Background: Euglycemic Diabetic Ketoacidosis (EDKA) is a rare but well-known adverse effect of sodium glucose transporter 2 (SGLT-2) inhibitors. This class of antidiabetic medications has ketogenic properties that predispose patients to develop EDKA, especially in the setting of intercurrent illnesses, major surgeries, increased alcohol intake, reduced insulin dosing, dehydration and reductions in carbohydrate intake. Case Presentation: A 68-year-old female with newly diagnosed metastatic adrenocortical carcinoma and adrenal insufficiency (AI) developed EDKA after palliative debulking that required ICU admission and intubation after being prescribed dapagliflozin by her outpatient provider. Conclusions: Healthcare providers must assess patient risk factors for developing EDKA prior to prescribing SGLT-2 inhibitors. This assessment requires an understanding of the inherent downstream metabolic effects of SGLT-2 inhibitor-induced glycosuria.
References
[1]
Patel, S.M., Kang, Y.M., Im, K., Neuen, B.L., Anker, S.D., Bhatt, D.L., etal. (2024) Sodium-glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis. Circulation, 149, 1789-1801. https://doi.org/10.1161/circulationaha.124.069568
[2]
FDA Revises Labels of SGLT2 Inhibitors for Diabetes to Include Warnings about Too Much Acid in the Blood and Serious Urinary Tract Infection. https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious
[3]
Zinman, B., Wanner, C., Lachin, J.M., Fitchett, D., Bluhmki, E., Hantel, S., etal. (2015) Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. NewEnglandJournalofMedicine, 373, 2117-2128. https://doi.org/10.1056/nejmoa1504720
[4]
Neal, B., Perkovic, V., Mahaffey, K.W., de Zeeuw, D., Fulcher, G., Erondu, N., etal. (2017) Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. NewEnglandJournalofMedicine, 377, 644-657. https://doi.org/10.1056/nejmoa1611925
[5]
Wiviott, S.D., Raz, I., Bonaca, M.P., Mosenzon, O., Kato, E.T., Cahn, A., etal. (2019) Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. NewEnglandJournalofMedicine, 380, 347-357. https://doi.org/10.1056/nejmoa1812389
[6]
Chao, E.C. (2014) SGLT-2 Inhibitors: A New Mechanism for Glycemic Control. ClinicalDiabetes, 32, 4-11. https://doi.org/10.2337/diaclin.32.1.4
[7]
Cheng, S.T.W., Chen, L., Li, S.Y.T., Mayoux, E. and Leung, P.S. (2016) The Effects of Empagliflozin, an SGLT2 Inhibitor, on Pancreatic Β-Cell Mass and Glucose Homeostasis in Type 1 Diabetes. PLOSONE, 11, e0147391. https://doi.org/10.1371/journal.pone.0147391
[8]
Henry, R.R., Rosenstock, J., Edelman, S., Mudaliar, S., Chalamandaris, A., Kasichayanula, S., etal. (2014) Exploring the Potential of the SGLT2 Inhibitor Dapagliflozin in Type 1 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Pilot Study. DiabetesCare, 38, 412-419. https://doi.org/10.2337/dc13-2955
[9]
Perkins, B.A., Cherney, D.Z.I., Partridge, H., Soleymanlou, N., Tschirhart, H., Zinman, B., etal. (2014) Sodium-glucose Cotransporter 2 Inhibition and Glycemic Control in Type 1 Diabetes: Results of an 8-Week Open-Label Proof-Of-Concept Trial. DiabetesCare, 37, 1480-1483. https://doi.org/10.2337/dc13-2338
[10]
Wang, Y., Desai, M., Ryan, P.B., DeFalco, F.J., Schuemie, M.J., Stang, P.E., etal. (2017) Incidence of Diabetic Ketoacidosis among Patients with Type 2 Diabetes Mellitus Treated with SGLT2 Inhibitors and Other Antihyperglycemic Agents. DiabetesResearchandClinicalPractice, 128, 83-90. https://doi.org/10.1016/j.diabres.2017.04.004
[11]
Rosenstock, J., Marquard, J., Laffel, L.M., Neubacher, D., Kaspers, S., Cherney, D.Z., etal. (2018) Empagliflozin as Adjunctive to Insulin Therapy in Type 1 Diabetes: The EASE Trials. DiabetesCare, 41, 2560-2569. https://doi.org/10.2337/dc18-1749
[12]
European Medicines Agency (2019) First Oral Add-On Treatment to Insulin for Treatment of Certain Patients with Type 1 Diabetes. https://www.ema.europa.eu/en/news/first-oral-add-treatment-insulin-treatment-certain-patients-type-1-diabetes#:~:text=1%20February%202019,below%2027%20kg/m2
[13]
Chow, E., Clement, S. and Garg, R. (2023) Euglycemic Diabetic Ketoacidosis in the Era of SGLT-2 Inhibitors. BMJ Open DiabetesResearch&Care, 11, e003666. https://doi.org/10.1136/bmjdrc-2023-003666
[14]
Plewa, M.C., Bryant, M. and King-Thiele, R. (2023) Euglycemic Diabetic Ketoacidosis. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK554570/
[15]
Matthew, D., Kimberley, E. and Elsen, J. (2021) Management of Euglycemic Diabetic Ketoacidosis. U.S. Pharmacist, 46, HS1-HS6. https://www.uspharmacist.com/article/management-of-euglycemic-diabetic-ketoacidosis
[16]
Marso, S.P., Daniels, G.H., Brown-Frandsen, K., Kristensen, P., Mann, J.F.E., Nauck, M.A., etal. (2016) Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. NewEnglandJournalofMedicine, 375, 311-322. https://doi.org/10.1056/nejmoa1603827
[17]
Yurista, S.R., Silljé, H.H.W., Oberdorf‐Maass, S.U., Schouten, E., Pavez Giani, M.G., Hillebrands, J., etal. (2019) Sodium-Glucose Co-Transporter 2 Inhibition with Empagliflozin Improves Cardiac Function in Non-Diabetic Rats with Left Ventricular Dysfunction after Myocardial Infarction. EuropeanJournalofHeartFailure, 21, 862-873. https://doi.org/10.1002/ejhf.1473
[18]
Petr, E.J. and Else, T. (2018) Adrenocortical Carcinoma (ACC): When and Why Should We Consider Germline Testing? LaPresseMédicale, 47, e119-e125. https://doi.org/10.1016/j.lpm.2018.07.004
[19]
Bornstein, S.R., Allolio, B., Arlt, W., Barthel, A., Don-Wauchope, A., Hammer, G.D., etal. (2016) Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. TheJournalofClinicalEndocrinology&Metabolism, 101, 364-389. https://doi.org/10.1210/jc.2015-1710
[20]
Ogawa, W. and Sakaguchi, K. (2015) Euglycemic Diabetic Ketoacidosis Induced by SGLT2 Inhibitors: Possible Mechanism and Contributing Factors. JournalofDiabetesInvestigation, 7, 135-138. https://doi.org/10.1111/jdi.12401
[21]
Taylor, S.I., Blau, J.E. and Rother, K.I. (2015) SGLT2 Inhibitors May Predispose to Ketoacidosis. TheJournalofClinicalEndocrinology&Metabolism, 100, 2849-2852. https://doi.org/10.1210/jc.2015-1884
[22]
Ferrannini, E., Muscelli, E., Frascerra, S., Baldi, S., Mari, A., Heise, T., etal. (2014) Metabolic Response to Sodium-Glucose Cotransporter 2 Inhibition in Type 2 Diabetic Patients. JournalofClinicalInvestigation, 124, 499-508. https://doi.org/10.1172/jci72227
[23]
Merovci, A., Solis-Herrera, C., Daniele, G., Eldor, R., Fiorentino, T.V., Tripathy, D., etal. (2014) Dapagliflozin Improves Muscle Insulin Sensitivity but Enhances Endogenous Glucose Production. JournalofClinicalInvestigation, 124, 509-514. https://doi.org/10.1172/jci70704
[24]
Cohen, J.J., Berglund, F. and Lotspeich, W.D. (1955) Renal Tubular Reabsorption of Acetoacetate, Inorganic Sulfate and Inorganic Phosphate in the Dog as Affected by Glucose and Phlorizin. AmericanJournalofPhysiology-LegacyContent, 184, 91-96. https://doi.org/10.1152/ajplegacy.1955.184.1.91
[25]
Rosenstock, J. and Ferrannini, E. (2015) Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern with SGLT2 Inhibitors. DiabetesCare, 38, 1638-1642. https://doi.org/10.2337/dc15-1380
[26]
Burke, K.R., Schumacher, C.A. and Harpe, S.E. (2017) sglt2 Inhibitors: A Systematic Review of Diabetic Ketoacidosis and Related Risk Factors in the Primary Literature. Pharmacotherapy:TheJournalofHumanPharmacologyandDrugTherapy, 37, 187-194. https://doi.org/10.1002/phar.1881