title: SGLT2 Inhibitors May Predispose to Ketoacidosis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 α-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 could also increase the plasma ketone body levels.
  
  
  CONCLUSIONS
  Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.
authors.affiliation: 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.
authors.forename: Simeon I
authors.initials: SI
authors.lastname: Taylor
authors.affiliation: 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.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Blau
authors.affiliation: 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.
authors.forename: Kristina I
authors.initials: KI
authors.lastname: Rother
mesh_terms: D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000453:epidemiology; D016883:Diabetic Ketoacidosis / Q000139:chemically induced* / Q000453:epidemiology; D004198:Disease Susceptibility; D005960:Glucosides / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D014481:United States / Q000453:epidemiology
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin