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Ketosis and Diabetic Ketoacidosis in Response to SGLT2 Inhibitors: Basic Mechanisms and Therapeutic Perspectives Hongyu Qiu, MD1,2, Aleksandra Novikov, MD2,3, and Volker Vallon, MD2,3* 1 Department of Nephrology, West China Hospital, Sichuan University, Chengdu Sichuan, P. R. China 2 Division of Nephrology Hypertension, Departments of Medicine and Pharmacology, University of California San Diego, La Jolla, California 92093 3 VA San Diego Healthcare System, San Diego, California 92161 Running head: SGLT2 inhibition and ketoacidosis Corresponding author: Volker Vallon, MD UC San Diego and VA San Diego Healthcare System 3350 La Jolla Village Dr. (9151) San Diego, CA 92161 Phone: (001) 858-552-8585 ext 5945 Fax: (001) 858- 642-1438 E-mail: vvallon@ This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/dmrr.2886 This article is protected by copyright. All rights reserved. Abstract Inhibitors of the sodium-glucose cotransporter SGLT2 are a new class of anti-hyperglycemic 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