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

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)

Effects of Sodium-Glucose Co-Transporter 2 Inhibitors on Vascular Cell Function and Arterial Remodeling

“…Post hoc analysis of five clinical trials showed that canagliflozin improves pulse pressure in patients with T2DM [133]. More recently, tofogliflozin was demonstrated to attenuate arterial stiffness, as reflected by a decrease in brachial-ankle pulse wave velocity, in patients with T2DM, whereas luseogliflozin fails to improve arterial stiffness in this patient population, as assessed by cardio-ankle vascular index and pulse wave velocity [134,135]. Failure of luseogliflozin to mitigate arterial stiffening may reflect the limited sample size and study duration.…”

The Role of SGLT2 Inhibitors in Atherosclerosis: A Narrative Mini-Review

“…After 104 weeks, tofogliflozin reduced the common mean cIMT compared to the baseline (mean change ±standard error, −0.132 ± 0.007, p < 0.001), but there was no significant difference between the tofogliflozin and the conventional treatment group. In a prespecified subanalysis of the UTOPIA trial, a significant attenuation of PWV was found in the tofogliflozin group compared to the conventional treatment group (mean change,-104.7 cm/s; 95% confidence interval [95%CI],−177 to −32.4) (Katakami et al, 2021). Another prospective, randomized study in 160 patients with T2DM also found significantly improved PWV in patients treated with SGLT2-is compared to those treated with basal insulin after a 12-month treatment period (Ikonomidis et al, 2020).…”

Large Artery Stiffness: A Companion to the 2015 AHA Science Statement on Arterial Stiffness

“…The improvement in mean baPWV using the change in the tofogliflozin minus the change in standard care was 105 cm/s. Linear regression using several models that controlled for a variety of risk factors, including systolic blood pressure, indicated that the changes in baPWV between the 2 groups were independent of a number of CV risk factors including systolic blood pressure [28].…”