In this multicenter retrospective observational study, initiation of basal insulin therapy was found to be an effective strategy for the treatment of T2D in a Japanese clinical setting regardless of the basal insulin type selected. In addition, duration of diabetes, BMI, and use of insulin secretagogues were significant determinants for the successful withdrawal of basal insulin therapy, but not selected insulin type. There were no differences in glycemic control among the study participants with T2D on the different basal insulin types—Gla100, Gla300, and Deg. To our knowledge, this is the first study to follow clinical features over a period of 6 months after the initiation of basal insulin and to compare the three types of basal insulin in a clinical setting among Japanese patients with T2D.
The principal objective of this study was to assess the impact of initiating basal insulin therapy among patients with T2D. Following the initiation of basal insulin by the study participants, HbA1c decreased smoothly over time, independently of the type of basal insulin, suggesting that basal insulin therapy may be a powerful strategy for managing T2D in clinical practice. In addition, 61 participants (16.2%) were able to withdraw from basal insulin therapy within 6 months. The characteristics of that group of participants were short duration of diabetes and high BMI, and the use of medications other than insulin secretagogues by many of the participants. While it is difficult to specify the best protocol for possible withdrawal of insulin treatment, these data indicate several clinical factors for the use of insulin, possibly providing support for the concept of a beneficial effect of “β-cell rest” with insulin therapy. In this context, insulin therapy would be expected to decrease the secretory demand for endogenous insulin from β-cells. In contrast, it was difficult for participants using insulin secretagogues, such as SU and glinides, with β-cell stimulatory effects to withdraw from insulin treatment within 6 months, presumably due to the increased burden on β-cells. One possible explanation is that these results indicate that the β-cell function of those patients who were successful in withdrawing from insulin therapy was preserved to a greater degree. In addition, short duration of diabetes was positively associated with the ability of participants to withdraw from insulin use. It has been reported that at the onset of T2D total pancreatic β-cell mass is decreased to approximately 50% of that in healthy persons , suggesting that β-cell function may decline at a constant rate after diabetes onset . The results of these studies suggest that T2D should be treated at an early stage. We also found that a high BMI, which was believed to be accompanied by high insulin secretion due to insulin resistance, was positively associated with successful withdrawal of insulin use. Taking these findings into consideration, the introduction of basal insulin therapy at an early stage of the disease would be beneficial in terms of remission of glucose intolerance with respect to β-cell insufficiency and preservation of β-cell function.
In the present study, no difference was found among the three insulin types in terms of changes in HbA1c and BMI at the beginning of the study or after 6 months, including the rate of successful withdrawal of insulin treatment during the observation period. The pharmacokinetic/pharmacodynamic properties of the basal insulin analogues Gla300 and Deg are improved compared with those of Gla100. The EDITION randomized controlled trial (RCT) program, conducted in Japanese persons with T2D, demonstrated that Gla300 provided similar reductions in HbA1c compared with Gla100, but with fewer hypoglycemic episodes . The BRIGHT study, the first RCT to directly compare the efficacy and safety of Gla300 and Deg in insulin-naïve patients with T2D, demonstrated that both analogues provided similar robust improvements in glycemic control with a low risk of hypoglycemia. Benefits were observed with Gla300 in terms of lower hypoglycemia rates during the active titration period (weeks 0–12) when compared with Deg . Indeed, compared with participants using Gla100 and Deg, those using Gla300 seemed to require higher doses of insulin and to experience slowly increased BMI in this study. On the other hand, in two earlier studies, Deg and Gla100 administered once daily in combination with OAAs provided similar long-term glycemic control in insulin-naïve T2D patients with lower rates of nocturnal hypoglycemia when compared with the use of only Deg [8, 15]. In addition, significantly improved HbA1c, larger reductions in the rates and likelihood of hypoglycemia, and lower risk of treatment discontinuation have been demonstrated with Deg or degludec U200 (the latter which was not available in Japan), compared with Gla300 in insulin-naïve patients with T2D . In that RCT, basal insulins were titrated, targeting the fasting glucose level, apart from the risk of hypoglycemia, in contrast with two studies that used propensity-score matching analyses [9, 10]. The design used in those studies might have made a difference among the basal insulin types. However, in the present study, as well as in previous Japanese prospective, observational studies [16, 17], basal insulins were titrated by attending physicians, targeting hypoglycemia-conscious glucose levels on an individual basis in routine clinical practice. There were fewer reports of hypoglycemic events in these latter two studies [16, 17] than in the other Japanese RCT studies [14, 15], although the present study did not investigate hypoglycemia. Differences in study design might be a reason why no differences were found in the present study among the three insulin types, including the rate of withdrawal of insulin therapy.
The results of the present study also revealed that bodyweight management was important for successful withdrawal of insulin treatment. The BMI among the W participants was maintained during the observation period, whereas the BMI among the C participants increased significantly, although the C participants had significantly lower BMI at the beginning of the study compared to the W participants. The decreasing BMI in the W participants during treatment implied that these participants’ improved compliance with diet and exercise therapy reduced the burden on β-cells. Accordingly, successful withdrawal of insulin treatment might be, as expected, important not only for baseline characteristics but also for ability to ensure lifestyle interventions in a clinical setting to prevent increases in bodyweight.
In this study, the BMI among participants that were started on Deg or Gla100 was significantly increased, whereas the BMI among participants started on Gla300 was not. We believe that any consideration of these results should be careful and conservative. To fully grasp the results, the period of medication use should also be considered. Gla100, Deg, and Gla300 were launched as treatment options in Japan in 2003, 2013, and 2015, respectively, while DPP-4I, GLP-1RA, and SGLT2I were launched in 2009, 2010, and 2014, respectively. Accordingly, it would be difficult to assess the benefits derived from the three types of insulin on a clinical basis because the opportunities for use of the new OAAs or GLP-1RA are inconsistent. In addition, medication changes during the observation period should be also considered, although among the three insulin categories, differences in medication use at the start of the study continued even after 6 months (Table 1). To avoid any such bias, it is necessary to perform further studies involving a larger study population and a shorter recruitment period.
There a several limitations to the study. First, it did not investigate hypoglycemic events accurately because some participants did not self-measure plasma glucose and there were no reported cases of severe hypoglycemia. It is highly likely that the number of hypoglycemic events were underestimated. In addition, it seems that treat-to-target by physician decision was not strictly implemented in the real-world clinical setting, unlike in clinical trials, which also contributed to low incidence of hypoglycemia reported in this study. Taken together, hypoglycemia may have been underreported. Second, the study included the observation of only four data points for a period of 6 months with a limited sample size. In addition, participants were not followed after withdrawal of insulin use. Lastly, habitual and comorbid factors, such as smoking status and activities of daily life, were not assessed either before the study or during the observation period.