Herein, we evaluated the effect of switching from Deg to Gla-300 in insulin-dependent type 1 diabetes patients treated with Deg on the GV and frequency of hypoglycemia. Switching from Deg to Gla-300 improved day-to-day GV expressed in SD-FBG and decreased the frequency of nocturnal hypoglycemia. The change of SD-FBG had negative correlation with SD-FBG and HbA1c values at baseline and positive correlation with s-Alb at baseline.
Both Deg and Gla-300 improve day-to-day GV unlike Gla-100, owing to their longer pharmacodynamic effect [11–18]. However, the action mechanisms of these two ultra-long-acting insulin analogues are different. Deg forms a soluble multi-hexametric chain after subcutaneous injection and the zinc moiety of the insulin molecule diffuses slowly from the terminal ends of Deg and gets absorbed into circulation. After absorption into the circulatory system, almost all Deg bind to albumin and is slowly released from albumin in the target tissue to achieve hypoglycemic effect . In contrast, Gla-300 does not bind to albumin in circulation . S-Alb levels fluctuate daily with high values in daytime, and low values at night . The decreased in s-Alb level increases free insulin level at night and decreases blood glucose level. Thus, large GV and frequent nocturnal hypoglycemia are observed in patients treated with Deg.
Kawaguchi et al. reported lower GV and frequency of hypoglycemia with Gla-300 treatment than that with Deg treatment in type 2 diabetes . Their findings indicated that the frequency of nocturnal hypoglycemia with Deg therapy was associated with low levels of s-Alb . Another report on type 2 diabetes showed that Gla-300 decreased total and nocturnal hypoglycemia compared with Deg in the cases with s-Alb < 3.8 g/dL . However, another clinical real-world study on type 2 diabetes showed that the first injection of Deg achieved larger reduction of HbA1c and frequency of hypoglycemia compared to these markers in Gla-300 therapy . This report showed controversial results to that reported by Kawaguchi et al , and the superiority of Gla-300 and Deg based on their effectiveness are not clear even in type 2 diabetes.
Similar studies on type 1 diabetes are even more limited than on type 2 diabetes. However, a few reports have compared Deg therapy with Gla-300 therapy in type 1 diabetes. A double-blind crossover euglycemic clump study showed that Gla-300 induced 20 % less fluctuation in steady state glucose infusion rate profiles than that of Deg in once-daily morning dosing regimen of 0.4 U/kg/day . However, another double-blind crossover euglycemic clump study showed that Deg exhibited lower day-to-day and within-day GV than that of Gla-300 in type 1 diabetes . Recently, Miura et al. conducted multicenter crossover trial on type 1 diabetes in which the efficiency of Deg and Gla-300 were compared . In this study, SD-FBG by CGM were evaluated as the marker of day-to-day GV. The results showed that there was no difference of SD-FBG between these two insulin analogues. However, time below the target range (< 70mg/dL) were shorter in Gla-300. On the other hand, time above the target range (> 180mg/dL) were shorter in Deg. As conclusion, they identified that these two insulins have comparable glucose stabilizing effects in patients with type 1 diabetes. Although this study is similar to ours, there were several differences. The first difference is the target patients. In the study described by Miura et al., the target patients included all insulin-dependent type 1 diabetes. Our target patients were insulin-dependent type 1 diabetes patients exhibiting large GV or frequent hypoglycemia, despite the use of Deg. The second difference was in the evaluation of factors having correlation with the change in GV. Miura et al. did not evaluate the factors influencing the superiority of these ultra-long-acting insulin analogues. In contrast, our study showed that low s-Alb, high HbA1c, and high SD-FBG are predictors of the superiority of Gla-300 over Deg in type 1 diabetes. Knowing these predictors of superiority may lead to the personalization of treatment in patients with type 1 diabetes patients .
Our study has several limitations. First, this study adopted a retrospective design and was conducted in a small number of patients. The second is the method used to evaluate the GV and frequency of hypoglycemia. The evaluation of GV and hypoglycemia by FGM or CGM is better than that by SMBG. The third is the points without the data of switching from Deg to Gla-300. Therefore, larger prospective crossover studies using FGM or CGM are necessary for supporting our results.