This randomized crossover study compared the effects of mitiglinide/voglibose and glimepiride on vascular endothelial function and glycemic variability in patients with type 2 diabetes. The co-primary endpoints were RHI and MAGE. The MAGE at baseline was 99.6 ± 31.9 mg/dL, and significantly decreased during mitiglinide/voglibose treatment (47.6 ± 18.5 mg/dL) compared to no change during glimepiride treatment (100.6 ± 32.2 mg/dL) (P < 0.001). Furthermore, MAGE was not affected by the phase of treatment (first, second) and sequence (allocation group). Other indices of glycemic variability, such as SD and CV, were also significantly lower for mitiglinide/voglibose. Fujimoto et al. [13] compared the effects of mitiglinide/voglibose and glimepiride (1.0 mg/day) using a crossover design, similar to our study, and reported that MAGE for mitiglinide/voglibose was 62.46 mg/dL, significantly lower than for glimepiride (95.04 mg/dL) [13]. However, the authors reported as limitations of their study the lack of washout period, evaluation of period effect or carryover effect, the short duration of drug administration, and the short application of CGM. Our present study design addressed these limitations, incorporating CGM measurements before drug administration. Our study clearly showed that mitiglinide/voglibose reduced MAGE by 50% from the baseline.
A previous study indicated that MAGE cut-off value of 3.4 mmol/L (61.3 mg/dL) was associated with coronary artery disease (CAD) in patients with type 2 diabetes experiencing chest pain [15]. In our study, MAGE during mitiglinide/voglibose treatment was well below the above cut-off value (61.3 mg/dL). Since a recently reported meta-analysis concluded that MAGE in hospitalized patients with acute coronary syndrome or stable CAD (n = 2,666) could accurately predict the subsequent onset of major adverse cardiovascular events [16], selection of drugs that suppress glycemic variability seems important in order to prevent cardiovascular diseases in patients with type 2 diabetes.
Our study showed no difference in RHI between the mitiglinide/voglibose and glimepiride groups. Regarding the effects of mitiglinide/voglibose on vascular endothelial function, only one report demonstrated that fasting and postprandial FMD improved at 3 months after switching from glimepiride to mitiglinide/voglibose [14]. However, the above study was a small-scale single-arm pilot study involving 6 patients only. To our knowledge, no other studies have compared the effects of mitiglinide/voglibose and glimepiride on vascular endothelial function by using a crossover design. Previous studies showed that glycemic variability detected by CGM is associated with vascular endothelial dysfunction [17], and our group has also reported the association of RHI with MAGE in patients with type 2 diabetes [4]. Furthermore, hypoglycemia may impair vascular endothelial function in patients with type 2 diabetes through increased production of reactive oxygen species, catecholamines [5], and proinflammatory cytokines [6], as well as activation of the sympathetic nervous system [7]. We also reported previously that hypoglycemia reduces RHI [8, 9] and is a factor that adversely affects the normalization of vascular endothelial function after educational hospitalization in patients with type 2 diabetes [18].
We conducted the present study based on the hypothesis that administration of mitiglinide/voglibose would suppress glycemic variability, thereby improve RHI, or that mitiglinide/voglibose would more effectively prevent the decrease in RHI than glimepiride due to the lower incidence of hypoglycemia during mitiglinide/voglibose treatment. However, the results showed no difference in RHI between mitiglinide/voglibose and glimepiride. This finding is probably due to the short treatment duration (5 days). While the administration of mitiglinide/voglibose suppressed glycemic variability, improvement in vascular endothelial function may require longer treatment/time. In this regard, Tuttolomondo et al. [19] conducted a randomized trial that evaluated the effect of dulaglutide on vascular endothelial function. Their findings included significantly lower HbA1c levels at 3 months after the addition of dulaglutide compared with after conventional therapy, whereas RHI remained unchanged at 3 months though it significantly improved at 9 months.
Another important finding of our study was that although hypoglycemia occurred more frequently during glimepiride treatment, only mild hypoglycemia (< 70 mg/dL) was recorded in the present study. For example, no statistical differences were observed in the incidence of hypoglycemia of < 54 mg/dL. In addition, during treatment with glimepiride, TBR < 70 mg was 2.64% and TBR < 54 mg/dL was 0.19%. These values sufficiently met the CGM management targets proposed by the international consensus, which are < 4% for TBR < 70 mg/dL and < 1% for TBR < 54 mg/dL [10]. Based on the results of our study, hypoglycemia caused by glimepiride was mild, which may have not been enough to reduce RHI.
We also compared mitiglinide/voglibose and glimepiride by analyzing the CGM parameters measured during 0:00–24:00, 07:00–24:00, and 00:00–7:00 hours, analyzed the width of postprandial glycemic variability, and examined new indices, such as TIR, TAR, and TBR. To our knowledge, our study is the first to analyze the combination of these parameters and indices. Since the estimated HbA1c levels were similar between the two treatment groups, no difference in all-day MBG was observed. However, the daytime MBG was significantly lower for mitiglinide/voglibose, whereas the nighttime MBG was lower for glimepiride. The effects of the two drugs differed. A possible factor for the lower daytime MBG in the mitiglinide/voglibose group is that administration of mitiglinide/voglibose significantly reduced postprandial glucose levels. In this study of patients admitted to the hospital, the time of starting meals was recorded, and thus we were able to calculate MPPGE more accurately. The MPPGE was 82.3 ± 27.7 mg/dL at baseline; it remained almost unchanged at 79.0 ± 25.9 mg/dL during treatment with glimepiride, but it was extremely low at 27.9 ± 14.5 mg/dL during treatment with mitiglinide/voglibose. This finding confirmed that mitiglinide/voglibose had an immediate and potent inhibitory effect on the increase in postprandial glucose level. Katsuno et al. [20] reported that in Japanese patients with type 2 diabetes, the addition of voglibose to mitiglinide inhibited postprandial glucose spikes and further increased glucagon-like peptide-1 (GLP-1) levels; however, these effects were not observed after administering a double dose of mitiglinide. The α-GI, which changes the site of glucose absorption from the upper intestine to the lower intestine, has been reported to eventually enhance the secretion of GLP-1, which is secreted in the lower intestine [21]. In Japanese individuals, impaired early-phase insulin secretion is markedly involved in the pathology of type 2 diabetes, and the secretory ability of pancreatic β cells is weaker in Japanese individuals than in Europeans and Americans [22, 23]. Thus, the concomitant use of mitiglinide and α-GI, which have different mechanisms of action, appears to be useful in Japanese patients with type 2 diabetes. In addition, because the use of mitiglinide/voglibose can reduce the number of medications, it may be a treatment that can contribute to improved medication adherence in patients with type 2 diabetes.
The CGM management targets proposed by the international consensus for type 2 diabetes are more than 70% for TIR, less than 25% for TAR > 180 mg/dL, less than 5% for TAR > 250 mg/dL, less than 4% for TBR < 70 mg/dL, and less than 1% for TBR < 54 mg/dL [10]. In the present study, the management targets for TIR, TAR, and TBR were achieved by treatment with both types of medications; mitiglinide/voglibose and glimepiride. However, during the treatment with mitiglinide/voglibose, TIR was significantly higher and TAR and TBR were significantly lower. Especially, TBR < 70 mg/dL was 0.06%, and TBR < 54 mg/dL was not detected during treatment with mitiglinide/voglibose. Therefore, this drug significantly improved postprandial hyperglycemia and was associated with an extremely low risk of hypoglycemia. Recent clinical trials have shown that decreased TIR is associated with the onset and progression of microvascular complications [24], intima-media thickness [25], and increased risks of all-cause and cardiovascular mortality [26] in patients with diabetes. We have also previously analyzed CGM data of 999 Japanese patients with type 2 diabetes and reported that glycemic variability and hypoglycemia were associated with the onset and progression of microvascular complications [27] and macroangiopathy [28, 29]. These studies also highlighted the potential usefulness of mitiglinide/voglibose in type 2 diabetes.
This study has several limitations. First, it was a short-term study involving hospitalized patients, and accordingly we could not evaluate the long-term benefits of the tested drugs. It is possible that the effects of the medications on RHI would be different during long-term use. Second, because the service of iPro2 was terminated during the study period, more than one type of CGM device had to be used in the study. However, only a single type of CGM device was used per patient during the study, and the study was conducted using a crossover design. Thus, we consider no problems with the comparison of the CGM parameters between mitiglinide/voglibose and glimepiride. Third, we did not measure the levels of C-peptide, GLP-1, and glucose-dependent insulinotropic polypeptide, which are hormones that may affect BG dynamics.
In conclusion, our study showed no difference in the effects of mitiglinide/voglibose and glimepiride on vascular endothelial function in patients with type 2 diabetes. However, the mitiglinide/voglibose tablet significantly reduced glycemic variability in terms of MAGE and other parameters. Our study also demonstrated for the first time that the use of mitiglinide/voglibose was associated with significantly higher TIR, significantly lower incidence of hyperglycemia (defined as BG level of ≥ 180 mg/dL), significantly milder postprandial glycemic variability, and extremely low risk of hypoglycemia. Based on these findings, mitiglinide/voglibose appears to be useful therapeutically through improvement of postprandial hyperglycemia and control of glycemic variability in patients with type 2 diabetes.