Lack of impact of ipragliflozin on endothelial function in patients with type 2 diabetes: sub-analysis of the PROTECT study
Authors: Kishimoto Shinji , Higashi Yukihito , Imai Takumi , Eguchi Kazuo , Fukumoto Kazuo , Tomiyama Hirofumi , Maemura Koji , Tanaka Atsushi , Node Koichi ,   the PROTECT investigators, Murohara Toyoaki , Kitakaze Masafumi , Nishio Yoshihiko , Inoue Teruo , Ohishi Mitsuru , Kario Kazuomi , Sata Masataka , Shimabukuro Michio , Shimizu Wataru , Jinnouchi Hideaki , Taguchi Isao , Suzuki Makoto , Ando Shinichi , Kamiya Haruo , Sakamoto Tomohiro , Teragawa Hiroki , Nanasato Mamoru , Matsuhisa Munehide , Ako Junya , Aso Yoshimasa , Ishihara Masaharu , Kitagawa Kazuo , Yamashina Akira , Ishizu Tomoko , Ikehara Yumi , Ueda Shinichiro , Takamori Ayako , Yoshida Hisako , Mori Miki , Yamaguchi Kaori , Asaka Machiko , Kaneko Tetsuya , Sakuma Masashi , Toyoda Shigeru , Nasuno Takahisa , Kageyama Michiya , Teruo Jojima , Toshie Iijima , Kishi Haruka , Yamada Hirotsugu , Kusunose Kenya , Fukuda Daiju , Yagi Shusuke , Yamaguchi Koji , Ise Takayuki , Kawabata Yutaka , Kuroda Akio , Akasaki Yuichi , Kurano Mihoko , Hoshide Satoshi , Komori Takahiro , Kabutoya Tomoyuki , Ogata Yukiyo , Koide Yuji , Kawano Hiroaki , Ikeda Satoshi , Fukae Satoki , Koga Seiji , Kajikawa Masato , Maruhashi Tatsuya , Kubota Yoshiaki , Shibata Yoshisato , Kuriyama Nehiro , Nakamura Ikuko , Hironori Kanemitsu , Takase Bonpei , Orita Yuichi , Oshita Chikage , Uchimura Yuko , Yoshida Ruka , Yoshida Yukihiko , Suzuki Hirohiko , Ogura Yasuhiro , Maeda Mayuho , Takenaka Masaki , Hayashi Takumi , Hirose Mirai , Hisauchi Itaru , Kadokami Toshiaki , Nakamura Ryo , Kanda Junji , Matsunaga Kazuo , Hoshiga Masaaki , Sohmiya Koichi , Kanzaki Yumiko , Koyosue Arihiro , Uehara Hiroki , Miyagi Naoto , Chinen Toshiya , Nakamura Kentaro , Nago Chikashi , Chiba Suguru , Hatano Sho , Gima Yoshikatsu , Abe Masami , Ajioka Masayoshi , Asano Hiroshi , Nakashima Yoshihiro , Osanai Hiroyuki , Kanbara Takahiro , Sakamoto Yusuke , Oguri Mitsutoshi , Ohguchi Shiou , Takahara Kunihiko , Izumi Kazuhiro , Yasuda Kenichiro , Kudo Akihiro , Machii Noritaka , Morimoto Ryota , Bando Yasuko , Okumura Takahiro , Kondo Toru , Miura Shin-ichiro , Shiga Yuhei , Mirii Joji , Sugihara Makoto , Arimura Tadaaki , Nakano Junko , Sakamoto Tomohiro , Kodama Kazuhisa , Ohte Nobuyuki , Sugiura Tomonori , Wakami Kazuaki , Takemoto Yasuhiko , Yoshiyama Minoru , Shuto Taichi , Okada Yosuke , Tanaka Kenichi , Sonoda Satomi , Tokutsu Akemi , Otsuka Takashi , Uemura Fumi , Koikawa Kenji , Miyazaki Megumi , Umikawa Maiko , Narisawa Manabu , Furuta Machi , Minami Hiroshi , Doi Masaru , Sugimoto Kazuhiro , Suzuki Susumu , Kurozumi Akira , Nishio Kosuke 
Published: May 2023

Abstract
Background
We assessed the impact of 24 months of treatment with ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on endothelial function in patients with type 2 diabetes as a sub-analysis of the PROTECT study.

Methods
In the PROTECT study, patients were randomized to receive either standard antihyperglycemic treatment (control group, n = 241 ) or add-on ipragliflozin treatment (ipragliflozin group, n = 241) in a 1:1 ratio. Among the 482 patients in the PROTECT study, flow-mediated vasodilation (FMD) was assessed in 32 patients in the control group and 26 patients in the ipragliflozin group before and after 24 months of treatment.

Results
HbA1c levels significantly decreased after 24 months of treatment compared to the baseline value in the ipragliflozin group, but not in the control group. However, there was no significant difference between the changes in HbA1c levels in the two groups (7.4 ± 0.8% vs. 7.0 ± 0.9% in the ipragliflozin group and 7.4 ± 0.7% vs. 7.3 ± 0.7% in the control group; P = 0.08). There was no significant difference between FMD values at baseline and after 24 months in both groups (5.2 ± 2.6% vs. 5.2 ± 2.6%, P = 0.98 in the ipragliflozin group; 5.4 ± 2.9% vs. 5.0 ± 3.2%, P = 0.34 in the control group). There was no significant difference in the estimated percentage change in FMD between the two groups (P = 0.77).

Conclusions
Over a 24-month period, the addition of ipragliflozin to standard therapy in patients with type 2 diabetes did not change endothelial function assessed by FMD in the brachial artery.

Trial registration

Registration Number for Clinical Trial: jRCT1071220089 (https://jrct.niph.go.jp/en-latest-detail/jRCT1071220089).