Pharmacokinetics (PK) and Pharmacodynamics (PD) of Dapagliflozin (DAPA) in Combination with Insulin in Japanese Patients with T1D
Authors: WATADA HIROTAKA , SHIRAMOTO MASANARI , UEDA SHINYA , TANG WEIFENG , ASANO MICHIKO , THOREN FREDRIK A. , KIM HYOSUNG , YAJIMA TOSHITAKA , BOULTON DAVID W. , ARAKI EIICHI 
Published: June 2018

This study evaluated the PK/PD of DAPA, a selective SGLT2 inhibitor, in Japanese T1D patients with poor glycemic control (A1C 7-10%; NCT02582840). Patients were randomized 1:1:1 to DAPA 5 mg, 10 mg or placebo (PBO; n=14 each) once daily for 7 days with adjustable insulin. Mean (SD) age was 39 (10) years, mean (SD) T1D duration was 16 (11) years and mean (SD) A1C was 8.0 (0.7)%. DAPA added to insulin resulted in dose-proportional increase in Cmax and AUCτ (Figure). Mean (SD) changes in 24h urinary glucose excretion (UGE) from baseline (BL) to Day 7 were 96.55 (30.08), 101.28 (20.13) and -6.16 (30.34) g/24h for DAPA 5 mg, 10 mg, and PBO, respectively, consistent with previous DAPA experience but with attenuated dose-response. Mean (SE) changes in total daily insulin dose from BL to Day 7 were larger than expected; -36.86 (3.32), -39.13 (2.68) and -4.97 (5.28)% for DAPA 5 mg, 10 mg and PBO, respectively. This reduction may be responsible for the attenuated glycemic response affecting UGE (explored in a separate abstract); mean (SD) changes in 7-point SMBG values from BL to Day 7 were -1.99 (23.58), -5.68 (40.36) and 6.54 (52.69) mg/dL for DAPA 5 mg, 10 mg and PBO, respectively. No DKA was reported. Adverse events and other laboratory findings were in line with the known DAPA safety profile; there was no increase in hypoglycemia. DAPA may be a clinically relevant adjunctive therapy for patients with T1D.

Disclosure
H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation. M. Shiramoto: None. S. Ueda: Employee; Self; AstraZeneca. W. Tang: Employee; Self; AstraZeneca. M. Asano: None. F.A. Thoren: Employee; Self; AstraZeneca. H. Kim: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. T. Yajima: Employee; Self; AstraZeneca. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. E. Araki: Speaker's Bureau; Self; Astellas Pharma US, Inc., MSD K.K., Kowa Pharmaceuticals America, Inc., Sanofi, Novo Nordisk Inc.. Research Support; Self; Astellas Pharma US, Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Takeda Pharmaceuticals U.S.A., Inc., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Sanofi, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co..