Introduction
The selection of appropriate therapy for the treatment of type 2 diabetes mellitus (T2DM) can often be challenging given the availability of a wide variety of therapeutic options. However, it is recognized that most patients with long-standing T2DM will need to incorporate insulin into their treatment regimen at some point because of the progressive nature of the condition [
1]. Early initiation of insulin is increasingly advocated to enable patients to achieve adequate glycemic control. Several international guidelines, as well as the Chinese treatment guidelines, recommend that insulin should be considered if the initiation of lifestyle modifications and metformin or combination therapy of two to three oral antidiabetic drugs (OADs) is unable to achieve and maintain target glycemic levels [
2‐
5]. While some guidelines recommend initiation with basal insulin [
3,
5], a long-acting insulin analogue that maintains basal glycemic levels throughout the day, others recommend initiation with basal or premixed insulin [
2,
4]. Premixed insulin, a combination of rapid-acting bolus insulin and intermediate-acting basal insulin, was developed to mimic physiological endogenous insulin secretion [
6,
7]. Premixed insulin is typically prescribed and initiated in approximately 70.0% of Chinese patients with T2DM, while only around 10.0% receive basal insulin [
8]. This is partly because premixed insulin was available in China earlier than basal insulin analogues, and is considerably cheaper [
7]. While premixed insulins are considered to be a good option for patients who require both basal and prandial insulin but wish to limit the number of daily injections, the fixed dose combination of basal and rapid-acting insulins means that the dose of insulins cannot be conveniently adjusted to meet individual patient requirements [
9]. Additionally, in comparison to treatment with basal insulin, premixed insulin has been associated with inadequate glycemic control, as well as an increased risk of hypoglycemia [
10,
11].
Various studies, including the recent Lantus Registry Study in China, have shown that switching to insulin glargine-based therapy can improve glycemic control in patients with T2DM who are poorly controlled on premixed insulin [
7,
9,
12‐
15]. These studies have demonstrated that a switch in therapy can lead to a significant reduction in glycated hemoglobin (HbA
1c) and an improvement in treatment satisfaction, along with a low incidence of hypoglycemic events [
7,
9,
12‐
15]. Once-daily insulin glargine is also considered to be a more flexible regimen with lower healthcare costs than premixed insulin, providing further evidence of the benefits of switching therapy [
12,
16].
The current study, a subgroup analysis of the Lantus Registry Study [
12], aims to identify independent factors associated with changes in blood glucose for patients with T2DM who have switched their treatment from premixed insulin therapy to insulin glargine plus OADs. In doing so, this study aims to determine the characteristics of patients who are more likely to obtain real-life clinical benefits from this switch in treatment.
Discussion
The Lantus Registry Study in China was a prospective, observational study that reported improved glycemic control and treatment satisfaction with a low incidence of hypoglycemia in adult Chinese patients with T2DM who switched from premixed insulin to insulin glargine plus OADs [
12]. This subgroup analysis of the Lantus Registry Study aimed to identify the characteristics of patients who may gain the greatest benefit by transitioning therapy from premixed insulin to insulin glargine plus OADs.
In this study, following a switch in treatment from premixed insulin to insulin glargine plus OADs, 55.2% of patients achieved an endpoint HbA1c level of <7.0% in comparison to the 28.6% of patients at baseline. Additionally, 63.2% demonstrated an improvement in HbA1c. These results indicate the benefits of this transition in treatment.
Patient characteristics influencing treatment outcomes identified in this study were baseline duration of diabetes, HbA1c, FPG, and age. Logistic regression analysis revealed that baseline duration of diabetes, HbA1c, FPG, and age were negatively associated with achieving target HbA1c levels of <7.0%. This was reflected in patients with endpoint HbA1c <7.0% having a shorter mean duration of diabetes, lower HbA1c and FPG, and younger age at baseline than patients with endpoint HbA1c ≥7.0%. Additionally, a higher proportion of patients with mean duration of diabetes ≤5 years were found in the HbA1c improvement group compared with the unchanged and deterioration groups. The mean age from the HbA1c improvement to deterioration groups also increased numerically.
The above results suggest that switching treatment to insulin glargine plus OADs in patients earlier, while they are younger, with a shorter duration of diabetes and with lower levels of HbA
1c and FPG, can provide them with a better chance of achieving target glycemic control. Given that islet beta cell function has been shown to progressively deteriorate over time in patients with T2DM [
19], an early transition in treatment for patients inadequately controlled on premixed insulin is more desirable. The above results have also been observed in two real-world Chinese studies which, similar to this study, have evaluated patient characteristics that aid in identifying patients who can benefit the most from a switch in treatment from premixed insulin to insulin glargine plus OADs. One of the studies by Zhang et al. demonstrated, through comparison of patient groups who did and did not reach HbA
1c targets (HbA
1c ≤6.5%, 6.5% < HbA
1c < 7.0%, or HbA
1c >7.0%) by the study end, that duration of diabetes and baseline HbA
1c were two factors closely associated with the success of the treatment transition [
7]. The other study by Yang et al. also demonstrated, through logistic regression analysis, that the probability of achieving a HbA
1c target of <7.0% is lower with increased disease duration (odds ratio [OR] = 0.785) and higher baseline HbA
1c (OR = 0.482) [
9]. The study by Yang et al. also demonstrated that patients with endpoint HbA
1c <7.0% were younger than patients with HbA
1c ≥7.0% (54.67 ± 7.99 vs 57.42 ± 8.42 years;
P = 0.0265) [
9]. Studies have shown that there is impaired beta cell function and tissue sensitivity to insulin with aging [
20,
21], which may be why younger patients are able to better respond to the switch in treatment, and therefore reach glycemic targets or demonstrate an improvement in HbA
1c, in comparison to those who are older.
This study also demonstrates that BMI could be a factor influencing efficacy outcomes. Patients with endpoint HbA
1c <7.0% were shown to have lower baseline BMI than patients with endpoint HbA
1c ≥7.0%. Higher BMI has been shown to be associated with decreased insulin sensitivity [
22,
23], which may be why patients with lower BMI exhibit greater glycemic control in response to insulin glargine.
Another factor of significance was the insulin glargine dose at endpoint, which was shown to be negatively associated with achieving HbA
1c <7.0%. This may have been on account of the suboptimal glycemic control of patients at baseline. At baseline, the mean HbA
1c of the mITT set was 7.8% and the mean FPG was 8.1 mmol/L [
12].
Findings from this study demonstrate that FPG is an important factor influencing the HbA
1c level of patients. Patients with an improvement in HbA
1c had significantly higher baseline HbA
1c in comparison to the unchanged and deterioration groups. This reflects a more marked reduction in HbA
1c for poorly controlled patients, although this does not necessarily indicate their achievement of HbA
1c <7.0%. Fasting hyperglycemia is the main contributor to glycemic load for poorly controlled T2DM [
7,
24,
25] and this suggests that for patients with poor glycemic control at baseline, treatment with insulin glargine, which targets FPG, has a greater impact on overall glycemic control. This has also been observed in the study by Zhang et al. [
7]. Patients with higher baseline HbA
1c levels, as a result of the nature of their hyperglycemia, are therefore likely to experience improvements in glycemic control in comparison to those with lower baseline HbA
1c levels during treatment switching.
Approximately three-quarters (74.5%) of patients unable to achieve HbA
1c <7.0% in this study also failed to achieve FPG ≤6.1 mmol/L. The lack of adequate FPG control in patients unable to achieve HbA
1c <7.0% is not surprising given the increased contribution of fasting hyperglycemia to poorly controlled T2DM [
24,
25]. Considering their high FPG levels, these patients would have a lower tendency to experience hypoglycemia. Our analysis also showed that the incidence of hypoglycemia did not increase in patients with endpoint HbA
1c ≥7.0% compared with patients achieving endpoint HbA
1c <7.0% (
P = 0.6889), even though patients in the ≥7.0% group were older, with a longer duration of diabetes, and a higher proportion of complications and comorbidities. The average endpoint insulin glargine dose for patients who failed both HbA
1c and FPG targets was 0.26 ± 0.09 U/kg/day, which was approximately 40% lower than the doses (0.4–0.5 U/kg/day) required to achieve adequate glycemic control while maintaining a low risk of hypoglycemia reported by other studies [
17,
26]. This indicates that there is still potential for up-titration of the dose of insulin glargine in patients who failed to reach both glycemic targets. Hence, further up-titration of the insulin glargine dose in patients who failed to reach both HbA
1c and FPG targets may not increase the risk of hypoglycemia, and improve the likelihood of achieving adequate FPG control and therefore target HbA
1c.
Optimally titrating the dose of insulin glargine is therefore a critical factor influencing achievement of adequate FPG control and therefore target HbA
1c. This finding holds particular significance as it demonstrates a mechanism by which patients can achieve target HbA
1c following a switch in therapy from premixed insulin to insulin glargine plus OADs. This finding is also relevant to Asia, given that physicians in Asia often have a cautious approach to the titration of insulin, especially as Asian patients with T2DM, who are leaner than Caucasian patients, are perceived to be at an increased risk of hypoglycemia [
27,
28]. This fear is unfounded as several studies conducted in Asian patients with T2DM have shown that the rates of hypoglycemia are low with insulin glargine when taken as combination therapy with OADs in insulin-naïve patients or in patients switching from premixed insulin [
7,
12,
27]. A study by Riddle et al. which sought to determine the relative contributions of basal hyperglycemia versus postprandial hyperglycemia in patients inadequately controlled on OADs prior to and following treatment intensification with various therapies, demonstrated that symptomatic hypoglycemic events were greater with the other treatments than with basal insulin [
25].
The main limitations of the Lantus Registry Study have been reported previously [
12]. Briefly, the lack of comparator arm in the trial means that it is difficult to determine whether observed improvements in glycemic control following the switch in treatment are solely on account of treatment effectiveness or influenced by study design. This is because observation can alter the behavior of both patients and physicians involved in a clinical trial, which can influence outcome measures. Another general limitation of observational and single-arm studies is the strong likelihood of bias and confounding in study design. Treatment was at the discretion of the physicians, which further exposes the study to bias.
Additionally, the duration of the Lantus Registry Study was relatively short and did not allow proper evaluation of the clinical challenges associated with optimal titration of insulin glargine along with OAD dosage adjustments. A longer study is required for more robust evaluation of these clinical challenges and insulin glargine titration. As a result of the widespread use of premixed insulin in China, there is lack of clinical experience with insulin glargine, which may have led to insufficient titration and therefore a lower achievement of glycemic control than would have otherwise been seen. However, the current subgroup analysis of the Lantus Registry Study does provide insight into the characteristics of patients associated with the clinical benefits of transitioning therapy from premixed insulin to insulin glargine plus oral OADs, based on real-world data. It also highlights the need to improve the management of T2DM in clinical practice, especially with regard to titrating the dose of insulin glargine to enable patients to achieve adequate glycemic control. This study also raises the need for further investigation of the effects of switching therapy on the incidence of hypoglycemia in Asian populations to encourage optimal titration of the dose of insulin glargine.
Acknowledgements
Sponsorship of this study and article processing charges were funded by Sanofi, Shanghai, China. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. Sanofi was responsible for the design of the study, collecting and managing data, and performing all statistical analyses. All authors had full access to all the data in this study, and were fully responsible for the data interpretation and all content and editorial decisions relating to this manuscript. Wenying Yang participated in study concept and design, data analysis; Shi Bu provided acquisition, analysis, interpretation of data, and critical revision of the manuscript for important intellectual content. Xuelian Zhang, Zhu Haiqing, Ying Shuai and Xiaoyan Xing participated in the data collection and manuscript composing. All authors have read and approved the final manuscript. Medical editorial and writing assistance in the preparation of this manuscript was provided by Priya Shreedhar of MediTech Media Asia Pacific and was funded by Sanofi. The authors would like to thank all of investigators and patients for their participation.