starting the drug. "I would encourage that these cases be studied so we can learn the scenarios behind them so they can be broadcast," said Farhad Zangeneh, MD, medical director of Endocrine, Diabetes and Osteoporosis Clinic, in an interview with MedPage Today. "The important 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: 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 >>

Canagliflozin-associated Diabetic Ketoacidosis

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Canagliflozin-associated Diabetic Ketoacidosis With Lower-than-anticipated Glucose Levels Vadi S, Agarwal M

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. Keywords:Canagliflozin, diabetic ketoacidosis with lower-than-anticipated glucose levels, euglycemic diabetic ketoacidosis, sodium-glucose co-transporter 2 inhibitors Vadi S, Agarwal M. Canagliflozin-associated diabetic ketoacidosis with lower-than-anticipated glucose levels. Indian J Crit Care Med 2017;21:793-5 Vadi S, Agarwal M. Canagliflozin-associated diabetic ketoacidosis with lower-than-anticipated glucose levels. Indian J Crit Care Med [serial online] 2017 [cited2018 Apr 2];21:793-5. Available from: As clinicians, we need to be aware that medications used for disease management can paradoxically induce effects, causing an already sick patient to become worse. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors, a fairly recent addition to the pool of diabetes medications, are associated with a variety of side effects, the fatal one being ketoacidosis. This adverse effect reported in the Continue reading >>

Canagliflozin-induced Diabetic Ketoacidosis

Go to: Case Report A 62-year-old woman with type 2 diabetes mellitus, hypertension, gastroesophageal reflux disease, and depression presented with 4 days of nausea, vomiting, and generalized weakness. Her symptoms became progressively worse such that by the day of admission she had decreased appetite, polydipsia, polyuria, and could not walk. The patient denied fever, chills, abdominal pain, diarrhea, or sick contacts. Home medications were atorvastatin, metformin, sucralfate, pioglitazone, canagliflozin, exenatide, omeprazole, fluoxetine, ranitidine, lisinopril, and alprazolam. On physical examination, the patient’s vital signs included a temperature of 38.3°C, blood pressure 134/61, heart rate 107, respiratory rate 24, and oxygen saturation of 100% on 2 liters nasal cannula oxygen. The patient appeared ill and distressed. She had dry mucous membranes, clear lung sounds bilaterally, and her heart was regular without murmurs, gallops, or rubs. Her abdomen was soft and nontender with present bowel sounds. Extremities showed no edema, and she had no focal neurological findings. Laboratory revealed a metabolic acidosis with a pH of 7.08 and anion gap >17. Chemistry panel indicated sodium 134 mEq/L, potassium 5.2 mEq/L, chloride 112 mEq/L, CO2 <5 mEq/L, blood urea nitrogen 22 mg/dL, and creatinine 1.3 mg/dL. Blood glucose was 213 mg/dL, and urinalysis revealed glucose 2+ and ketones 3+. Serum ketones were present at 1:8 dilution, with a lactic acid of 0.8 mmol/L. The patient’s hemoglobin A1C (HbA1c) was 11.1. The patient was admitted to the intensive care unit for severe metabolic acidosis secondary to DKA. Aggressive fluid resuscitation was undertaken and an insulin drip initiated. Within 6 hours, the anion gap metabolic acidosis improved. On further review of her med Continue reading >>

Sglt2 Inhibitors (canagliflozin, Dapagliflozin, Empagliflozin): Risk Of Diabetic Ketoacidosis

Test for raised ketones in patients with acidosis symptoms, even if plasma glucose levels are near-normal. When treating patients who are taking an SGLT2 inhibitor (canagliflozin, dapagliflozin or empagliflozin): test for raised ketones in patients with symptoms of diabetic ketoacidosis (DKA); omitting this test could delay diagnosis of DKA if you suspect DKA, stop SGLT2 inhibitor treatment if DKA is confirmed, take appropriate measures to correct the DKA and to monitor glucose levels inform patients of the symptoms and signs of DKA (see below); advise them to get immediate medical help if these occur be aware that SGLT2 inhibitors are not approved for treatment of type 1 diabetes please continue to report suspected side effects to SGLT2 inhibitors or any other medicines on a Yellow Card Reports of diabetic acidosis Sodium glucose co-transporter 2 (SGLT2) inhibitors are licensed for use in adults with type 2 diabetes to improve glycaemic control. Serious and life-threatening cases of DKA have been reported in patients taking SGLT2 inhibitors (canagliflozin, dapagliflozin or empagliflozin). In several cases, blood glucose levels were only moderately elevated (eg <14 mmol/L or 250 mg/dL), which is atypical for DKA. This atypical presentation could delay diagnosis and treatment. Therefore inform patients of the signs and symptoms of DKA (eg nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness) and test for raised ketones in patients with these signs and symptoms. Half of the cases occurred during the first 2 months of treatment. Some cases occurred shortly after stopping the SGLT2 inhibitor. One third of the cases involved off-label use in patients with type 1 diabetes. We remind you that this drug cla 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 >>

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 >>

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 With Canagliflozin

Euglycemic diabetic ketoacidosis with canagliflozin Not-so-sweet but avoidable complication of sodium-glucose cotransporter-2 inhibitor use Clinical Assistant Professor at the University of British Columbia in Vancouver, a family physician with a consulting practice in diabetes in the interior of British Columbia, and Medical Lead for the Interior Health Authority Diabetes Strategy. Professor, Director of the Division of Endocrinology and Metabolism, and Medical Director of the Clinical Islet Transplant Program at the University of Alberta in Edmonton. Correspondence : Dr Maureen Clement; e-mail [email protected] Cet article est disponible en franais. Voyez " Lacidoctose diabtique euglycmique due la canagliflozine ". This article has been cited by other articles in PMC. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been approved in Canada for use in the management of type 2 diabetes (T2DM) since May 2014. Three agents from this class are licensed in Canada (canagliflozin, dapagliflozin, and empagliflozin). These agents are likely to be used commonly in family practice because they are once-daily oral medications that lower blood glucose levels and they are associated with weight loss, lower blood pressure, and a low risk of hypoglycemia. Furthermore, recent evidence showed reduced cardiovascular mortality with empagliflozin. 1 The Canadian Diabetes Association clinical practice guidelines were updated in 2015 to include this class. They note a risk of rare diabetic ketoacidosis [DKA] (may occur with no hyperglycemia), 2 a potentially life-threatening condition that has been observed in some postmarketing reports. Here we present a case of euglycemic DKA associated with use of an SGLT2 inhibitor, with discussion of the potential mechanism of pro Continue reading >>

Sglt2 Inhibitors Double The Risk For Diabetic Ketoacidosis. N Engl J Med

SGLT2 Inhibitors Double the Risk for Diabetic Ketoacidosis. N Engl J Med 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 werepublishedas a research letter in the June 8 issue of theNew England Journal of Medicineby 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 toldMedscape Medical News. He estimates that between 5 and 8 patients per 1000 initiating SGLT2 inhibitors will develop DKA. And he advisesthat patients be monitored for signs of DKA or full information to thew patients of the symtoms of DKA to seek help if DKA appears 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 theEmpagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients(EMPA-REG OUTCOME) study showing 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 >>