title: Factors Affecting Canagliflozin-Induced Transient Urine Volume Increase in Patients with Type 2 Diabetes Mellitus.
abstract: Sodium glucose co-transporter 2 (SGLT2) inhibitors exhibit diuretic activity, which is a possible mechanism underlying the cardiovascular benefit of these inhibitors. However, the osmotic diuresis-induced increase in urine volume, and the risk of dehydration have been of concern with SGLT2 inhibitor treatment. This study aimed to investigate the mechanism underlying SGLT2 inhibitor canagliflozin-induced diuresis in Japanese type 2 diabetes mellitus (T2DM) patients.
  
  
  
  Thirteen T2DM patients received a daily oral dose of 100 mg canagliflozin before breakfast for 6 days. Blood and urine samples were collected at predetermined time points. The primary endpoint was evaluation of correlations between changes from baseline in urine volume and factors that are known to affect urine volume and between actual urine volume and these factors.
  
  
  
  Canagliflozin transiently increased urine volume and urinary sodium excretion on Day 1 with a return to baseline levels thereafter. Canagliflozin administration increased urinary glucose excretion, which was sustained during repeated-dose administration. Plasma atrial natriuretic peptide (ANP) and N-terminal pro-b-type natriuretic peptide (NT-proBNP) levels decreased, while plasma renin activity increased. On Day 1 of treatment, changes in sodium and potassium excretion were closely correlated with changes in urine output. A post hoc multiple regression analysis showed changes in sodium excretion and water intake as factors that affected urine volume change at Day 1. Furthermore, relative to that at baseline, canagliflozin decreased blood glucose throughout the day and increased plasma total GLP-1 after breakfast.
  
  
  
  Canagliflozin induced transient sodium excretion and did not induce water intake at Day 1; hence, natriuresis rather than glucose-induced osmotic diuresis may be a major factor involved in the canagliflozin-induced transient increase in urine output. In addition, canagliflozin decreased plasma ANP and NT-proBNP levels and increased plasma renin activity, which may be a compensatory mechanism for sodium retention, leading to subsequent urine output recovery.
  
  
  
  UMIN000019462.
  
  
  
  Mitsubishi Tanabe Pharma Corporation.
authors.affiliation: Medical Affairs Department II, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Medical Corporation Hokubukai Utsukushigaoka Hospital, Sapporo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takano
authors.affiliation: Science Communication Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. Iijima.Hiroaki@mm.mt-pharma.co.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Iijima
authors.affiliation: Ikuyaku Medical Research Department, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
authors.affiliation: Clinical Planning Department II, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Maruyama
authors.affiliation: Product Coordination Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Ikuyaku Medical Research Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Arakawa
authors.affiliation: Medical Science Center, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Togo
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
authors.affiliation: Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kaku
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D000068896:Canagliflozin / Q000008:administration & dosage / Q000009:adverse effects; D003681:Dehydration / Q000139:chemically induced / Q000175:diagnosis / Q000378:metabolism / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology / Q000652:urine; D005260:Female; D006029:Glycosuria / Q000139:chemically induced / Q000175:diagnosis; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C109794:pro-brain natriuretic peptide (1-76); D000068896:Canagliflozin; D020097:Natriuretic Peptide, Brain
keywords: Canagliflozin; Diuresis; Natriuresis; Sodium glucose co-transporter 2; Type 2 diabetes mellitus