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

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 ).