Based on the results from this study, we found that although fasting plasma glucose (FPG), HbA1c, and GA were equally improved in both empagliflozin and glimepiride groups, ΔFMD was not significant. A previous study has reported that glimepiride does not demonstrate an improvement in the endothelial function [15]. In this study, empagliflozin had no effect towards the improvement of endothelial function, irrespective of the improvement in glucose levels. To observe the changes in endothelial function induced by drugs that lack the ability to improve the glucose levels, this study was conducted in patients with a steady glucose–controlled state. Although a baseline HbA1c was targeted in this study, severe hypoglycemia did not occur after reducing glargine dose, as the fasting plasma glucose was maintained under 90 mg/dL. Additionally, GA improved significantly in both the groups. It is possible that glucose variation was improved by both the additional treatment. The insulin dose was also decreased significantly in both the groups, and this may have resulted in the increase in body weight. The improvements in ΔHbA1c, body weight, HDL-C, and TG and the reduction in HbA1c in the empagliflozin group did not affect the FMD, although the correlation between the change in the levels of a decrease in visceral adipose tissue mass, waist circumference, and ΔFMD has been shown in previous studies[8, 16]. These findings suggest that empagliflozin had no effect in improving FMD although empagliflozin is effective in improving HbA1c.
Although long-term administration of empagliflozin has been shown to maintain a stable eGFR [17], we observed that the renal function worsened in the empagliflozin group during the relatively short observation period. It was reported that empagliflozin decreased hyperfiltration by diuresis in the initial term [18]. This may be attributed to the changes in renal dynamics induced by empagliflozin. In a recent study, canagliflozin reduced the risk of kidney failure at a median follow up time of 2.62 years [19]. Losartan showed a rapid initial decline in the renal function which led to a slower decrease in long-term renal function [20]. However, it has been reported that an initial rapid decline of renal function leads to kidney failure [21]. Therefore, empagliflozin would be expected to prevent the progression of kidney disease over an extended period of time.
In Body720, an eight–polar BIA was shown to accurately estimate total and appendicular body composition, independent of age and sex [20]. The body fluid volume was significantly decreased following 12 weeks of empagliflozin treatment. However, it was unclear whether the effect of empagliflozin on the body fluid volume was greater than that of glimepiride. Empagliflozin has been shown to improve hospitalization rates after heart failure [21] and is thought to ameliorate the effects of this disease by decreasing body fluid volume. During the observational period of our study, heart failure was not observed in either treatment group. This suggests that empagliflozin might have a coronary protective effect that is not derived from the impact on the endothelial function. This diuretic medication is known to decrease congested heart failure, although its effect in reduction of the cardiovascular event risk is unclear. It was reported that SGLT2 inhibitors reduce more interstitial fluid volume than blood volume compared to the loop diuretics [22]. It was hypothesized that improvement of systemic congestion and renal function, derived from decreased hyperfiltration, resulted in prevention of cardiovascular event without reducing arterial filling and perfusion.
The FMD may be improved when the baseline FMD is low[23]. However, in both the subgroups that showed a lower than median baseline FMD, the ΔFMD did not significantly differ between the two groups (P = 0.83) (Table 6). Notably, although SGLT2 inhibitors have a secondary preventive role in adverse cardiovascular events, they lack a primary preventive role [12]. However, results from the DECLARE-TIMI 58 study demonstrated that dapagliflozin had both primary as well as secondary roles in preventing adverse cardiovascular events. Dapagliflozin decreased cardiovascular death and hospitalization due to heart failure in patients without previous cardiovascular disease [24]. However, in this study, no patient had a similar background, and hence it was necessary to undertake a secondary intervention.
The effects of other oral hypoglycemic agents, like pioglitazone and glucagon-like peptide 1 (GLP–1) analogs, in improving endothelial function have been reported previously [15, 25]. A dipeptidyl peptidase 4 (DPP-4) inhibitor either improved [23], had no effect [26], or worsened [27] endothelial function but did not affect cardiovascular events [28, 29]. In another study, GLP–1 analog treatment enhanced [30, 31] or had no effect on [32] endothelial function. In patients with type 2 diabetes, liraglutide, a GLP–1 analog, was successful in preventing nonfatal myocardial infarction or stroke, along with death from cardiovascular causes [33]. Similar to these findings, results from a meta-analysis showed that significant heterogeneity existed between DPP-4 inhibitor and GLP–1 [34]. Factors such as the size of the study, duration of intervention, and age or sex of the participants did not affect the mean difference in FMD [34]. Rather, a change in FMD was found to be dependent on the baseline FMD. The low baseline FMD in our study compared to other reported studies [23, 25, 35] might have an effect on the results.
Several limitations were evident in this study. First, as the study participants were outpatients, it was not possible to completely exclude patients who smoked or had a meal before the FMD examination. Moreover, non-compliance of dietary requirements in some patients might have affected the observed change in body weight. Additionally, even though we had included wash out periods of anti-diabetic therapy for 12 weeks before the study, the long-term effects of anti-diabetic therapy before admission cannot be completely ruled out. Finally, although the number of patients to detect a significant difference in comparisons of the two groups was adequate, the observation period was relatively short. Although, an evidence of observation period assessed by FMD has not been established yet, a longer study period to monitor any adverse events is required for future studies.