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Effect of Tofogliflozin on Arterial Stiffness in Patients with Type 2

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Effect of Tofogliflozin on Arterial Stiffness in Patients with Type 2 Katakami et al. Cardiovasc Diabetol (2021) 20:4 https://doi.org/10.1186/s12933-020-01206-1 Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Efect of tofoglifozin on arterial stifness in patients with type 2 diabetes: prespecifed sub-analysis of the prospective, randomized, open-label, parallel-group comparative UTOPIA trial Naoto Katakami1,2* , Tomoya Mita3, Hidenori Yoshii4, Toshihiko Shiraiwa5, Tetsuyuki Yasuda6, Yosuke Okada7, Keiichi Torimoto7, Yutaka Umayahara8, Hideaki Kaneto9, Takeshi Osonoi10, Tsunehiko Yamamoto11, Nobuichi Kuribayashi12, Kazuhisa Maeda13, Hiroki Yokoyama14, Keisuke Kosugi15, Kentaro Ohtoshi16, Isao Hayashi17, Satoru Sumitani18, Mamiko Tsugawa19, Kayoko Ryomoto20, Hideki Taki21, Tadashi Nakamura22, Satoshi Kawashima23, Yasunori Sato24, Hirotaka Watada3, Iichiro Shimomura1 and On behalf of the UTOPIA study investigators Abstract Background: Tofoglifozin, an SGLT2 inhibitor, is associated with favorable metabolic efects, including improved glycemic control and serum lipid profle and decreased body weight, visceral adipose tissue, and blood pressure (BP). This study evaluated the efects of tofoglifozin 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 tofoglifozin 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 prespecifed secondary outcomes, changes in baPWV over 104 weeks were evaluated in 154 individuals (80 in the tofoglifozin group and 74 in the conventional treatment group) who completed baPWV measurement at baseline. Results: In a mixed-efects model, the progression in the right, left, and mean baPWV over 104 weeks was signif- cantly attenuated with tofoglifozin 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, respec- tively). Similar fndings were= obtained even after adjusting the =mixed-efects 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 fndings of the analysis of covariance (ANCOVA) models, which included the treatment group, baseline baPWV, and traditional cardio- vascular risk factors, resembled those generated by the mixed-efects models. *Correspondence: [email protected] 1 Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan Full list of author information is available at the end of the article © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Katakami et al. Cardiovasc Diabetol (2021) 20:4 Page 2 of 13 Conclusions: Tofoglifozin signifcantly inhibited the increased baPWV in patients with T2DM without a history of apparent cardiovascular disease, suggesting that tofoglifozin suppressed the progression of arterial stifness. Trial Registration UMIN000017607. Registered 18 May 2015. (https ://www.umin.ac.jp/icdr/index .html) Keywords: Arterial stifness, Pulse wave velocity, Arteriosclerosis, Diabetes, SGLT2 inhibitor, Tofoglifozin Background Methods Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a Study design class of antidiabetic agents, have a pleiotropic efect, Te study design, study schedule, and outcomes of the and thus diminish several cardiovascular risk factors original UTOPIA trial have been described in detail by reducing visceral adipose tissue, body weight, and previously [22, 23]. In brief, the UTOPIA trial was a blood pressure (BP); improving the blood lipid pro- prospective, randomized, open-label, multicenter, par- fle; and generating a renoprotective efect independ- allel-group comparative study to evaluate the efcacy of ent of glycemic efects [1, 2]. Previous clinical trials tofoglifozin in preventing the progression of atheroscle- have shown that SGLT2 inhibitors signifcantly reduced rosis over a 2-year intervention period in patients with major cardiovascular (CV) adverse events and/or hos- T2DM. Te study period was 104 weeks following patient pitalization for heart failure in patients with type 2 dia- registration (registration period: January to November betes mellitus (T2DM) at high risk of cardiovascular 2016). All randomized patients were followed up until disease (CVD) [3–5]. In addition, a recent meta-anal- the scheduled end of the study, irrespective of adherence ysis indicated that SGLT2 inhibitors have robust ben- to or discontinuation of study medication for any reason. efts in reducing hospitalization for heart failure and Clinical and biochemical data were collected at 0, 26, 52, progression of renal disease, regardless of existing ath- 78, and 104 weeks after randomization. Primary study erosclerotic CVD or a history of heart failure [6]. Tese outcomes were changes in mean intima–media thick- results suggest that SGLT2 inhibitors exert a broad ness (IMT) of the common carotid artery. As one of the range of benefcial efects on the CV system through prespecifed secondary outcomes, changes in the right multiple mechanisms. and left baPWV values over the 104-week observation Reduction in the arterial wall elasticity increases period were evaluated. In addition, as a post-hoc analy- the vascular wall stress, resulting in the progression sis, the efects of tofoglifozin on changes in the mean of atherosclerosis, an increase in the left ventricular baPWV values (mean derived from the left- and right- afterload, left ventricular diastolic dysfunction, and side baPWV values) were evaluated. coronary perfusion disorder. Moreover, deterioration in Tis study was registered at the University Hospital arterial stifness was associated with hospitalization for Medical Information Network Clinical Trials Registry new-onset heart failure in asymptomatic patients with (UMIN-CTR), a nonproft organization in Japan, and CV risk factors [7]. Tus, arterial stifness may refect met the requirements of the International Committee of not only atherosclerotic changes but also risks of an Medical Journal Editors (UMIN000017607). extensive range of CVDs including cardiac dysfunction. Previous studies have evaluated the efect of SGLT2 Study population inhibitors on arterial stifness using several indices Te eligibility criteria of the original UTOPIA trial have [8–19], some of which indicated the benefcial efect been previously described in detail [22]. Te inclusion of SGLT inhibitors. Pulse wave velocity (PWV) is com- criteria were: (1) Japanese with T2DM and inadequate monly used to measure the severity of arterial stifness, glycemic control (HbA1c ≥ 6% but < 9%), along with the showing the structural and functional properties of the inability to achieve the blood glucose level stated in the arterial wall [20, 21]. However, evidence on the efect of Diabetes Treatment Guidelines of 2014–2015 despite SGLT2 inhibitors on the progression of PWV remains being on drugs, except SGLT2 inhibitors—with diet and limited [8–11]. physical therapy, on diet and physical therapy without Tis study evaluated the efects of tofoglifozin, an being on drugs for at least 12 weeks, or on SGLT2 inhibi- SGLT2 inhibitor that has been clinically used in Japan, tors in the past but without them for at least 12 weeks on the brachial-ankle pulse wave velocity (baPWV) as before signing the consent form; (2) no changes in the one of the prespecifed secondary outcomes of the using antidiabetic, antithrombotic, antihypertensive medica- tofoglifozin for possible better intervention against ath- tion, or a therapeutic agent for dyslipidemia manage- erosclerosis for type 2 diabetes patients (UTOPIA) trial ment for at least 12 weeks before signing the consent [22, 23]. form; (3) age 30 to 74 years at the time of giving consent; Katakami et al. Cardiovasc Diabetol (2021) 20:4 Page 3 of 13 and (4) able to provide informed consent. Furthermore, drug was titrated. Te use of antihyperlipidemic and anti- the following exclusion criteria were applied: (1) type 1 hypertensive drugs was allowed during the study. or secondary diabetes; (2) in the perioperative period or with a serious
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