Discussion
atherosclerotic, atrial fibrillation, heart failure, TG, diabetes
ACUTE MYOCARDIAL INFARCTION, RECURRENCE, CAROTID ATHEROSCLEROSIS, ADVERSE EVENTS, UNSTABLE ANGINA, HEART FAILURE, ARTERIAL STIFFNESS, ATRIAL FIBRILLATION, ATHEROSCLEROSIS, TYPE 2 DIABETES MELLITUS, DIABETES
This UTOPIA Extension study showed that tofogliflozin was not associated with improved inhibition of carotid wall thickening but induced long-term attenuation of baPWV progression and improvement of HbA1c and HDL-C levels, BMI, waist circumference, and systolic blood pressure while maintaining a good safety profile. This study is the first to demonstrate that the beneficial effect of SGLT2 inhibitors on arterial stiffness lasts for a long time (more than 4 years).The main UTOPIA study was the first RCT to assess the effect of SGLT2 inhibitors on carotid atherosclerosis, which demonstrated a significant decrease in IMT with tofogliflozin treatment. Similarly, in this UTOPIA Extension study, a significant reduction in the mean IMT-CCA and a tendency towards decreased right and left max-IMT-CCA were maintained throughout the follow-up period in the tofogliflozin treatment group (Table One possible explanation for these findings is that the effect of tofogliflozin on the atherosclerotic changes that occur in the large arteries, including the carotid arteries, is limited. Indeed, a sub-analysis of the main UTOPIA trial has recently shown that the tissue characteristics of the carotid arterial wall did not change in either the tofogliflozin or conventional treatment groups during a 104-week treatment period [It is also possible that the beneficial effects of tofogliflozin on the carotid wall, if any, were masked by the administration of additional antidiabetic, antihypertensive, and antilipidemic agents. Biguanides [In contrast, the increase in baPWV, an indicator of arterial stiffness, was significantly attenuated with tofogliflozin treatment but not with conventional treatment in both the UTOPIA main and extension studies (Table The results of the UTOPIA main and extension studies indicate that tofogliflozin could have different effects on IMT and baPWV. IMT and baPWV are both indicators of atherosclerosis; however, they are believed to reflect different aspects of cardiovascular risk. Carotid IMT primarily reflects the degree of atherosclerosis, particularly structural changes that develop in large arteries [Recently, there has been a growing number of research reports suggesting a cardiovascular protective effect of tofogliflozin. Kishima et al. conducted a prospective RCT to compare the suppressive effects of tofogliflozin and anagliptin, a DPP-4 inhibitor, on atrial fibrillation recurrence after catheter ablation in patients with type 2 diabetes mellitus. In their study, greater suppression of atrial fibrillation recurrence was achieved with tofogliflozin than with anagliptin [In this study, the tofogliflozin group showed significantly lower HbA1c levels at week 208 compared with baseline, and this reduction in HbA1c levels was significantly greater than that in the conventional treatment group. Throughout the observation period, there was no difference between the treatment groups in the proportion of patients concomitantly receiving other diabetes medications. This suggests that the effect of tofogliflozin on glycemic control lasts at least 4 years. Although tofogliflozin did not affect serum TC, LDL-C, and TG levels, it elevated serum HDL-C levels compared to conventional treatment, even during the UTOPIA Extension study (Table Tofogliflozin did not affect renal function biomarkers (serum creatinine, UAE, and eGFR) in this study. This was not consistent with previous reports demonstrating the renal benefits of SGLT2 inhibitors [Regarding safety, during the 2-year intervention with tofogliflozin and 2-year extensional observation, the frequency of all adverse events did not vary between the groups. However, the frequency of the composite cardiovascular endpoint comprising cardiovascular mortality, acute myocardial infarction, unstable angina, and heart failure was significantly lower in the tofogliflozin group than in the conventional treatment group (Additional file Collectively, these results indicate that tofogliflozin treatment improves various cardiovascular risk factors and that such beneficial effects persist for at least 4 years, suggesting that tofogliflozin should be used early in diabetes management.This study had several limitations. First, the main UTOPIA study was not a double-blind, placebo-controlled trial but rather a prospective, open-label, randomized trial with a blinded endpoint. In addition, the UTOPIA Extension study is a prospective observational study without any restriction in medication in both groups. Although the assessment of endpoints was blinded and conducted by expert committees, the study design may have caused unexpected bias. Second, all participants in this study were Japanese. Therefore, generalizing the results of this study to other racial or ethnic groups should be approached with caution. Finally, we did not correct for multiplicity in this study. This may lead to false-positive results.