Efficacy and safety of combination therapy with candesartan cilexetil and pioglitazone hydrochloride in patients with hypertension and type 2 diabetes mellitus

Abstract

Objective:

To evaluate the efficacy and safety of combination therapy with candesartan cilexetil (CC) and pioglitazone hydrochloride (PIO) in patients with hypertension and type 2 diabetes mellitus.

Methods:

A 12-week, double-blind, randomized, parallel-group study in patients with mild-to-moderate essential hypertension and type 2 diabetes mellitus was followed by a 40-week, single-blind study. Patients (N = 377) were randomized to treatment with CC 8 mg/PIO 30 mg (n = 62), CC 8 mg/PIO 15 mg (n = 63), CC 4 mg/PIO 30 mg (n = 63), CC 4 mg/PIO 15 mg (n = 63), CC 8 mg/PIO 0 mg (n = 63), or CC 0 mg/PIO 30 mg (n = 63). Primary efficacy measures were changes in diastolic blood pressure (DBP) and HbA_1C at Week 12.

Results:

CC/PIO combination therapy improved blood pressure (BP)/glycemic control for 52 weeks. At the end of 12-week treatment period, DBP decreased to a significantly greater extent in the 8/30 + 8/15 + 8/0 (combined CC 8 mg) group (−10.5 mmHg, p < 0.0001) and the 4/30 + 4/15 (combined CC 4 mg) group (−9.1 mmHg, p = 0.0022) than in the 0/30 (CC 0 mg) group (−5.3 mmHg). HbA_1C significantly decreased in the 8/30 + 4/30 + 0/30 (combined PIO 30 mg) group (−0.35%, p < 0.0001) and the 8/15 + 4/15 (combined PIO 15 mg) group (−0.15%, p < 0.0001) compared with the 8/0 (PIO 0 mg) group (0.35%). Urinary albumin excretion reduction seen with the 0/30 and the 8/0 groups was significantly enhanced by CC/PIO combination. Clinical significance of this renoprotective effect of CC/PIO combination therapy needs to be studied further. Prolonged combined use of CC/PIO did not increase adverse events. Drug-related adverse events were similar to those during clinical use of CC and PIO.

Conclusion:

CC/PIO combination therapy improved BP/glycemic control and was well tolerated for 52 weeks. Thus, CC/PIO combination therapy is useful in patients with hypertension and type 2 diabetes mellitus.

Key words::

• Candesartan
• Hypertension
• Pioglitazone
• Type 2 diabetes mellitus

Transparency

Declaration of funding

This study was financially supported by Takeda Pharmaceutical Company, Limited (Osaka, Japan) in designing, implementing, monitoring, analyzing, and other activities related to this study.

Declaration of financial/other relationships

K.E., K.S. and N.T. are employees of Takeda Pharmaceutical Company, Limited. K.K. has disclosed receiving research grant funding from Takeda, Novo Nordisk, Daiichi Sankyo, Astellas, Sanofi-aventis, MSD; and has acted as a consultant to Takeda, Novo Nordisk, Daiichi Sankyo, Astellas, AstraZeneca, Sanwa Kagaku Kenkyusho, Chugai, Kissei, Taisho.

Acknowledgements

We acknowledge the investigators and other staff members who participated in this study. The study centers and investigators were as follows: Shin Aoki, MD, Aoki Clinic; Kazuko Takahashi, MD, Takahashi Clinic; Masahiro Mizutani, MD, Asahiyama Medical Clinic; Tsutomu Yoshida, MD, Kiyomizu Kouen Clinic; Shigemichi Tanaka, MD, Teine Keijinkai Hospital; Kenichi Yamada, MD, Kenichi Yamada Internal Medicine Clinic; Etsuo Ohtomo, MD, Morinoizumi Naika Junkankika; Seiichi Nakayama, MD, Tochigi National Hospital; Yo Kageyama, MD, Tochigi National Hospital; Hiroshi Oohashi, MD, Oyama East Clinic; Shintaro Yano, MD, Maebashi Hirosegawa Clinic; Takeshi Inazawa, MD, Kashiwa City Hospital; Keiji Mikami, MD, Omigawa General Hospital; Hiroaki Hosaka, MD, Omigawa General Hospital; Nobuichi Kuribayashi, MD, Misaki Naika Clinic; Kenichi Ishibashi, MD, Ishibashi Clinic; Katsuhiko Masuda, MD, Masuda Clinic; Yoshito Hayashibe, MD, Chofu Hospital; Yukiko Onishi, MD, The Institute for Adult Diseases, Asahi Life Foundation; Akifumi Kushiyama, MD, The Institute for Adult Diseases, Asahi Life Foundation; Akiyuki Yamaguchi, MD, Yamaguchi Hospital; Makiko Suzuki, MD, Koseikai Suzuki Hospital; Fujio Nagasaka, MD, Shimamura Memorial Hospital; Jun Hashida, MD, Eisei Hospital; Yoshihiko Suzuki, MD, Hoken Dohjin Medical Foundation; Kyo Sanoyama, MD, Sanoyama Clinic; Yoshio Oh-hashi, MD, Tokyo Ekimae-building Clinic; Masayoshi Sone, MD, Sone Clinic; Takayuki Azuma, MD, Haruna Clinic; Tomonori Tamura, MD, Sannou Medical Clinic; Masanori Takeishi, MD, Takeishi Clinic; Keiichi Shimoda, MD, Kanazawa Medical Clinic; Takashi Yasuda, MD, St. Marianna University School of Medicine Hospital; Takuyuki Katabami, MD, St. Marianna University School of Medicine Hospital; Makoto Ujihara, MD, National Hospital Organization Yokohama Medical Center; Koutarou Iemitsu, MD, Kounandai Iemitsu Clinic; Fuyuki Minagawa, MD, Minagawa Clinic; Masamichi Yamada, MD, Idaimae-naika Clinic; Kouji Osako, MD, Osako Naika Clinic; Mafumi Owa, MD, Japanese Red Cross Society Suwa Hospital; Michio Nakagawa, MD, Matsumoto Nakagawa Hospital; Atsushi Momose, MD, Koujindo Clinic; Toshihiro Murai, MD, Matsunami General Hospital; Tomoko Kita, MD, Haibara General Hospital; Shunichi Kojima, MD, National Hospital Organization Shizuoka Medical Center; Toyohisa Eguchi, MD, Eguchi Clinic; Akira Yamauchi, MD, Suruga Clinic; Shinichi Hinata, MD, Hinata Clinic; Tetsuhiro Yamada, MD, Yamada Naika; Sizuo Kajiyama, MD, Kajiyama Clinic; Masaya Kino, MD, Hokusetsu General Hospital; Eiichi Imano, MD, Osaka Koseinenkin Hospital; Rieko Ishibashi, MD, Osaka Koseinenkin Hospital; Hidehiko Itoh, MD, Otemae Hospital: Kenei Shimada, MD, Osaka Hospital of Japan Seafarers relief Association; Keisuke Kosugi, MD, Osaka Police Hospital; Shigeichi Shouji, MD, Minamiosaka Hospiral; Noriaki Utsu, MD, Minamiosaka Hospital; Yoshikazu Irie, MD, Irie Hospital; Hiroyuki Miyazaki, MD, National Hospital Organization Kobe Medical Center; Masanobu Funamoto, MD, Funamoto Clinic; Masahiro Maeda, MD, Iryouhoujin Shadan Kouseikai Maeda Iin; Shintaro Shokoku, MD, Okayama-daiichi Hospital; Kenichi Kato, MD, Yamana Hospital; Kazuhiro Harada, MD, Kasaoka Daiichi Hospital; Kouki Takata, MD, Hiroshima General Hospital of West Japan Railway Company; Akira Miyauchi, MD, Chugoku Rosai Hospital; Keita Ishii, MD, Chugoku Central Hospital; Tetsuro Hiraoka, MD, Hiraoka Naika Clinic; Shinkuro Kataoka, MD, Kataoka Internal Medicine Clinic; Yasushi Inoue, MD, Yamaguchi Grand Medical Center; Shinya Furukawa, MD, Ehime University Hospital; Hiroaki Miyaoka, MD, Saiseikai Matsuyama Hospital; Takenori Sakai, MD, Yawatahama City General Hospital; Hisaka Minami, MD, Saiseikai Saijo Hospital; Shouichi Akazawa, MD, Shinkoga Hospital; Yoshikatsu Nishi, MD, Nagata Hospital; Kazuhei Kurosawa, MD, Okabe Hospital; Hideyuki Ikematsu, MD, Hara-Doi Hospital; Keisuke Egashira, MD, Sakura Hospital; Kensuke Fukuyo, MD, Fukuyo Internal Medicine Clinic; Toyonari Endo, MD, Shimesougoushinryojo; Yasuhiko Hirata, MD, Hirata Clinic; Ryuji Yoshimura, MD, Yoshimura Internal Medicine; Makoto Kunisaki, MD, Kunisaki Makoto Clinic; Hironori Kimura, MD, National Hospital Organization Nagasaki Medical Center; Kimiaki Nagase, MD, Oita Oka Hospital; Masaharu Hiraga, MD, Nakamura Hospital; Yoshito Inobe, MD, Inobe Funai Clinic; Yumi Miyazono, MD, Zenjinkai Shimin-no-mori Hospital; Kuninobu Nakatsuru, MD, Miyazakizenjinkai Hospital; Seitaro Nakama, MD, Uranishi Clinic; Osamu Kanashiro, MD, Kanashiro Medical Clinic; Seigo Nakada, MD, Chibana Clinic. We also appreciate Dr Michihiro Yoshida and Mr Shunsuke Touno, Takeda Pharmaceutical Company, Limited, for their editorial assistance in preparing this manuscript.