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1. Effect of tofogliflozin on arterial stiffness in patients with type 2 diabetes: prespecified sub-analysis of the prospective, randomized, open-label, parallel-group comparative UTOPIA trial

Author

Naoto Katakami, Tomoya Mita, Hidenori Yoshii, Toshihiko Shiraiwa, Tetsuyuki Yasuda, Yosuke Okada, Keiichi Torimoto, Yutaka Umayahara, Hideaki Kaneto, Takeshi Osonoi, Tsunehiko Yamamoto, Nobuichi Kuribayashi, Kazuhisa Maeda, Hiroki Yokoyama, Keisuke Kosugi, Kentaro Ohtoshi, Isao Hayashi, Satoru Sumitani, Mamiko Tsugawa, Kayoko Ryomoto, Hideki Taki, Tadashi Nakamura, Satoshi Kawashima, Yasunori Sato, Hirotaka Watada, Iichiro Shimomura, and On behalf of the UTOPIA study investigators

Subjects
Arterial stiffness, Pulse wave velocity, Arteriosclerosis, Diabetes, SGLT2 inhibitor, Tofogliflozin, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background Tofogliflozin, an SGLT2 inhibitor, is associated with favorable metabolic effects, including improved glycemic control and serum lipid profile and decreased body weight, visceral adipose tissue, and blood pressure (BP). This study evaluated the effects of tofogliflozin on the brachial-ankle pulse wave velocity (baPWV) in patients with type 2 diabetes (T2DM) without a history of apparent cardiovascular disease. Methods The using tofogliflozin for possible better intervention against atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. As one of the prespecified secondary outcomes, changes in baPWV over 104 weeks were evaluated in 154 individuals (80 in the tofogliflozin group and 74 in the conventional treatment group) who completed baPWV measurement at baseline. Results In a mixed-effects model, the progression in the right, left, and mean baPWV over 104 weeks was significantly attenuated with tofogliflozin compared to that with conventional treatment (– 109.3 [– 184.3, – 34.3] (mean change [95% CI] cm/s, p = 0.005; – 98.3 [– 172.6, – 24.1] cm/s, p = 0.010; – 104.7 [– 177.0, – 32.4] cm/s, p = 0.005, respectively). Similar findings were obtained even after adjusting the mixed-effects models for traditional cardiovascular risk factors, including body mass index (BMI), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, systolic blood pressure (SBP), hypertension, smoking, and/or administration of drugs, including hypoglycemic agents, antihypertensive agents, statins, and anti-platelets, at baseline. The findings of the analysis of covariance (ANCOVA) models, which included the treatment group, baseline baPWV, and traditional cardiovascular risk factors, resembled those generated by the mixed-effects models. Conclusions Tofogliflozin significantly inhibited the increased baPWV in patients with T2DM without a history of apparent cardiovascular disease, suggesting that tofogliflozin suppressed the progression of arterial stiffness. Trial Registration UMIN000017607. Registered 18 May 2015. ( https://www.umin.ac.jp/icdr/index.html )

Published
2021
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2. Tofogliflozin does not delay progression of carotid atherosclerosis in patients with type 2 diabetes: a prospective, randomized, open-label, parallel-group comparative study

Author

Naoto Katakami, Tomoya Mita, Hidenori Yoshii, Toshihiko Shiraiwa, Tetsuyuki Yasuda, Yosuke Okada, Keiichi Torimoto, Yutaka Umayahara, Hideaki Kaneto, Takeshi Osonoi, Tsunehiko Yamamoto, Nobuichi Kuribayashi, Kazuhisa Maeda, Hiroki Yokoyama, Keisuke Kosugi, Kentaro Ohtoshi, Isao Hayashi, Satoru Sumitani, Mamiko Tsugawa, Kayoko Ryomoto, Hideki Taki, Tadashi Nakamura, Satoshi Kawashima, Yasunori Sato, Hirotaka Watada, Iichiro Shimomura, and the UTOPIA study investigators

Subjects
Atherosclerosis, Diabetes, Intima-media thickness, SGLT2 inhibitor, Tofogliflozin, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Background This study aimed to investigate the preventive effects of tofogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD) by monitoring carotid intima-media thickness (IMT). Methods This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study included 340 subjects with T2DM and no history of apparent CVD recruited at 24 clinical units. Subjects were randomly allocated to either the tofogliflozin treatment group (n = 169) or conventional treatment group using drugs other than SGLT2 inhibitors (n = 171). Primary outcomes were changes in mean and maximum common carotid IMT measured by echography during a 104-week treatment period. Results In a mixed-effects model for repeated measures, the mean IMT of the common carotid artery (mean-IMT-CCA), along with the right and left maximum IMT of the CCA (max-IMT-CCA), significantly declined in both the tofogliflozin (− 0.132 mm, SE 0.007; − 0.163 mm, SE 0.013; − 0.170 mm, SE 0.020, respectively) and the control group (− 0.140 mm, SE 0.006; − 0.190 mm, SE 0.012; − 0.190 mm, SE 0.020, respectively). Furthermore, the tofogliflozin and the conventional treatment group did not significantly differ in the progression of the mean-IMT-CCA (mean change (95% CI) 0.008 (− 0.009, 0.025) mm, P = 0.34), along with the right (mean change (95% CI) 0.027 (− 0.005, 0.059) mm, P = 0.10) and the left max-IMT-CCA (mean change (95% CI) 0.020 (− 0.030, 0.070), P = 0.43). Similar findings were obtained even after adjusting for traditional CV risk factors and/or administration of drugs at baseline. Relative to the control treatment effects, tofogliflozin significantly reduced the HbA1c, blood glucose level, body weight/body mass index, abdominal circumference, and systolic blood pressure, and significantly increased the HDL-C. The total and serious adverse events incidences did not significantly vary between the treatment groups. Conclusions/interpretation No IMT changes were observed between the tofogliflozin and the conventional treatment groups. However, tofogliflozin is a safe and effective treatment option for managing primary CVD risk factors in this population. Clinical Trial Registration UMIN000017607 ( https://www.umin.ac.jp/icdr/index.html ).

Published
2020
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3. Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry)

Author

Masakazu Kobayashi, Hirohito Sone, Haruhiko Osawa, Daisuke Koya, Takanori Miura, Yoshihito Atsumi, Udai Nakamura, Eiichi Araki, Hitoshi Shimano, Yukio Tanizawa, Jiro Nakamura, Yuichiro Yamada, Nobuya Inagaki, Atsuko Abiko, Hideki Katagiri, Michio Hayashi, Keiko Naruse, Shimpei Fujimoto, Masazumi Fujiwara, Kenichi Shikata, Yosuke Okada, Tsutomu Yamazaki, Sou Nagai, Katsuyuki Yanagisawa, Hiromichi Kijima, Shinji Taneda, Shigeyuki Saitoh, Daisuke Ikeda, Fuminori Hirano, Haruhiko Yoshimura, Mitsutaka Inoue, Masahiko Katoh, Osamu Nakagaki, Chiho Yamamoto, Akitsuki Morikawa, Shin Furukawa, Takeshi Koshiya, Hajime Sugawara, Takumi Uchida, Noe Takakubo, Yasushi Ishigaki, Susumu Suzuki, Takashi Shimotomai, Naoki Tamasawa, Jun Matsui, Takashi Goto, Toshihide Oizumi, Shinji Susa, Makoto Daimon, Hiroshi Murakami, Takashi Sugawara, Hiroaki Akai, Mari Nakamura, Yoshiji Ogawa, Takao Yokoshima, Tsuyoshi Watanabe, Michio Shimabukuro, Kazuhisa Tsukamoto, Motoei Kunimi, Jo Satoh, Atushi Okuyama, Kazutaka Ogawa, Hideyuki Eguchi, Mamoru Kimura, Hiroshi Kouno, Yohei Horikawa, Shin Ikejima, Masaru Saitoh, Naoyoshi Minami, Akihiro Sekikawa, Toyoyoshi Uchida, Toshihide Kawai, Nobuya Fujita, Ken Tomotsune, Shigeo Yamashita, Motoji Naka, Toru Hiyoshi, Tomotaka Katoh, Kumiko Hamano, Kouichi Inukai, Takuma Kondo, Kazuhiro Tsumura, Yoko Matsuzawa, Masahiro Mimura, Masahiko Kawasumi, Izumi Takei, Masafumi Matsuda, Ichiro Tatsuno, Nobuyuki Banba, Akihiko Ando, Masao Toyoda, Daisuke Suzuki, Takahiro Iijima, Yasumichi Mori, Yutaka Uehara, Yoshihiko Satoh, Kazuaki Yahata, Yoshimasa Asoh, Koichiro Kuwabara, Souichi Takizawa, Yasushi Tanaka, Koutaroh Yokote, Masako Tohgo, Takanobu Itoi, Shigeru Miyazaki, Hiroshi Itoh, Teruo Shiba, Takahisa Hirose, Mariko Higa, Masanobu Yamada, Osamu Ogawa, Masatoshi Kuroki, Shinobu Satoh, Makoto Ujihara, Kenjiroh Yamanaka, Hajime Koyano, Tadashi Yamakawa, Kenichiroh Takahashi, Kazuki Orime, Tsutomu Hirano, Jiroh Morimoto, Takashi Itoh, Yuzoh Mizuno, Naoyuki Yamamoto, Han Miyatake, Mina Yamaguchi, Kenji Yamane, Masahiko Kure, Satoko Kawabe, Masahumi Kakei, Masashi Yoshida, Hiroyuki Itoh, Nobuaki Minami, Kazuki Kobayashi, Yusuke Fujino, Makoto Shibuya, Midori Hosokawa, Isao Nozaki, Chigure Nawa, Tamio Ieiri, Takayuki Watanabe, Yoshio Katoh, Takuyuki Katabami, Michiko Handa, Issei Shimada, Kenichi Ohya, Yoshihiro Ogawa, Takanobu Yoshimoto, Jiroh Nakamura, Naotsuka Okayama, Kenro Imaeda, Syuko Yoshioka, Masako Murakami, Takashi Murase, Yoshihiko Yamada, Yutaka Yano, Hiromitsu Sasaki, Yasuhiro Sumida, Osamu Yonaha, Hiroshi Sobajima, Mitsuyasu Ito, Atushi Suzuki, Atsuko Ishikawa, Takehiko Ichikawa, Shogo Asano, Shinobu Goto, Sakuma Hiroya, Hiroshi Murase, Shozo Ogawa, Hideki Okamoto, Kotaro Nagai, Koji Nagayama, Masanori Yoshida, Norio Takahashi, Kazuhisa Takami, Tsuneo Ono, Takanobu Morihiro, Daisuke Tanaka, Noriko Takahara, Satoshi Miyata, Mamiko Tsugawa, Koichiro Yasuda, Seiji Muro, Masanori Emoto, Ikuo Mineo, Ichiro Shiojima, Takeshi Kurose, Makoto Ohashi, Yumiko Kawabata, Mitsushige Nishikawa, Emiko Nomura, Yasuyuki Nishimura, Yasuhiro Ono, Yasuhisa Yamamoto, Keigo Naka, Taizo Yamamoto, Rika Usuda, Hiroshi Akahori, Seika Kato, Hiroyuki Konya, Yutaka Umayahara, Takashi Seta, Hideki Taki, Masashi Sekiya, Shinichi Mogami, Sumie Fujii, Toshiyuki Hibuse, Shingo Tsuji, Hirofumi Sumi, Yasuro Kumeda, Akinori Kogure, Kenji Furukawa, Akira Kuroe, Hideaki Sawaki, Narihiro Hibiki, Yoshihiro Kitagawa, Yukihiro Bando, Akira Ono, Rikako Uenaka, Seitaro Omoto, Yuki Kita, Eiko Ri, Ryutaro Numaguchi, Sachiko Kawashima, Ichiro Kisimoto, Kiminori Hosoda, Yoshihiko Araki, Tetsuroh Arimura, Mitsuru Hashiramoto, Koumei Takeda, Akira Matsutani, Yasushi Inoue, Fumio Sawano, Nozomu Kamei, Yasuo Ito, Miwa Morita, Yoshiaki Oda, Rui Kishimoto, Katsuhiro Hatao, Tomoatsu Mune, Fumiko Kawasaki, Hiroki Teragawa, Ken Yaga, Keita Ishii, Kyouji Hirata, Tatsuaki Nakatou, Yutaka Nitta, Naoki Fujita, Masayasu Yoneda, Masatoshi Tsuru, Shinichirou Ando, Toshiaki Kakiba, Michihiro Toyoshige, Tsuguka Shiwa, Hiroaki Miyaoka, Yasumi Shintani, Takenori Sakai, Tetsuji Niiya, Shinpei Fujimoto, Hisaka Minami, Yoshihiko Noma, Masaaki Tamaru, Yoshitaka Sayou, Tomoyo Oyama, Masamoto Torisu, Yuichi Fujinaka, Yoshitaka Kumon, Shozo Miyauchi, Morikazu Onji, Toru Nakamura, Yousuke Okada, Toshihiko Yanase, Kenro Nishida, Syuji Nakamura, Kunihisa Kobayashi, Nobuhiko Wada, Moritake Higa, Koji Matsushita, Yoshihiko Nishio, Ryoji Fujimoto, Yasuyuki Kihara, Shinichiro Mine, Tadashi Arao, Hiromi Tasaki, Yasuto Matsuo, Hirofumi Matsuda, Kohei Uriu, Kazuko Kanda, Kazuo Ibaraki, Yoshio Kaku, Yasuhiro Takaki, Iwaho Hazekawa, Kenji Ebihara, Eiichiro Watanabe, Iku Sakurada, Kazuhisa Muraishi, Tamami Oshige, Junichi Yasuda, Toyoshi Iguchi, Noriyuki Sonoda, Masahiro Adachi, Isao Ichino, Yuko Horiuchi, Souichi Uekihara, Shingo Morimitsu, Mitsuhiro Nakazawa, Tadashi Seguchi, and Kengo Kaneko

Subjects
Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Introduction Given an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methods We registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.Results Of the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.Conclusions Alogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Published
2021
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4. Comparative Effects of Direct Renin Inhibitor and Angiotensin Receptor Blocker on Albuminuria in Hypertensive Patients with Type 2 Diabetes. A Randomized Controlled Trial.

Author

Takashi Uzu, Shin-Ichi Araki, Atsunori Kashiwagi, Masakazu Haneda, Daisuke Koya, Hiroki Yokoyama, Yasuo Kida, Motoyoshi Ikebuchi, Takaaki Nakamura, Masataka Nishimura, Noriko Takahara, Toshiyuki Obata, Nobuyuki Omichi, Katsuhiko Sakamoto, Ryosuke Shingu, Hideki Taki, Yoshio Nagai, Hiroaki Tokuda, Munehiro Kitada, Miwa Misawa, Akira Nishiyama, Hiroyuki Kobori, Hiroshi Maegawa, and Shiga Committee for Preventing Diabetic Nephropathy

Subjects
Medicine, Science
Abstract

In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity.We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to

Published
2016
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5. The Influence of Tofogliflozin on Treatment-Related Quality of Life in Patients with Type 2 Diabetes Mellitus

Author

Utopia Study Investigators, Yutaka Umayahara, Takeshi Osonoi, Hiroki Yokoyama, Tsunehiko Yamamoto, Mamiko Tsugawa, Toshihiko Shiraiwa, Naoto Katakami, Nobuichi Kuribayashi, Satoru Sumitani, Kayoko Ryomoto, Hidenori Yoshii, Keisuke Kosugi, Kazuhisa Maeda, Keiichi Torimoto, Iichiro Shimomura, Yosuke Okada, Hideki Taki, Tadashi Nakamura, Hirotaka Watada, Isao Hayashi, Tomoya Mita, Hideaki Kaneto, Yasunori Sato, Satoshi Kawashima, Kentaro Ohtoshi, and Tetsuyuki Yasuda

Subjects
medicine.medical_specialty, Waist, Type 2 diabetes mellitus, business.industry, Endocrinology, Diabetes and Metabolism, Tofogliflozin, Type 2 Diabetes Mellitus, medicine.disease, chemistry.chemical_compound, Quality of life (QOL), Quality of life, chemistry, Diabetes management, Internal medicine, Diabetes mellitus, Internal Medicine, Medicine, In patient, business, Trial registration, Sodium-glucose cotransporter 2 (SGLT2) inhibitor, Original Research
Abstract

Introduction Treatment-related quality of life (QOL) is an important aspect of diabetes management. We evaluated the influence of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, tofogliflozin, on treatment-related QOL in Japanese patients with type 2 diabetes mellitus (T2DM). Methods This is the prespecified subanalysis study of the “Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)” trial. Treatment-related QOL was evaluated at baseline, week 26, week 52, and week 104 after the initiation of the study using the Diabetes Therapy-Related QOL questionnaire (DTR-QOL). Among the 340 patients in the original UTOPIA study, a total of 252 patients (127, tofogliflozin group; 125, conventional treatment group) who completed the DTR-QOL questionnaire at baseline were the study subjects of the current subanalysis. Results The tofogliflozin and conventional treatment groups exhibited almost comparable baseline clinical characteristics, while the use of antihypertensive drugs and lipid-lowering agents was significantly lower in the tofogliflozin treatment group than in the conventional treatment group. Tofogliflozin treatment increased the total score of DTR-QOL7 from baseline (P

Published
2021

6. Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry)

Author

Masakazu Kobayashi, Hirohito Sone, Haruhiko Osawa, Daisuke Koya, Takanori Miura, Yoshihito Atsumi, Udai Nakamura, Eiichi Araki, Hitoshi Shimano, Yukio Tanizawa, Jiro Nakamura, Yuichiro Yamada, Nobuya Inagaki, Atsuko Abiko, Hideki Katagiri, Michio Hayashi, Keiko Naruse, Shimpei Fujimoto, Masazumi Fujiwara, Kenichi Shikata, Yosuke Okada, Tsutomu Yamazaki, Sou Nagai, Katsuyuki Yanagisawa, Hiromichi Kijima, Shinji Taneda, Shigeyuki Saitoh, Daisuke Ikeda, Fuminori Hirano, Haruhiko Yoshimura, Mitsutaka Inoue, Masahiko Katoh, Osamu Nakagaki, Chiho Yamamoto, Akitsuki Morikawa, Shin Furukawa, Takeshi Koshiya, Hajime Sugawara, Takumi Uchida, Noe Takakubo, Yasushi Ishigaki, Susumu Suzuki, Takashi Shimotomai, Naoki Tamasawa, Jun Matsui, Takashi Goto, Toshihide Oizumi, Shinji Susa, Makoto Daimon, Hiroshi Murakami, Takashi Sugawara, Hiroaki Akai, Mari Nakamura, Yoshiji Ogawa, Takao Yokoshima, Tsuyoshi Watanabe, Michio Shimabukuro, Kazuhisa Tsukamoto, Motoei Kunimi, Jo Satoh, Atushi Okuyama, Kazutaka Ogawa, Hideyuki Eguchi, Mamoru Kimura, Hiroshi Kouno, Yohei Horikawa, Shin Ikejima, Masaru Saitoh, Naoyoshi Minami, Akihiro Sekikawa, Toyoyoshi Uchida, Toshihide Kawai, Nobuya Fujita, Ken Tomotsune, Shigeo Yamashita, Motoji Naka, Toru Hiyoshi, Tomotaka Katoh, Kumiko Hamano, Kouichi Inukai, Takuma Kondo, Kazuhiro Tsumura, Yoko Matsuzawa, Masahiro Mimura, Masahiko Kawasumi, Izumi Takei, Masafumi Matsuda, Ichiro Tatsuno, Nobuyuki Banba, Akihiko Ando, Masao Toyoda, Daisuke Suzuki, Takahiro Iijima, Yasumichi Mori, Yutaka Uehara, Yoshihiko Satoh, Kazuaki Yahata, Yoshimasa Asoh, Koichiro Kuwabara, Souichi Takizawa, Yasushi Tanaka, Koutaroh Yokote, Masako Tohgo, Takanobu Itoi, Shigeru Miyazaki, Hiroshi Itoh, Teruo Shiba, Takahisa Hirose, Mariko Higa, Masanobu Yamada, Osamu Ogawa, Masatoshi Kuroki, Shinobu Satoh, Makoto Ujihara, Kenjiroh Yamanaka, Hajime Koyano, Tadashi Yamakawa, Kenichiroh Takahashi, Kazuki Orime, Tsutomu Hirano, Jiroh Morimoto, Takashi Itoh, Yuzoh Mizuno, Naoyuki Yamamoto, Han Miyatake, Mina Yamaguchi, Kenji Yamane, Masahiko Kure, Satoko Kawabe, Masahumi Kakei, Masashi Yoshida, Hiroyuki Itoh, Nobuaki Minami, Kazuki Kobayashi, Yusuke Fujino, Makoto Shibuya, Midori Hosokawa, Isao Nozaki, Chigure Nawa, Tamio Ieiri, Takayuki Watanabe, Yoshio Katoh, Takuyuki Katabami, Michiko Handa, Issei Shimada, Kenichi Ohya, Yoshihiro Ogawa, Takanobu Yoshimoto, Jiroh Nakamura, Naotsuka Okayama, Kenro Imaeda, Syuko Yoshioka, Masako Murakami, Takashi Murase, Yoshihiko Yamada, Yutaka Yano, Hiromitsu Sasaki, Yasuhiro Sumida, Osamu Yonaha, Hiroshi Sobajima, Mitsuyasu Ito, Atushi Suzuki, Atsuko Ishikawa, Takehiko Ichikawa, Shogo Asano, Shinobu Goto, Sakuma Hiroya, Hiroshi Murase, Shozo Ogawa, Hideki Okamoto, Kotaro Nagai, Koji Nagayama, Masanori Yoshida, Norio Takahashi, Kazuhisa Takami, Tsuneo Ono, Takanobu Morihiro, Daisuke Tanaka, Noriko Takahara, Satoshi Miyata, Mamiko Tsugawa, Koichiro Yasuda, Seiji Muro, Masanori Emoto, Ikuo Mineo, Ichiro Shiojima, Takeshi Kurose, Makoto Ohashi, Yumiko Kawabata, Mitsushige Nishikawa, Emiko Nomura, Yasuyuki Nishimura, Yasuhiro Ono, Yasuhisa Yamamoto, Keigo Naka, Taizo Yamamoto, Rika Usuda, Hiroshi Akahori, Seika Kato, Hiroyuki Konya, Yutaka Umayahara, Takashi Seta, Hideki Taki, Masashi Sekiya, Shinichi Mogami, Sumie Fujii, Toshiyuki Hibuse, Shingo Tsuji, Hirofumi Sumi, Yasuro Kumeda, Akinori Kogure, Kenji Furukawa, Akira Kuroe, Hideaki Sawaki, Narihiro Hibiki, Yoshihiro Kitagawa, Yukihiro Bando, Akira Ono, Rikako Uenaka, Seitaro Omoto, Yuki Kita, Eiko Ri, Ryutaro Numaguchi, Sachiko Kawashima, Ichiro Kisimoto, Kiminori Hosoda, Yoshihiko Araki, Tetsuroh Arimura, Mitsuru Hashiramoto, Koumei Takeda, Akira Matsutani, Yasushi Inoue, Fumio Sawano, Nozomu Kamei, Yasuo Ito, Miwa Morita, Yoshiaki Oda, Rui Kishimoto, Katsuhiro Hatao, Tomoatsu Mune, Fumiko Kawasaki, Hiroki Teragawa, Ken Yaga, Keita Ishii, Kyouji Hirata, Tatsuaki Nakatou, Yutaka Nitta, Naoki Fujita, Masayasu Yoneda, Masatoshi Tsuru, Shinichirou Ando, Toshiaki Kakiba, Michihiro Toyoshige, Tsuguka Shiwa, Hiroaki Miyaoka, Yasumi Shintani, Takenori Sakai, Tetsuji Niiya, Shinpei Fujimoto, Hisaka Minami, Yoshihiko Noma, Masaaki Tamaru, Yoshitaka Sayou, Tomoyo Oyama, Masamoto Torisu, Yuichi Fujinaka, Yoshitaka Kumon, Shozo Miyauchi, Morikazu Onji, Toru Nakamura, Yousuke Okada, Toshihiko Yanase, Kenro Nishida, Syuji Nakamura, Kunihisa Kobayashi, Nobuhiko Wada, Moritake Higa, Koji Matsushita, Yoshihiko Nishio, Ryoji Fujimoto, Yasuyuki Kihara, Shinichiro Mine, Tadashi Arao, Hiromi Tasaki, Yasuto Matsuo, Hirofumi Matsuda, Kohei Uriu, Kazuko Kanda, Kazuo Ibaraki, Yoshio Kaku, Yasuhiro Takaki, Iwaho Hazekawa, Kenji Ebihara, Eiichiro Watanabe, Iku Sakurada, Kazuhisa Muraishi, Tamami Oshige, Junichi Yasuda, Toyoshi Iguchi, Noriyuki Sonoda, Masahiro Adachi, Isao Ichino, Yuko Horiuchi, Souichi Uekihara, Shingo Morimitsu, Mitsuhiro Nakazawa, Tadashi Seguchi, and Kengo Kaneko

Subjects
Blood Glucose, safety, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Hypoglycemia, Group B, Diseases of the endocrine glands. Clinical endocrinology, dipeptidyl peptidase 4, Japan, Piperidines, Internal medicine, Diabetes mellitus, medicine, Humans, Hypoglycemic Agents, Prospective Studies, Adverse effect, Uracil, Aged, Dipeptidyl-Peptidase IV Inhibitors, business.industry, Incidence (epidemiology), Type 2 Diabetes Mellitus, registries, medicine.disease, RC648-665, Diabetes Mellitus, Type 2, type 2, diabetes mellitus, Clinical care/Education/Nutrition, business, Alogliptin
Abstract

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Published
2020

7. Effect of Tofogliflozin on Carotid Intima-Media Thickness in Patients with Type 2 Diabetes: Results from the Prospective, Randomized, Open-Label, Parallel-Group Comparative UTOPIA Trial

Author

Tomoya Mita, Utopia Study Investigators, Kazuhisa Maeda, Keiichi Torimoto, Naoto Katakami, Tetsuyuki Yasuda, Takeshi Osonoi, Yutaka Umayahara, Tsunehiko Yamamoto, Toshihiko Shiraiwa, Kayoko Ryomoto, Hirotaka Watada, Iichiro Shimomura, Hidenori Yoshii, Mamiko Tsugawa, Tadashi Nakamura, Isao Hayashi, Keisuke Kosugi, Hideaki Kaneto, Nobuichi Kuribayashi, Satoru Sumitani, Satoshi Kawashima, Kentaro Ohtoshi, Yasunori Sato, Yosuke Okada, Hideki Taki, and Hiroki Yokoyama

Subjects
Control treatment, business.industry, Abdominal circumference, Significant difference, Helsinki declaration, Management, chemistry.chemical_compound, chemistry, Medicine, In patient, Open label, Trial registration, business, Tofogliflozin
Abstract

Background: This study aimed to investigate the preventive effects of tofogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD) by monitoring carotid intima-media thickness (IMT). Methods: This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study included 340 subjects with T2DM but no history of apparent CVD recruited at 24 clinical units. Subjects were randomly allocated to either the tofogliflozin treatment group (n=169) or conventional treatment group using drugs other than SGLT2 inhibitors (n=171). Primary outcomes were changes in mean and maximum common carotid IMT measured by echography during a 104-week treatment period. Findings: Although the mean IMT of the common carotid artery (mean-IMT-CCA), along with the right and left maximum IMT of the CCA (max-IMT-CCA), statistically significantly declined in both the tofogliflozin (-0.132 mm, SE 0.007; -0.163 mm, SE 0.013; -0.170 mm, SE 0.020; respectively) and the control group (-0·140 mm, SE 0·006; -0·190 mm, SE 0·012; -0·190 mm, SE 0·020; respectively), no significant difference was observed between the two groups. Relative to the control treatment effects, tofogliflozin statistically significantly reduced the HbA1c, blood glucose level, body weight/body mass index, abdominal circumference, and systolic blood pressure, and statistically significantly increased the HDL-C. Interpretation: A tofogliflozin treatment regimen of 104 weeks was not associated with improved inhibition of carotid wall thickening in T2DM patients without apparent CVD, as compared to the effect of the control treatment. Trial Registration: UMIN000017607. Funding Statement: Kowa Co., Ltd., Tokyo, Japan. Declaration of Interests: Naoto Katakami is a staff member of the endowed chair established by funds from Kowa Co., Ltd., and has received research funds from MSD, and lecture fees from Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim, Daiichi Sankyo Inc., Eli Lilly, Kowa Pharmaceutical Co., Kyowa Hakko Kirin Co. Ltd., Mitsubishi Tanabe Pharma Co., Novartis Pharmaceuticals, Novo Nordisk Pharma, Ono Pharmaceutical Co., Taisho Toyama Pharmaceutical Co., Takeda Pharmaceutical Co., and Sanofi-Aventis, and Shionogi & Co. Tomoya Mita has received lecture fees from Astellas Pharma Inc., Daiichi Sankyo Inc., Eli Lilly, Kowa Pharmaceutical Co., Kyowa Hakko Kirin Co. Ltd., Mitsubishi Tanabe Pharma Co., Novo Nordisk Pharma, Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited and Sanofi-Aventis, scholarship donations from MSD K.K., Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co. Ltd., Sanofi-Aventis K.K., Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Terumo Corporation, Nippon Boehringer Ingelheim Co., Ltd., Novo Nordisk Pharma Ltd., Pfizer Japan Inc., Benefit One Health Care Inc., Mochida Pharmaceutical Co., Ltd., and Nitto Boseki Co., Ltd. as well as funds of endowed chair from MSD K.K., Takeda Pharmaceutical Company Limited. Toshihiko Shiraiwa has received lecture fees from Sanofi-Aventis K.K. and Takeda Pharmaceutical Company Limited and research funding from Novo Nordisk Pharma Ltd., Sanofi-Aventis K.K., Takeda Pharmaceutical Company Limited, AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., and Mitsubishi Tanabe Pharma Corporation. Tetsuyuki Yasuda has received lecture fees from Nippon Boehringer Ingelheim Co., Ltd. and Sanofi-Aventis K.K. Yosuke Okada has received lecture fees from Astellas Pharma Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Bayer Holding Ltd., Novartis Pharmaceuticals Corp., Novo Nordisk Pharma Ltd., Eli Lilly Japan K.K., and Kissei Pharmaceutical Co., Ltd. as well as research funding from Kowa Pharmaceutical Co. Ltd. and Mitsubishi Tanabe Pharma Corporation. Hideaki Kaneto has received lecture fees from Nippon Boehringer Ingelheim Co., Ltd., Sanofi-Aventis K.K., Novo Nordisk Pharma Ltd., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, AstraZeneca K.K., Astellas Pharma Inc., Novartis Pharmaceuticals Corp., and Sumitomo Dainippon Pharma Co.; scholarship donations from Novo Nordisk Pharma Ltd., Nippon Boehringer Ingelheim Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis K.K., Eli Lilly Japan K.K., Astellas Pharma Inc., Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, MSD K.K., Takeda Pharmaceutical Company Limited, AstraZeneca K.K., Mochida Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Kissei Pharmaceutical Co., Ltd., and Kyowa Hakko Kirin Co. Ltd; and research funding from Taisho Pharmaceutical Co., Sumitomo Dainippon Pharma Co. Takeshi Osonoi has received lecture fees from Takeda Pharmaceutical Company Limited, Astellas Pharma Inc., Novo Nordisk Pharma Ltd., and Sanwa Kagaku Kenkyusho Co., Ltd.; manuscript fees from Sanwa Kagaku Kenkyusho Co., Ltd.; and research funding from Takeda Pharmaceutical Company Limited, Novo Nordisk Pharma Ltd., Astellas Pharma Inc., Sanwa Kagaku Kenkyusho Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., Taisho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Daiichi Sankyo Company, Limited, Bayer Holding Ltd., Kowa Pharmaceutical Co. Ltd., and AbbVie Inc. Nobuichi Kuribayashi has received lecture fees from Takeda Pharmaceutical Company Limited, Sanofi-Aventis K.K., Novo Nordisk Pharma Ltd., MSD K.K., and Mitsubishi Tanabe Pharma Corporation. Satoru Sumitani has received lecture fees from Sumitomo Dainippon Pharma Co., Ltd. Yasunori Sato has received lecture fees from Mochida Pharmaceutical Co., Ltd. Hirotaka Watada has received lecture fees from Sumitomo Dainippon Pharma CO., Ltd., Bayer Yakuhin, Ltd. Sanofi-Aventis K.K., MSD K.K., Astellas Pharma Inc., Takeda Pharmaceutical Company Ltd, Mitsubishi Tanabe Pharma Co., AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Novo Nordisk Pharma Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Kowa Co., Ltd., Novartis Pharmaceuticals Corp., Daiichi Sankyo Company, Ltd, Kyowa Hakko Kirin Co. Ltd., Ono Pharmaceutical Co., Ltd., and Kissei Pharmaceutical Co., Ltd. and research support from Novartis Pharmaceuticals Corp., Otsuka Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., MSD K.K., Astellas Pharma Inc., Bayer Yakuhin, Ltd. Teijin Pharma Ltd., Ono Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co. Ltd., Kowa Pharmaceutical Co. Ltd., Sanofi-Aventis K.K., Sanwa Kagaku Kenkyusho Co., Ltd., Daiichi Sankyo Company, Ltd, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Ltd, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., Novo Nordisk Pharma Ltd., Pfizer Japan Inc., Shionogi & Co., Ltd. Yakult, and Kissei Pharmaceutical Co., Ltd. Iichiro Shimomura has received lecture fees from Astellas Pharma Inc., AstraZeneca K.K., MSD K.K., Ono Pharmaceutical Co., Kyowa Kirin Co., Ltd., Kowa Company, Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho Co., Daiichi Sankyo Co., Takeda Pharma K.K., Mitsubishi Tanabe Pharma Co., Teijin Pharma, Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Novartis Pharma K.K., Novo Nordisk Pharma, Mochida Pharmaceutical Co., Taisho Pharmaceutical Co. Ltd., Nippon Chemiphar Co., Ltd., Covidien Japan Inc., Amgen Astellas Biopharma K.K., KOBAYASHI Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Rohto Pharmaceutical Co., Ltd.; and research funds from Astellas Pharma Inc., MSD K.K, Ono Pharmaceutical Co., Kaken Pharmaceutical Co., Kyowa Kirin Co., Ltd., Sanofi K.K., Shionogi & Co., Daiichi Sankyo Co., Dainippon Sumitomo Pharma Co., Takeda Pharma K.K., Mitsubishi Tanabe Pharma Co., Teijin Pharma, Novartis Pharma K.K., Novo Nordisk Pharma, Eli Lilly Japan K.K, Kowa Company, Ltd.; and consulting fees from AstraZeneca K.K., MSD K.K., Taisho Pharmaceutical Co. Ltd., Novo Nordisk Pharma, Lotte Co., Ltd. Hidenori Yoshii, Yutaka Umayahara, Tsunehiko Yamamoto, Kazuhisa Maeda, Hiroki Yokoyama, Keisuke Kosugi, Kentaro Ohtoshi, Isao Hayashi, Mamiko Tsugawa, Kayoko Ryomoto, Hideki Taki, Tadashi Nakamura, and Satoshi Kawashima declare that they have no conflict of interest. Ethics Approval Statement: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients for being included in the study.

Published
2020

8. Rationale, Design, and Baseline Characteristics of the Utopia Trial for Preventing Diabetic Atherosclerosis Using an SGLT2 Inhibitor: A Prospective, Randomized, Open-Label, Parallel-Group Comparative Study

Author

Toshihiko Shiraiwa, Tomoya Mita, Naoto Katakami, Keisuke Kosugi, Tsunehiko Yamamoto, Takeshi Osonoi, Iichiro Shimomura, Yutaka Umayahara, Hidenori Yoshii, Satoshi Kawashima, Kazuhisa Maeda, Hirotaka Watada, Makoto Ohashi, Yasunori Sato, Mamiko Tsugawa, Hideaki Kaneto, Kentaro Ohtoshi, Yosuke Okada, Hideki Taki, Hiroki Yokoyama, Tetsuyuki Yasuda, Tadashi Nakamura, Isao Hayashi, Nobuichi Kuribayashi, and Satoru Sumitani

Subjects
medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Intima-media thickness, Tofogliflozin, Type 2 diabetes, 030204 cardiovascular system & hematology, Hypoglycemia, Diabetic nephropathy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, cardiovascular diseases, 030212 general & internal medicine, Adverse effect, Glycemic, Original Research, business.industry, Diabetes, SGLT2 inhibitor, medicine.disease, Atherosclerosis, Surgery, chemistry, business
Abstract

Introduction Sodium-glucose co-transporter-2 (SGLT2) inhibitors are anti-diabetic agents that improve glycemic control with a low risk of hypoglycemia and ameliorate a variety of cardiovascular risk factors. The aim of the ongoing study described herein is to investigate the preventive effects of tofogliflozin, a potent and selective SGLT2 inhibitor, on the progression of atherosclerosis in subjects with type 2 diabetes (T2DM) using carotid intima-media thickness (IMT), an established marker of cardiovascular disease (CVD), as a marker. Methods The Study of Using Tofogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, blinded-endpoint, multicenter, and parallel-group comparative study. The aim was to recruit a total of 340 subjects with T2DM but no history of apparent CVD at 24 clinical sites and randomly allocate these to a tofogliflozin treatment group or a conventional treatment group using drugs other than SGLT2 inhibitors. As primary outcomes, changes in mean and maximum IMT of the common carotid artery during a 104-week treatment period will be measured by carotid echography. Secondary outcomes include changes in glycemic control, parameters related to β-cell function and diabetic nephropathy, the occurrence of CVD and adverse events, and biochemical measurements reflecting vascular function. Conclusion This is the first study to address the effects of SGLT2 inhibitors on the progression of carotid IMT in subjects with T2DM without a history of CVD. The results will be available in the very near future, and these findings are expected to provide clinical data that will be helpful in the prevention of diabetic atherosclerosis and subsequent CVD. Funding Kowa Co., Ltd. Clinical Trial Registration UMIN000017607. Electronic supplementary material The online version of this article (doi:10.1007/s13300-017-0292-1) contains supplementary material, which is available to authorized users.

Published
2017

9. Survival of macrovascular disease, chronic kidney disease, chronic respiratory disease, cancer and smoking in patients with type 2 diabetes: BioBank Japan cohort

Author

Hiroshi Yokomichi, Akiko Nagai, Makoto Hirata, Yutaka Kiyohara, Kaori Muto, Toshiharu Ninomiya, Koichi Matsuda, Yoichiro Kamatani, Akiko Tamakoshi, Michiaki Kubo, Yusuke Nakamura, Zentaro Yamagata, Hiromasa Harada, Sunao Matsubayashi, Rieko Komi, Kazuo Misumi, Shiro Minami, Hitoshi Sugihara, Eitaro Kodani, Akio Kanazawa, Hiromasa Gotoh, Hidenori Haruna, Satoshi Asai, Mitsuhiko Moriyama, Yasuo Takahashi, Tomoaki Fujioka, Wataru Obara, Seijiro Mori, Hideki Ito, Satoshi Nagayama, Yoshio Miki, Akihide Masumoto, Akira Yamada, Yasuko Nishizawa, Ken Kodama, Satoshi Ugi, Shinichi Araki, Yukihiro Koretsune, Hideki Taki, and Takayuki Nakagawa

Subjects
Adult, Male, medicine.medical_specialty, Epidemiology, Respiratory Tract Diseases, Type 2 diabetes, Comorbidity, 030204 cardiovascular system & hematology, Risk Assessment, Cohort Studies, Diabetes Complications, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Japan, Diabetes mellitus, Internal medicine, Neoplasms, medicine, Risk of mortality, Humans, 030212 general & internal medicine, Vascular Diseases, Renal Insufficiency, Chronic, Macrovascular disease, Cancer, Aged, Biological Specimen Banks, Aged, 80 and over, lcsh:R5-920, business.industry, Respiratory disease, Hazard ratio, Diabetes, Smoking, General Medicine, Survival analysis, Middle Aged, medicine.disease, Cardiovascular diseases, Diabetes Mellitus, Type 2, Chronic Disease, Physical therapy, Original Article, Female, business, lcsh:Medicine (General), Kidney disease
Abstract

Background The number of patients with diabetes is increasing worldwide. Macrovascular disease, chronic kidney disease, chronic respiratory disease, cancer and smoking frequently accompany type 2 diabetes. Few data are available related to mortality of Asians with diabetes associated with these serious comorbidities. The present study aimed to quantify the excess mortality risks of type 2 diabetic patients with comorbidities. Methods We analysed the available records of 30,834 Japanese patients with type 2 diabetes from the BioBank Japan Project between 2003 and 2007. Men and women were followed up for median 8.03 and 8.30 years, respectively. We applied Cox proportional hazard model and Kaplan–Meier estimates for survival curves to evaluate mortality in diabetic patients with or without macrovascular disease, chronic respiratory disease, chronic kidney disease, cancer and smoking. Results Adjusted hazard ratios (HRs) for mortality were 1.39 (95% CI, 1.09–1.78) for male sex, 2.01 (95% CI, 1.78–2.26) per 10-year increment of age. Adjusted HRs of primary interest were 1.77 (95% CI, 1.42–2.22), macrovascular disease; 1.58 (95% CI, 1.08–2.31), chronic respiratory disease; 2.03 (95% CI, 1.67–2.47), chronic kidney disease; 1.16 (95% CI, 0.86–1.56), cancer; and 1.74 (95% CI, 1.30–2.31), current smoking. Conclusions Diabetic patients with a past or current history of chronic kidney, macrovascular or respiratory diseases or smoking habit have exhibited the highest risk of mortality. Data were limited to those of survivors of comorbidities but we propose the need to improve comorbidities and terminate cigarette smoking for better prognosis in patients with diabetes., Highlights • Fatal diseases frequently accompany diabetes. • Data for survival of Asian patients with diabetes with comorbidities are scarce. • Comorbid chronic kidney disease was associated with the most fatalities. • Current smoking was as fatal as 10 years of ageing in diabetic patients. • Values of 1% HbA1c and 10 mmHg blood pressure confer 11% excess mortality risk.

Published
2017

10. Clinical and endocrinological characteristics of adrenal incidentaloma in Osaka region, Japan

Author

Keisuke Kosugi, Akihisa Imagawa, Soji Kasayama, Mamiko Tsugawa, Michio Otsuki, Shogo Kurebayashi, Haruhiko Kouhara, Tsunehiko Yamamoto, Tohru Funahashi, Tadashi Nakamura, Iichiro Shimomura, Taka-aki Matsuoka, Hideki Taki, Makoto Ohashi, Ikuo Mineo, Yuya Yamada, Yutaka Umayahara, Kunihiko Hashimoto, and Yukiko Tabuchi

Subjects
Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Adrenal Gland Neoplasms, 030209 endocrinology & metabolism, Pheochromocytoma, 030204 cardiovascular system & hematology, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Primary aldosteronism, Japan, Internal medicine, Hyperaldosteronism, medicine, Humans, Aldosterone, Cushing Syndrome, Aged, Retrospective Studies, Subclinical infection, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Retrospective cohort study, Middle Aged, medicine.disease, Positron emission tomography, Abdominal ultrasonography, Female, business, Dyslipidemia
Abstract

The aim of this study was to investigate the clinical and endocrinological characteristics of adrenal incidentalomas in Osaka region, Japan. The study was a multicenter retrospective analysis of 150 patients with adrenal incidentalomas who underwent radiographic and endocrine evaluations between 2005 and 2013. Most adrenal incidentalomas were discovered by computed tomography (77.0%) and the rest were identified by abdominal ultrasonography (14.6%), magnetic resonance imaging (4.2%), or positron emission tomography (4.2%). Adrenal incidentalomas were more frequently localized on the left side than on the right. The average diameter of tumors was 21 ± 11 mm. On endocrinological evaluation, 14 patients were diagnosed with primary aldosteronism (9.3%), 10 with subclinical Cushing's syndrome (6.7%), 7 with pheochromocytoma (4.7%), 7 with Cushing's syndrome (4.7%), 2 with both subclinical Cushing's syndrome and primary aldosteronism (1.3%), and 110 with non-functioning tumors (73.3%). Patients with functioning tumors were significantly younger and had larger tumor diameters than those with non-functioning tumors. Except for hypertension, complications were comparable between patients with functioning and non-functioning tumors, including the presence of glucose intolerance, cardiovascular disease, and dyslipidemia. In conclusion, a higher prevalence of primary aldosteronism was observed compared with a previous report. Complications were comparable between patients with functioning and non-functioning tumors, including the frequencies of glucose intolerance, cardiovascular disease, and dyslipidemia. Long-term follow-up is required in patients with non-functioning tumors because the frequency of complications, such as glucose intolerance, cardiovascular disease, and dyslipidemia, was equal to that in patients with functioning tumors.

Published
2016

11. Serum glucose, cholesterol and blood pressure levels in Japanese type 1 and 2 diabetic patients: BioBank Japan

Author

Hiroshi Yokomichi, Akiko Nagai, Makoto Hirata, Yutaka Kiyohara, Kaori Muto, Toshiharu Ninomiya, Koichi Matsuda, Yoichiro Kamatani, Akiko Tamakoshi, Michiaki Kubo, Yusuke Nakamura, Zentaro Yamagata, Sunao Matsu-bayashi, Hiromasa Harada, Kazuo Misumi, Rieko Komi, Shiro Minami, Hitoshi Sugihara, Naoya Emoto, Akio Kanazawa, Yusuke Suzuki, Yoshimune Hiratsuka, Satoshi Asai, Mitsuhiko Moriyama, Yasuo Takahashi, Tomoaki Fujioka, Wataru Obara, Seijiro Mori, Hideki Ito, Satoshi Nagayama, Yoshio Miki, Akihide Masumoto, Akira Yamada, Yasuko Nishizawa, Ken Kodama, Satoshi Ugi, Hiroshi Maegawa, Yukihiro Koretsune, Hideki Taki, and Takeshi Osawa

Subjects
Adult, Blood Glucose, Male, medicine.medical_specialty, Epidemiology, Glycated haemoglobin A1c, Population, 030209 endocrinology & metabolism, Blood Pressure, Type 2 diabetes, Comorbidity, Diabetes Complications, 03 medical and health sciences, 0302 clinical medicine, Japan, Diabetes mellitus, Internal medicine, medicine, Humans, 030212 general & internal medicine, education, Survival analysis, Aged, Biological Specimen Banks, Type 1 diabetes, education.field_of_study, lcsh:R5-920, business.industry, Diabetes, Smoking, General Medicine, Middle Aged, medicine.disease, Survival Analysis, Endocrinology, Blood pressure, Cholesterol, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Original Article, Female, business, lcsh:Medicine (General), Body mass index, Kaplan–Meier estimate
Abstract

Background Evidence of characteristics of Japanese patients with diabetes from a large-scale population is necessary. Few studies have compared glycaemic controls, complications and comorbidities between type 1 and 2 diabetic patients. This paper focuses on illustrating a clinical picture of Japanese diabetic patients and comparing glycaemic control and prognoses between type 1 and 2 diabetes using multi-institutional data. Methods The BioBank Japan Project enrolled adult type 1 and 2 diabetic patients between fiscal years 2003 and 2007. We have presented characteristics, controls of serum glucose, cholesterol and blood pressure, prevalence of complications and comorbidities and survival curves. We have also shown glycaemic controls according to various individual profiles of diabetic patients. Results A total of 558 type 1 diabetic patients and 30,834 type 2 diabetic patients participated in this study. The mean glycated haemoglobin A1c was higher in type 1 diabetes than in type 2 diabetes. In the type 1 diabetic patients, the glycated haemoglobin A1c had no consistent trend according to age and body mass index. The Kaplan–Meier estimates represented a longer survival time from baseline with type 1 diabetes than with type 2 diabetes. Compared with type 1 diabetic patients, type 2 diabetic patients had double the prevalence of macrovascular complications. Conclusions This work has revealed detailed plasma glucose levels of type 1 and 2 diabetic patients according to age, body mass index, blood pressure, serum cholesterol levels and smoking and drinking habits. Our data have also shown that the prognosis is worse for type 2 diabetes than for type 1 diabetes in Japan., Highlights • Detailed glycaemic control data of diabetic patients are necessary. • Few studies have compared the survival times between type 1 and 2 diabetes. • Higher glycated HbA1c was observed in type 1 than in type 2 diabetes. • Data showed higher hazard ratio of mortality in type 1 than in type 2 diabetes. • Fewer macrovascular complications accompany type 1 than type 2 diabetes.

Published
2017

12. Effect of Home Blood Pressure on Inducing Remission/Regression of Microalbuminuria in Patients With Type 2 Diabetes Mellitus

Author

Motonobu Nishimura, Hideki Taki, Kazunori Yamada, Yutaka Ando, Tsuyoshi Tanaka, Seiji Suzuki, Atsuhito Tone, Yoshiharu Hoshiyama, Miho Saito, and Yasuhisa Kato

Subjects
Male, medicine.medical_specialty, Remission, Spontaneous, Urology, Spontaneous remission, Blood Pressure, 030204 cardiovascular system & hematology, Diabetic nephropathy, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Japan, Internal medicine, Internal Medicine, Medicine, Albuminuria, Humans, Diabetic Nephropathies, 030212 general & internal medicine, Prospective Studies, Aged, business.industry, Incidence (epidemiology), Incidence, Remission/regression, Hazard ratio, Remission Induction, Type 2 Diabetes Mellitus, Middle Aged, medicine.disease, Endocrinology, Blood pressure, Diabetes Mellitus, Type 2, Creatinine, Microalbuminuria, Female, business
Abstract

BACKGROUND The Home Blood Pressure for Diabetic Nephropathy study is a prospective observational study conducted to determine the effect of home blood pressure (HBP) on remission/regression of microalbuminuria in patients with type 2 diabetes mellitus (DM). METHODS Patients with type 2 DM having microalbuminuria were followed-up for 3 years. Remission of microalbuminuria was defined as shift from microalbuminuria to normoalbuminuria. Regression of microalbuminuria was defined as a 50% reduction in urinary albumin–creatinine ratio from baseline. All measurements of morning and evening HBP were averaged every year and defined as all HBP. RESULTS In total, 235 patients were followed up. The 3-year cumulative incidences of remission and regression were 32.3% and 44.7%, respectively. Following analysis of all cases, the degree of decline in all home systolic blood pressure (AHSBP), rather than mean AHSBP, influenced the incidence of remission/regression. There was a strong relationship between the decline in AHSBP during the follow-up period and AHSBP at baseline. Therefore, separate analyses of the patients with AHSBP below 140 mm Hg at baseline were performed, which revealed that mean AHSBP during the follow-up period independently affected the incidence of remission/regression. The hazard ratio for inducing remission/regression was significantly lower in patients with AHSBP during the follow-up period above 130 mm Hg than in those with AHSBP below 120 mm Hg. CONCLUSIONS Optimal AHSBP for the induction of remission/regression of microalbuminuria might be below 130 mm Hg. It is required to confirm whether keeping AHSBP below 130 mm Hg leads to subsequent renoprotection or not. CLINICAL TRIALS REGISTRATION Trial Number UMIN000000804.

Published
2016

13. Pyruvate improves deleterious effects of high glucose on activation of pentose phosphate pathway and glutathione redox cycle in endothelial cells

Author

Toshiyuki Obata, Noriko Takahara, Atsunori Kashiwagi, Hideki Hidaka, Ryuichi Kikkawa, Natsuki Harada, Takayuki Asahina, Motoyoshi Ikebuchi, Yasushi Tanaka, Hideki Taki, Yoshihiko Nishio, and Yukikazu Saeki

Subjects
medicine.medical_specialty, Umbilical Veins, Endocrinology, Diabetes and Metabolism, Pentose phosphate pathway, Biology, medicine.disease_cause, Umbilical vein, Pentose Phosphate Pathway, chemistry.chemical_compound, Adenosine Triphosphate, Diabetes mellitus, Internal medicine, Pyruvic Acid, medicine, Fructosediphosphates, Internal Medicine, Humans, Lactic Acid, Cells, Cultured, Glutathione, Hydrogen Peroxide, medicine.disease, NAD, In vitro, Endothelial stem cell, Endocrinology, Glucose, L-Glucose, chemistry, Endothelium, Vascular, Oxidation-Reduction, Oxidative stress, NADP
Abstract

In our previous study (Diabetes 44:520–526, 1995), endothelial cells cultured in high glucose condition showed impairment of an oxidant-induced activation of the pentose phosphate pathway (PPP) and a reduced supply of NADPH to the glutathione redox cycle. To gain insight into the mechanisms of this impairment, the protective effect of pyruvate was studied in human umbilical vein endothelial cells cultured in either 5.5 mmol/l glucose (normal glucose [NG] condition) or 33 mmol/l glucose (high glucose [HG] condition). Through pretreatment of cells with 0.2 mmol/l pyruvate for 5–7 days in the HG condition, glucose oxidation through the PPP and total cellular NADPH content in the presence of 0.2 mmol/l H2O2 were increased by 54 (P < 0.05) and 34%, respectively, and glutathione-dependent degradation of H2O2 in HG cells was enhanced by 41% (P < 0.01), when compared with those cells to which pyruvate was not added. The addition of pyruvate significantly reduced the fructose 1,6-bisphosphate (FDP) content and free cytoplasmic NADH/NAD ratio, estimated by increased pyruvate/lactate ratio in NG and HG cells exposed to H2O2. Furthermore, the addition of pyruvate also showed a 46% reduction (P < 0.01) of endothelial cell damage induced by H2O2 in HG cells. These results indicate that abnormalities in PPP activation and glutathione redox cycle activity induced by H2O2 in HG cells are compensated, and that the accentuated reductive stress is improved by an addition of pyruvate. These pyruvate effects are associated with protection against an oxidant-induced endothelial cell injury in the high glucose condition.

Published
1997

14. Rationale, Design, and Baseline Characteristics of the Utopia Trial for Preventing Diabetic Atherosclerosis Using an SGLT2 Inhibitor: A Prospective, Randomized, Open-Label, Parallel-Group Comparative Study.

Author

Naoto Katakami, Tomoya Mita, Hidenori Yoshii, Toshihiko Shiraiwa, Tetsuyuki Yasuda, Yosuke Okada, Yutaka Umayahara, Hideaki Kaneto, Takeshi Osonoi, Tsunehiko Yamamoto, Nobuichi Kuribayashi, Kazuhisa Maeda, Hiroki Yokoyama, Keisuke Kosugi, Kentaro Ohtoshi, Isao Hayashi, Satoru Sumitani, Mamiko Tsugawa, Makoto Ohashi, and Hideki Taki

Subjects
SODIUM-chloride cotransporter, ION channels, SODIUM cotransport systems, ATHEROSCLEROSIS, DIABETES complications, DIABETES prevention, CARDIOVASCULAR disease prevention
Abstract

Introduction: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are anti-diabetic agents that improve glycemic control with a low risk of hypoglycemia and ameliorate a variety of cardiovascular risk factors. The aim of the ongoing study described herein is to investigate the preventive effects of tofogliflozin, a potent and selective SGLT2 inhibitor, on the progression of atherosclerosis in subjects with type 2 diabetes (T2DM) using carotid intima-media thickness (IMT), an established marker of cardiovascular disease (CVD), as a marker. Methods: The Study of Using Tofogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, blinded-endpoint, multicenter, and parallel- group comparative study. The aim was to recruit a total of 340 subjects with T2DM but no history of apparent CVD at 24 clinical sites and randomly allocate these to a tofogliflozin treatment group or a conventional treatment group using drugs other than SGLT2 inhibitors. As primary outcomes, changes in mean and maximum IMT of the common carotid artery during a 104-week treatment period will be measured by carotid echography. Secondary outcomes include changes in glycemic control, parameters related to b-cell function and diabetic nephropathy, the occurrence of CVD and adverse events, and biochemical measurements reflecting vascular function. Conclusion: This is the first study to address the effects of SGLT2 inhibitors on the progression of carotid IMT in subjects with T2DM without a history of CVD. The results will be available in the very near future, and these findings are expected to provide clinical data that will be helpful in the prevention of diabetic atherosclerosis and subsequent CVD. [ABSTRACT FROM AUTHOR]

Published
2017
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15. Evaluation of peripheral vascular disease in hemodialysis patients using transcutaneous oximetry

Author

Iwao Mashiro, Hideki Taki, Yasuo Kida, Hiroko Nakagawa, Ryuichi Kikkawa, and Kazuhiko Ebata

Subjects
medicine.medical_specialty, Transcutaneous Oximetry, business.industry, Vascular disease, Internal medicine, medicine.medical_treatment, medicine, Cardiology, Hemodialysis, business, medicine.disease, Peripheral
Abstract

透析患者の下肢末梢循環障害の頻度, 虚血の程度を評価するため, 65例の透析患者 (HD群) と35例の性, 年齢をマッチした健常対照者 (C群) に安静仰臥位で足背の経皮酸素分圧 (TCPO2, 単位mmHg) を測定し比較した. さらに透析患者でのTCPO2低下の危険因子を調べた.1) TCPO2はC群と比べHD群は有意に低値であった (p

Published
1994

16. Clinical and immunologic characteristics of Japanese patients with anti-glomerular basement membrane disease: case reports and literature review

Author

Yoshinosuke Shimamura, Takuto Maeda, Koki Abe, Yayoi Ogawa, and Hideki Takizawa

Subjects
Anti-glomerular basement membrane disease, Literature review, Survival, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Abstract Background Clinical studies of anti-glomerular basement membrane (GBM) disease were limited because of the low incidence. We aimed to report the characteristics, treatments, and outcomes of patients with anti-GBM disease at a tertiary reference medical center in Japan and review the literature of mortality in patients with anti-GBM disease. Case presentation Case 1 was a 72-year-old Japanese man that was referred with worsening of the serum creatinine (from 1.1 to 27.3 mg/dL). Anti-GBM disease was confirmed by renal biopsy, and treatments with oral prednisolone and plasmapheresis were initiated. Although his anti-GBM antibody decreased (from 476 to 18 units/mL) after the treatments, the patient died from lung abscess. Case 2 was a 32-year-old Japanese man that presented with fever and macroscopic hematuria. At presentation, his serum creatinine was 4.2 mg/dL, and anti-GBM antibody was 265 units/mL. Renal biopsy confirmed the diagnosis of anti-GBM disease, and intensive treatments with plasmapheresis and methyl prednisolone were started, followed by oral prednisolone. Living-donor kidney transplantation was performed because his anti-GBM antibody had remained undetectable for 1 year after diagnosis. In the main text, clinicopathological characteristics of 12 patients with anti-GBM disease at our institution were summarized. Conclusions We found that the 1-year survival rate of patients with anti-GBM disease was 88% in our cohort, which was comparable to previous studies. Multicenter, nationwide studies are expected to evaluate prognosis of Japanese patients with this rare entity.

Published
2021
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17. Significance of urinary fatty acid-binding protein 4 level as a possible biomarker for the identification of minimal change disease in patents with nephrotic-range proteinuria

Author

Marenao Tanaka, Masato Furuhashi, Norihito Moniwa, Takuto Maeda, Hideki Takizawa, Megumi Matsumoto, Akiko Sakai, Yukimura Higashiura, Yufu Gocho, Masayuki Koyama, Yayoi Ogawa, and Tetsuji Miura

Subjects
Fatty acid-binding protein, Nephrotic syndrome, Membranous nephropathy, Minor glomerular abnormalities, Kidney biopsy, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Abstract Background Fatty acid-binding protein 4 (FABP4), but not FABP1 (liver-type FABP), is ectopically induced in injured glomerular endothelial cells, and urinary FABP4 (U-FABP4) level is associated with proteinuria and renal dysfunction in a general population. Methods The clinical significance of U-FABP4 was investigated in 81 patients (male/female: 43/38, age: 57 ± 17 years) who underwent kidney biopsy. Results U-FABP4 was negatively correlated with estimated glomerular filtration rate (eGFR) (r = − 0.56, P

Published
2020
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18. Effect of Home Blood Pressure on Inducing Remission/Regression of Microalbuminuria in Patients With Type 2 Diabetes Mellitus.

Author

Motonobu Nishimura, Yasuhisa Kato, Tsuyoshi Tanaka, Hideki Taki, Atsuhito Tone, Kazunori Yamada, Seiji Suzuki, Miho Saito, Yutaka Ando, and Yoshiharu Hoshiyama

Subjects
BLOOD pressure, PEOPLE with diabetes, DIABETIC nephropathies, HYPERTENSION, DISEASE remission
Abstract

BACKGROUND The Home Blood Pressure for Diabetic Nephropathy study is a prospective observational study conducted to determine the effect of home blood pressure (HBP) on remission/regression of microalbuminuria in patients with type 2 diabetes mellitus (DM). METHODS Patients with type 2 DM having microalbuminuria were followed-up for 3 years. Remission of microalbuminuria was defined as shift from microalbuminuria to normoalbuminuria. Regression of microalbuminuria was defined as a 50% reduction in urinary albumin--creatinine ratio from baseline. All measurements of morning and evening HBP were averaged every year and defined as all HBP. RESULTS In total, 235 patients were followed up. The 3-year cumulative incidences of remission and regression were 32.3% and 44.7%, respectively. Following analysis of all cases, the degree of decline in all home systolic blood pressure (AHSBP), rather than mean AHSBP, influenced the incidence of remission/regression. There was a strong relationship between the decline in AHSBP during the follow-up period and AHSBP at baseline. Therefore, separate analyses of the patients with AHSBP below 140 mm Hg at baseline were performed, which revealed that mean AHSBP during the follow-up period independently affected the incidence of remission/ regression. The hazard ratio for inducing remission/regression was significantly lower in patients with AHSBP during the follow-up period above 130 mm Hg than in those with AHSBP below 120 mm Hg. CONCLUSIONS Optimal AHSBP for the induction of remission/regression of microalbuminuria might be below 130 mm Hg. It is required to confirm whether keeping AHSBP below 130 mm Hg leads to subsequent renoprotection or not. [ABSTRACT FROM AUTHOR]

Published
2017
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19. Emphysematous cystitis with severe hemorrhagic anemia resulting from diabetes mellitus type 2

Author

Ikeda Masahiko, Ryohei Todo, Toshiaki Yamagata, Akira Wada, Hideki Taki, Sayaka Tsukurimichi, Yoshifumi Fukuhara, Fumie Sakamoto, Hideki Etani, and Toshihiro Sugiura

Subjects
medicine.medical_specialty, Anemia, Urology, Hemorrhage, urologic and male genital diseases, Emphysematous cystitis, Cystitis, Internal Medicine, medicine, Humans, Emphysema, Urinary bladder, medicine.diagnostic_test, business.industry, Metabolic acidosis, General Medicine, Cystoscopy, Middle Aged, medicine.disease, Surgery, Urethra, medicine.anatomical_structure, Diabetes Mellitus, Type 2, Abdominal ultrasonography, Female, business, Tomography, X-Ray Computed, Hemorrhagic cystitis
Abstract

A 48-year-old woman suffering from hematuria was admitted to our hospital due to conscious disturbance. She had lower abdominal phantom tumor, anemia, renal dysfunction, hyperglycemia, metabolic acidosis and electrolyte abnormalities. Because of pelvocaliceal dilatation noted on abdominal ultrasonography, we first diagnosed her as having postrenal failure. With massive blood clots and gas emission from her urethra upon attempting cystoscopy, the remarkable expansion of the urinary bladder and a three-layered structure of gas, urine and complex of blood and debris inside her urinary bladder noted on abdominal CT scan, as well as the increased white blood cell count, we finally concluded our diagnosis as emphysematous cystitis.

Published
2004

21. Intradialytic exercise in the treatment of social frailty: a single-center prospective study—preliminary results during the unexpected COVID-19 pandemic

Author

Koki Abe, Yoshinosuke Shimamura, Takuto Maeda, Yoshikazu Kato, Yasuyoshi Yoshimura, Tomomi Tanaka, and Hideki Takizawa

Subjects
Hemodialysis, Intradialytic exercise, Social frailty, Physical function, COVID-19, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Abstract Background Social frailty—the lack of a connection to society and infrequent social activities—has been reported to be associated with future declines in physical function in elderly individuals. This study aimed to evaluate both the association of social frailty with the physical function and the efficacy of intradialytic exercise as a therapy for social frailty among hemodialysis patients. Methods All 16 outpatient hemodialysis patients in the hemodialysis department of a single medical center were enrolled in this single-center prospective single-arm interventional study. Patients received five questions which asked about going out infrequently, lack of visiting friends, feeling unhelpful to friends or family, living alone, and lack of talking with someone. Those to whom two or more of the above were applicable were categorized as socially frail. All patients were placed into exercise therapy to be performed during their thrice-weekly hemodialysis visits. Participants’ physical function (walking speed), muscle strength (grip strength), muscle mass (appendicular skeletal muscle mass index), and social frailty were evaluated at baseline and after 3 months of therapy. Results Four (25%) of the 16 participants (median age 71.5 years, 8 women) were categorized as being socially frail. In comparison to the non-socially frail group (non-SF), the socially frail group (SF) had a significantly lower walking speed (0.70 ± 0.12 m/s vs 1.15 ± 0.26 m/s, p = 0.005) and significantly worse performance on the Short Physical Performance Battery. Three months of intradialytic exercise therapy significantly improved their walking speed, from 1.04 ± 0.30 m/s to 1.16 ± 0.29 m/s (p = 0.003). intradialytic exercise therapy significantly improved walking speed in both the SF group and the non-SF group. The 2019 coronavirus disease pandemic unexpectedly occurred in the middle of the intervention period of this study, and although it was not statistically significant, the number of socially frail individuals among our participants increased to seven (43.8%, p = 0.248). Conclusions Social frailty was associated with reduced physical function among hemodialysis patients. Intradialytic exercise therapy improved physical function regardless of the presence of social frailty. Trial registration UMIN-CTR, UMIN-CTR000038313. Registered November 1, 2019, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000043639 .

Published
2020
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22. Gastrointestinal bleeding is associated with renal prognosis in adult patients with IgA vasculitis with nephritis

Author

Yoshinosuke Shimamura, Takuto Maeda, Keitaro Nishizawa, Yayoi Ogawa, and Hideki Takizawa

Subjects
clinical remission, end‐stage kidney disease, gastrointestinal bleeding, IgA vasculitis with nephritis, Medicine (General), R5-920
Abstract

Abstract Background Although the prediction of renal prognosis in patients with IgA vasculitis with nephritis (IgAVN) is important, the association between gastrointestinal bleeding (GIB) and its renal prognosis is unknown. This study investigated the effect of GIB on the progression to end‐stage kidney disease (ESKD) in patients with IgAVN. Methods We compared the clinicopathological findings at diagnosis, therapy, and clinical outcomes between 10 patients with GIB and 20 patients without GIB in 30 patients with IgAVN aged ≥18 years at the renal biopsy. The primary outcome was the incidence of ESKD. Secondary outcomes included clinical remission and all‐cause mortality. The outcomes and factors affecting the progression to ESKD were evaluated using the Kaplan‐Meier method with log‐rank test and Cox proportional hazards models. Results End‐stage kidney disease, clinical remission, and deaths from any related cause occurred in 6, 17, and 2 patients, respectively. In Kaplan‐Meier analyses, the GIB group showed a higher incidence of ESKD (50% vs 5%, P = .003) and a lower incidence of clinical remission (20% vs 75%, P = .003). Although the numbers were not statistically significant, this group tended to have a greater number of deaths than the non‐GIB group (7% vs 0%, P = .07). In a multivariable Cox model adjusted for hypertension and urinary proteinuria, GIB could not demonstrate a significant association with ESKD (hazard ratio, 4.51; 95% confidence interval, 0.39‐52.7; P = .23). Conclusion IgAVN with GIB has worse renal outcome, but GIB does not have a statistically significant association with progression to ESKD.

Published
2020
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23. Altered activities of transcription factors and their related gene expression in cardiac tissues of diabetic rats

Author

Hitoshi Yasuda, Kazuya Shinozaki, Yasuhiro Maeno, Ryuichi Kikkawa, Hideto Kojima, Hideki Taki, Atsunori Kashiwagi, Hideki Hidaka, Masakazu Haneda, Yoshihiko Nishio, Kihachiro Horiike, and Hiroshi Maegawa

Subjects
Male, medicine.medical_specialty, Lipid Peroxides, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Probucol, Gene Expression, Biology, medicine.disease_cause, Antioxidants, Diabetes Mellitus, Experimental, Rats, Sprague-Dawley, chemistry.chemical_compound, Diabetes mellitus, Internal medicine, Gene expression, Internal Medicine, medicine, Animals, RNA, Messenger, Heme, Transcription factor, Regulation of gene expression, Insulin, Myocardium, Heart, medicine.disease, Rats, Endocrinology, chemistry, Heme Oxygenase (Decyclizing), Oxidoreductases, Oxidative stress, Heme Oxygenase-1, medicine.drug, Transcription Factors
Abstract

Gene regulation in the cardiovascular tissues of diabetic subjects has been reported to be altered. To examine abnormal activities in transcription factors as a possible cause of this altered gene regulation, we studied the activity of two redox-sensitive transcription factors— nuclear factor-KB (NF-KB) and activating protein-1 (AP-1)—and the change in the mRNA content of heme oxygenase-1, which is regulated by these transcription factors in the cardiac tissues of rats with streptozotocin-induced diabetes. Increased activity of NF-KB and AP-1 but not nuclear transcription-activating factor, as determined by an electrophoretic mobility shift assay, was found in the hearts of 4-week diabetic rats. Glycemic control by a subcutaneous injection of insulin prevented these diabetes-induced changes in transcription factor activity. In accordance with these changes, the mRNA content of heme oxygenase-1 was increased fourfold in 4-week diabetic rats and threefold in 24-week diabetic rats as compared with control rats (P < 0.01 and P < 0.05, respectively). Insulin treatment also consistently prevented changes in the mRNA content of heme oxygenase-1. The oral administration of an antioxidant, probucol, to these diabetic rats partially prevented the elevation of the activity of both NFKB and AP-1, and normalized the mRNA content of heme oxygenase-1 without producing any change in the plasma glucose concentration. These results suggest that elevated oxidative stress is involved in the activation of the transcription factors NF-KB and AP-1 in the cardiac tissues of diabetic rats, and that these abnormal activities of transcription factors could be associated with the altered gene regulation observed in the cardiovascular tissues of diabetic rats.

Published
1998

25. Expression of intercellular adhesion molecules 1 (ICAM-1) via an osmotic effect in human umbilical vein endothelial cells exposed to high glucose medium

Author

Kihachiro Horiike, Tanaka Y, Atsunori Kashiwagi, and Hideki Taki

Subjects
ICAM-1, Umbilical Veins, Osmotic concentration, Cell adhesion molecule, Intercellular Adhesion Molecule-1, Osmolar Concentration, General Medicine, Adhesion, Biology, Molecular biology, General Biochemistry, Genetics and Molecular Biology, Umbilical vein, Cell Line, Glucose, Biochemistry, medicine, Cell Adhesion, Humans, Mannitol, Endothelium, Vascular, RNA, Messenger, General Pharmacology, Toxicology and Pharmaceutics, Cell adhesion, medicine.drug
Abstract

To clarify the etiology of accelerated atherosclerosis in patients with diabetes mellitus, we measured expression of intercellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1), and E-selectin on the cell surface by enzyme-linked immunosorbent assay and ICAM-1 mRNA content in human umbilical vein endothelial cells exposed to 5.5 mM glucose (NG), 33 mM glucose (HG), or 27.5 mM mannitol plus 5.5 mM glucose (HM). 1) Cell-surface ICAM-1 expression in HG and HM cells was maximally increased by 37% and 32% (P < 0.01), respectively. This effect was dependent on glucose concentration in the medium and was found as early as 24 h and maintained until 6 days after exposing cells to HG. However, neither VCAM-1 nor E-selectin expression were affected by HG conditions. 2) Both HG and HM induced increased mRNA content between 6 and 12 h after the stimulation. 3) Adhesion of THP-1 cells to endothelial cells exposed to HG and HM was increased, when compared to NG conditions. These results indicate that osmotic effects can induce increased mRNA and cell-surface expression of ICAM-1 via an as yet unknown mechanism.

Published
1996

26. Expression of adhesion molecules in endothelial cells-implication of diabetic vascular dysfunction

Author

Y. Shigeta, Hideki Taki, N. Takahara, Kihachiro Horiike, A. Kashiwagi, Y. Tanaka, and H. Maegawa

Subjects
Vascular endothelial growth factor A, Vascular endothelial growth factor C, Chemistry, Cell adhesion molecule, Physiology (medical), Soluble cell adhesion molecules, Neural cell adhesion molecule, Intercellular adhesion molecule, Pathology and Forensic Medicine, Cell biology
Published
1994

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