PMID- 27981497 OWN - NLM STAT- MEDLINE DCOM- 20170814 LR - 20181202 IS - 1865-8652 (Electronic) IS - 0741-238X (Print) IS - 0741-238X (Linking) VI - 34 IP - 2 DP - 2017 Feb TI - Factors Affecting Canagliflozin-Induced Transient Urine Volume Increase in Patients with Type 2 Diabetes Mellitus. PG - 436-451 LID - 10.1007/s12325-016-0457-8 [doi] AB - INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. CLINICAL TRIAL REGISTRATION: UMIN000019462. FUNDING: Mitsubishi Tanabe Pharma Corporation. FAU - Tanaka, Hiroyuki AU - Tanaka H AD - Medical Affairs Department II, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. FAU - Takano, Kazuhiko AU - Takano K AD - Medical Corporation Hokubukai Utsukushigaoka Hospital, Sapporo, Japan. FAU - Iijima, Hiroaki AU - Iijima H AD - Science Communication Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. Iijima.Hiroaki@mm.mt-pharma.co.jp. FAU - Kubo, Hajime AU - Kubo H AD - Ikuyaku Medical Research Department, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan. FAU - Maruyama, Nobuko AU - Maruyama N AD - Clinical Planning Department II, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. FAU - Hashimoto, Toshio AU - Hashimoto T AD - Product Coordination Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. FAU - Arakawa, Kenji AU - Arakawa K AD - Ikuyaku Medical Research Department, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan. FAU - Togo, Masanori AU - Togo M AD - Medical Science Center, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan. FAU - Inagaki, Nobuya AU - Inagaki N AD - Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan. FAU - Kaku, Kohei AU - Kaku K AD - Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan. LA - eng PT - Clinical Trial PT - Journal Article DEP - 20161215 PL - United States TA - Adv Ther JT - Advances in therapy JID - 8611864 RN - 0 (Blood Glucose) RN - 0 (Hypoglycemic Agents) RN - 0 (Peptide Fragments) RN - 0 (Sodium-Glucose Transporter 2) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (pro-brain natriuretic peptide (1-76)) RN - 0SAC974Z85 (Canagliflozin) RN - 114471-18-0 (Natriuretic Peptide, Brain) MH - Adult MH - Blood Glucose/analysis MH - *Canagliflozin/administration & dosage/adverse effects MH - *Dehydration/chemically induced/diagnosis/metabolism/prevention & control MH - *Diabetes Mellitus, Type 2/blood/drug therapy/epidemiology/urine MH - Female MH - *Glycosuria/chemically induced/diagnosis MH - Humans MH - Hypoglycemic Agents/administration & dosage/adverse effects MH - Japan/epidemiology MH - Male MH - Middle Aged MH - Natriuretic Peptide, Brain/blood MH - Peptide Fragments/blood MH - *Sodium-Glucose Transporter 2/metabolism MH - Sodium-Glucose Transporter 2 Inhibitors MH - Treatment Outcome PMC - PMC5331075 OTO - NOTNLM OT - Canagliflozin OT - Diuresis OT - Natriuresis OT - Sodium glucose co-transporter 2 OT - Type 2 diabetes mellitus EDAT- 2016/12/17 06:00 MHDA- 2017/08/15 06:00 PMCR- 2016/12/15 CRDT- 2016/12/17 06:00 PHST- 2016/10/06 00:00 [received] PHST- 2016/12/17 06:00 [pubmed] PHST- 2017/08/15 06:00 [medline] PHST- 2016/12/17 06:00 [entrez] PHST- 2016/12/15 00:00 [pmc-release] AID - 10.1007/s12325-016-0457-8 [pii] AID - 457 [pii] AID - 10.1007/s12325-016-0457-8 [doi] PST - ppublish SO - Adv Ther. 2017 Feb;34(2):436-451. doi: 10.1007/s12325-016-0457-8. Epub 2016 Dec 15.