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Original Article
Drug/Regimen Efficacy and Safety of Self-Titration Algorithms of Insulin Glargine 300 units/mL in Individuals with Uncontrolled Type 2 Diabetes Mellitus (The Korean TITRATION Study): A Randomized Controlled Trial
Jae Hyun Bae1,2orcid, Chang Ho Ahn1,3, Ye Seul Yang1,4, Sun Joon Moon1,5, Soo Heon Kwak1, Hye Seung Jung1, Kyong Soo Park1, Young Min Cho1orcidcorresp_icon
Diabetes & Metabolism Journal 2022;46(1):71-80.
DOI: https://doi.org/10.4093/dmj.2020.0274
Published online: June 16, 2021
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1Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

2Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea

3Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

4Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea

5Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

corresp_icon Corresponding author: Young Min Cho orcid Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea E-mail: ymchomd@snu.ac.kr
• Received: November 24, 2020   • Accepted: February 4, 2021

Copyright © 2022 Korean Diabetes Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Background
    To compare the efficacy and safety of two insulin self-titration algorithms, Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment (INSIGHT) and EDITION, for insulin glargine 300 units/mL (Gla-300) in Korean individuals with uncontrolled type 2 diabetes mellitus (T2DM).
  • Methods
    In a 12-week, randomized, open-label trial, individuals with uncontrolled T2DM requiring basal insulin were randomized to either the INSIGHT (adjusted by 1 unit/day) or EDITION (adjusted by 3 units/week) algorithm to achieve a fasting self-monitoring of blood glucose (SMBG) in the range of 4.4 to 5.6 mmol/L. The primary outcome was the proportion of individuals achieving a fasting SMBG ≤5.6 mmol/L without nocturnal hypoglycemia at week 12.
  • Results
    Of 129 individuals (age, 64.1±9.5 years; 66 [51.2%] women), 65 and 64 were randomized to the INSIGHT and EDITION algorithms, respectively. The primary outcome of achievement was comparable between the two groups (24.6% vs. 23.4%, P=0.876). Compared with the EDITION group, the INSIGHT group had a greater reduction in 7-point SMBG but a similar decrease in fasting plasma glucose and glycosylated hemoglobin. The increment of total daily insulin dose was significantly higher in the INSIGHT group than in the EDITION group (between-group difference: 5.8±2.7 units/day, P=0.033). However, body weight was significantly increased only in the EDITION group (0.6±2.4 kg, P=0.038). There was no difference in the occurrence of hypoglycemia between the two groups. Patient satisfaction was significantly increased in the INSIGHT group (P=0.014).
  • Conclusion
    The self-titration of Gla-300 using the INSIGHT algorithm was effective and safe compared with that using the EDITION algorithm in Korean individuals with uncontrolled T2DM (ClinicalTrials.gov number: NCT03406663).
Insulin glargine 300 units/mL (Gla-300) is a three-fold concentrated formulation of insulin glargine 100 units/mL (Gla-100) that can be calibrated in 1-unit increments up to 80 units per injection [1]. In euglycemic clamp studies, Gla-300 provided more constant pharmacokinetic and pharmacodynamic profiles than Gla-100 in individuals with type 1 diabetes mellitus (T1DM) [2,3]. The EDITION program compared the efficacy and safety of Gla-300 and Gla-100 in individuals with type 2 diabetes mellitus (T2DM) [4-7] and T1DM [8,9]. In the EDITION 1–3 trials [4-6], the doses of Gla-300 and Gla-100 were self-titrated to increase 3 or 6 units and to decrease 3 units once weekly (but no more often than every 3 days) with fasting self-monitoring of blood glucose (SMBG) to achieve a target range of 4.4 to 5.6 mmol/L (the EDITION algorithm). In the EDITION JP 2 trial for Japanese patients [7], the insulin doses were self-titrated to increase 1.5 or 3 units and to decrease 3 units to achieve the same target range. Both the EDITION 2 [5] and the EDITION JP 2 [7] trials were conducted in individuals with T2DM using basal insulin plus oral antidiabetic drugs (OADs). At the end of the study, the EDITION JP 2 trial showed a lower total daily insulin dose (TDD) (0.3 to 0.4 units/kg/day vs. 0.8 to 0.9 units/kg/day) and lower insulin increments from baseline (0.1 units/kg/day vs. 0.2 to 0.3 units/kg/day) than the EDITION 2 trial [5,7]. However, hypoglycemia occurred more frequently in the EDITION JP 2 trial than in the EDITION 2 trial [5,7]. The changes in glycosylated hemoglobin (HbA1c) levels from baseline were similar between the two studies [5,7]. In the EDITION 2 trial, the participants were mainly Caucasians, with a body mass index (BMI) of 34.8±6.4 kg/m2 at baseline [5]. In contrast, in the EDITION JP 2 trial, all participants were Japanese, with a baseline BMI of 25.3±3.8 kg/m2 [7]. Asians develop T2DM at a lower BMI than Caucasians [10], and there are ethnic differences in β-cell function [11], insulin sensitivity [12,13], and the incretin effect [14]. Therefore, these findings suggest that for the Asian population, a smaller dose of basal insulin adjustment may be more suitable than the EDITION algorithm.
The Canadian Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment (INSIGHT) study compared the efficacy of adding Gla-300 with that of titrating and/or adding OADs in individuals with uncontrolled T2DM who were taking moderate doses of OADs or not taking OADs [15]. Participants assigned to Gla-300 started with 10 units of Gla-300 and adjusted the dose by 1 unit every day until a fasting SMBG reached ≤5.5 mmol/L (the INSIGHT algorithm). In this study, the addition of Gla-300 using the INSIGHT algorithm showed better glycemic control with no difference in hypoglycemia compared with the titration and/or addition of OADs [15].
Currently, international clinical practice guidelines provide recommendations on the initiation and adjustment of basal insulin therapy [16-19]. Nevertheless, there is insufficient evidence to support or contradict a specific insulin titration algorithm for the management of T2DM. The TITRATION study compared the efficacy and safety of the two titration algorithms, INSIGHT and EDITION, for Gla-300 in individuals with T2DM, mainly from a primary care setting in Canada [20]. In a 12-week, randomized trial, the INSIGHT algorithm was as effective as the EDITION algorithm, but had greater patient and healthcare provider (HCP) satisfaction [20]. However, the efficacy and safety of the two algorithms have not been evaluated in the Asian population. In this regard, we investigated the efficacy and safety of the INSIGHT and EDITION algorithms for Gla-300 in Korean individuals with uncontrolled T2DM.
Study population and ethical statement
We included individuals who were aged ≥19 years and had been treated for T2DM with or without basal insulin on noninsulin antihyperglycemic agents (NIAHAs). They had either an HbA1c level >7% and ≤10% with basal insulin (Gla-300, Gla-100, neutral protamine Hagedorn [NPH] insulin, or insulin detemir) or an HbA1c level >7% and ≤11% without basal insulin (insulin-naïve). We excluded individuals who were diagnosed with T1DM, who were unwilling to inject insulin or to perform SMBG, who initiated NIAHAs or changed the dose of NIAHAs in the previous 3 months, who were not on stable doses (±20%) of basal insulin in the previous 3 months, who were treated with insulin other than basal insulin in the last 3 months prior to screening, who were pregnant or lactating, and who were night shift workers.
This study was conducted following the principles established in the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. 1708-078-878) and is registered at ClinicalTrials.gov (ClinicalTrials.gov number: NCT03406663). All study participants provided written informed consent before participating in any study-related activities.
Study design
This study was a 12-week, single-center, pragmatic, randomized, open-label, and treat-to-target trial. The participants were randomly assigned to either the INSIGHT or EDITION algorithm (1:1 ratio, stratified by prior insulin use) using webbased randomization from the Medical Research Collaborating Center at Seoul National University Hospital. Treatment allocation was concealed until the algorithms were assigned. As in the Canadian TITRATION study [20], all participants received Gla-300 with or without NIAHAs. Insulin-naïve individuals started Gla-300 at 0.2 units/kg. Individuals receiving once-daily Gla-100, NPH insulin, or insulin detemir switched basal insulin to the same dose of Gla-300. Individuals receiving twice-daily NPH insulin or insulin detemir started Gla-300 at 80% of the previous daily dose. Gla-300 was administered once daily at the same time of the day. In the INSIGHT group, the participants self-titrated the dose of Gla-300 by 1 unit/day until achieving a fasting SMBG in the range of 4.4 to 5.6 mmol/L (Supplementary Table 1). In the EDITION group, the participants self-titrated the dose of Gla-300 according to the median SMBG values of the last 3 days at least once weekly but no more often than every 3 days to achieve the same target range (Supplementary Table 1). The participants continued taking NIAHAs at the same dose during the study period. Fasting SMBG values were measured using participants’ glucometers before breakfast and the administration of insulin or NIAHAs. After the instruction for each algorithm, the participants were followed up under usual care conditions to mimic real-world clinical practice in this pragmatic trial. They were allowed to contact the study site if they had any episodes of hypoglycemia or wanted to discuss insulin dose adjustments between scheduled visits. The study flow is depicted in Fig. 1.
The primary outcome was the proportion of individuals achieving a fasting SMBG ≤5.6 mmol/L without nocturnal hypoglycemia at week 12 (Supplementary Table 2). The fasting SMBG value was measured with 7-point SMBG on one of the three days prior to the week 12 visit. The secondary outcomes were changes in 7-point SMBG, laboratory-measured fasting plasma glucose (FPG), and HbA1c from week 0 to week 12; the proportion of individuals with HbA1c ≤7.0% at week 12; changes in body weight and TDD from week 0 to week 12; the rate of hypoglycemic events (confirmed, symptomatic, or severe) (Supplementary Table 2) [21] during the study period; adherence and patient satisfaction to insulin titration algorithms. We evaluated treatment adherence with the proportion of patients adjusting the dose of Gla-300 according to each algorithm during the study period. Patient satisfaction was measured using the Korean version of the Diabetes Treatment Satisfaction Questionnaire-status (DTSQs) score, ranging from 0 (very dissatisfied/inconvenient/inflexible, none of the time, or definitely not recommend) to 6 (very satisfied/convenient/flexible, most of the time, or definitely recommend) [22,23].
We assessed the degree of pragmatism using the PRagmatic Explanatory Continuum Indicator Summary 2 (PRECIS-2) tool (Supplementary Table 3), scored from 1 (very explanatory) to 5 (very pragmatic) [24], and reported the results according to the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement (Supplementary Table 4) [25].
Statistical analysis
The objective of the study is to provide descriptive statistics on the efficacy and safety of the two insulin titration algorithms in Korean individuals with uncontrolled T2DM. The initial planned number of participants was 180. The sample size was calculated, assuming that the proportion of individuals reaching the primary outcome was 30% with a 95% confidence interval and that the dropout rate was 10% in each group. However, since this was a single-center study, some difficulties were encountered with timely patient recruitment. Based on the interim analysis, we amended the assumed proportion of individuals with the primary outcome and the dropout rate as 20% and 5%, respectively. As a result, 130 individuals were finally enrolled in this study.
Continuous variables are presented as the mean±standard deviation. Categorical variables are presented as numbers (%). All analyses were conducted according to the intention-to-treat principle. The primary outcome and the proportion of individuals with HbA1c ≤7.0% at week 12 were analyzed by the chi-square test. Changes in 7-point SMBG from week 0 to week 12 were analyzed using repeated measures analysis of variance (ANOVA). Changes in the area under the curve (AUC) of 7-point SMBG, FPG, HbA1c, body weight, TDD, and DTSQs scores from week 0 to 12 were analyzed using paired t-test. Adherence to each algorithm was analyzed by unpaired t-tests. All analyses were performed with GraphPad Prism version 8.4.3 (GraphPad Software Inc., San Diego, CA, USA). P values <0.05 were regarded as statistically significant.
Characteristics of the study participants
Of 130 individuals evaluated for this study, 129 (65 and 64 in the INSIGHT and EDITION groups, respectively) were included. One individual was excluded owing to the withdrawal of informed consent. The baseline characteristics of the participants are described in Table 1. The mean HbA1c level was 8.4%, and 90.7% of the participants had been using basal insulin. The mean body weight and TDD were 66.2 kg and 26.4 units/day, respectively. There were no significant differences between the two groups at baseline.
Glycemic control, insulin dosage, and body weight
The percentages of individuals achieving a fasting SMBG ≤5.6 mmol/L without nocturnal hypoglycemia at week 12 were 24.6% and 23.4% in the INSIGHT and EDITION groups, respectively (P=0.876) (Fig. 2). From week 0 to week 12, the corresponding differences in the mean 7-point SMBG values were –2.47 mmol/L (P<0.001) and –1.03 mmol/L (P=0.017) in the two groups. In the INSIGHT group, the SMBG values were significantly decreased at prebreakfast (P=0.001), postlunch (P=0.002), predinner (P<0.001), postdinner (P=0.001), and bedtime (P=0.001) (Fig. 3A). In the EDITION group, the SMBG values were significantly decreased only at prebreakfast (P=0.031) (Fig. 3A). The AUC of 7-point SMBG was significantly reduced in the INSIGHT group (–15.41±17.68 mmol·hr/L, P<0.001) but not in the EDITION group (–3.78±15.58 mmol·hr/L, P=0.107) during the same period (Fig. 3B). The INSIGHT and EDITION groups showed similar decreases in laboratory-measured FPG (–1.7±2.5 mmol/L vs. –1.5±2.6 mmol/L, P=0.568) and HbA1c (–0.7%±0.8% vs. –0.5%±0.9%, P=0.200) from week 0 to week 12. There was no difference in the proportion of individuals with HbA1c ≤7.0% at week 12 between the two groups (23.1% vs. 20.3%, P=0.703).
The TDD of Gla-300 was significantly increased from week 0 to week 12 in both the INSIGHT (12.7±19.0 units/day, P<0.001) and EDITION (6.8±10.5 units/day, P<0.001) groups (Fig. 4A). The increment of TDD was significantly higher in the INSIGHT group than in the EDITION group (between-group difference: 5.8±2.7 units/day, P=0.033). At week 12, body weight was not changed from baseline in the INSIGHT group (–0.5±7.2 kg, P=0.576). However, in the EDITION group, there was a small but significant increase in body weight (0.6±2.4 kg, P=0.038) (Fig. 4B). There was no significant change in BMI from baseline to week 12 in the INSIGHT (–0.3±3.8 kg/m2, P=0.487) and EDITION (–0.1±3.6 kg/m2, P=0.857) groups.
Hypoglycemia and adverse events
During the study period, there was no difference in the rate of hypoglycemic events between the INSIGHT and EDITION groups (0.8±1.8 events/person vs. 0.7±1.5 events/person, P=0.785). None of the participants experienced severe hypoglycemia. No treatment-emergent adverse events, except for hypoglycemia, were observed.
Adherence and patient satisfaction
Adherence to the insulin titration algorithms during the entire study period tended to be higher in the INSIGHT group than in the EDITION group (45.7%±35.0% vs. 35.3%±33.7%, P=0.088). Patient satisfaction, measured by the DTSQs scores, was significantly increased in the INSIGHT group (2.5±7.6, P=0.014) but significantly decreased in the EDITION group (–0.1±7.5, P=0.020).
This 12-week, pragmatic, randomized trial compared the efficacy and safety of the two insulin titration algorithms, INSIGHT and EDITION, for Gla-300 in Korean individuals with uncontrolled T2DM. The proportion of individuals achieving a fasting SMBG ≤5.6 mmol/L without nocturnal hypoglycemia at week 12 was comparable between the two groups. The INSIGHT group showed a greater reduction in 7-point SMBG than the EDITION group. The changes in laboratory-measured FPG and HbA1c and the proportion of individuals with HbA1c ≤7.0% at week 12 were similar in the two groups. Compared with the EDITION group, the INSIGHT group had a significantly higher increment of Gla-300 dose but showed less weight gain and no difference in hypoglycemia. Patient satisfaction was greater in the INSIGHT group than in the EDITION group, along with nominally higher treatment adherence.
The progressive nature of T2DM necessitates insulin therapy in addition to NIAHAs in many patients, particularly in those with longer disease durations [26]. Insulin therapy should also be considered when patients have evidence of catabolic features such as weight loss and ketosis or have severe and symptomatic hyperglycemia [17]. Basal insulin with or without NIAHAs is usually preferred, and, if the treatment fails, prandial or bolus insulin needs to be added [27]. However, both patients and HCPs often delay treatment initiation or intensification owing to barriers to insulin therapy, including clinical inertia, burdensome regimens, and fear of hypoglycemia or weight gain [28]. Therefore, a simple, effective, and safe insulin regimen is needed to improve glycemic control in individuals with T2DM.
The INSIGHT group, which used a simpler self-titration of Gla-300, showed similar glycemic responses with significant improvement in 7-point SMBG values compared with the EDITION group. Insulin dose optimization using the INSIGHT algorithm improved postprandial hyperglycemia accompanied by a decrease in fasting or preprandial glucose levels, leading to improvement in the AUC of 7-point SMBG. In both groups, the participants adjusted the dose of Gla-300 based on fasting SMBG values. Previous studies demonstrated that the self-titration of basal insulin was superior to physician-led titration in terms of HbA1c reduction [29,30]. In our study, the INSIGHT group showed no difference in HbA1c reduction despite the improvement of 7-point SMBG values compared with the EDITION group. These findings were probably because the duration of improvement in the SMBG values was not enough to lower HbA1c levels in the INSIGHT group. A longer duration of follow-up would have revealed a greater HbA1c reduction in the INSIGHT group than in the EDITION group. In addition, individuals in our study were more likely to achieve the primary endpoint of a fasting SMBG ≤5.6 mmol/L without nocturnal hypoglycemia at week 12 than those in the Canadian TITRATION study (24.6% vs. 19.4% for the INSIGHT group; 23.4% vs. 18.3% for the EDITION group) [20]. In summary, patient-led insulin titration according to the INSIGHT algorithm would also be suitable for Korean individuals with uncontrolled T2DM.
The TDD of Gla-300 was significantly increased from week 0 to week 12 in the INSIGHT (0.4 to 0.6 units/kg) and EDITION (0.4 to 0.5 units/kg) groups. Treat-to-target trials [31,32] often used a higher TDD of basal insulin than observational studies [33,34]. In our study, the increase in the Gla-300 dose was significantly higher in the INSIGHT group than in the EDITION group. However, there was no difference in hypoglycemic events (confirmed, symptomatic, or severe) between the two groups, and weight gain, albeit very small in amount, was observed only in the EDITION group. Despite advances in insulin therapy, it was reported that many individuals with T2DM using basal insulin did not achieve individualized HbA1c targets in a real-world setting [35]. Concerns regarding hypoglycemia and weight gain are important factors leading to suboptimal insulin titration by both patients and HCPs [28,36-38]. However, optimizing insulin therapy with timely intensification could reduce hyperglycemia without worsening hypoglycemia or weight gain [39]. Furthermore, in line with our findings, the simple self-titration of Gla-100 increased the insulin dose but significantly improved glycemic control with a low incidence of severe hypoglycemia compared with physician-led titration [30]. Therefore, our results indicated that the INSIGHT algorithm could result in the optimal dosing of basal insulin without an increase in hypoglycemia and body weight compared with the EDITION algorithm.
In the present study, adherence to the insulin titration algorithms tended to be higher in the INSIGHT group than in the EDITION group. As our study was a pragmatic trial conducted under routine clinical practice, treatment adherence to each algorithm was lower than that in the Canadian TITRATION study (45.7%±35.0% vs. 94.2%±16.2% for the INSIGHT group; 35.3%±33.7% vs. 96.1%±11.1% for the EDITION group) [20]. Adherence to insulin therapy is affected by various factors related to patients, HCPs, and treatments [40]. In the Canadian TITRATION study [20], investigators assessed the treatment responses weekly and determined the insulin dose adjustment for the EDITION group. Moreover, investigators could contact participants at any time to ensure that they titrated insulin by the SMBG results in both groups [20]. On the other hand, in our study, the participants were allowed to call the study site if they had hypoglycemia or would like to discuss insulin titration, but no actual contact was made during the study period. A retrospective cohort study showed that medication nonadherence, defined as the proportion of days covered <80%, was associated with an increase in HbA1c, hospitalization, and mortality in patients with diabetes mellitus (DM) [41]. Furthermore, in patients with T2DM taking insulin, medication nonadherence, defined as ≥1 missing visit or provider code for not taking medications, was associated with an increased risk of all-cause mortality [42]. Consequently, the INSIGHT algorithm may enhance treatment adherence, thereby improving clinical outcomes in patients with T2DM who require insulin therapy.
Patient satisfaction was significantly increased in the INSIGHT group but significantly decreased in the EDITION group. Previous studies with injectable therapies have shown that a simplified regimen improves patient satisfaction in patients with T2DM [43,44]. From psychosocial and behavioral perspectives, diabetes-related distress, including the burden of treatment and worries about adverse consequences, can influence treatment satisfaction and health outcomes in patients with DM [45]. In insulin-naïve patients with T2DM, those who were ambivalent or unwilling to start insulin had more negative perceptions and diabetes-related stress than willing patients [46]. In a cross-sectional study in Europe, treatment satisfaction in patients with T2DM on insulin therapy was also associated with diabetes education, perceived and actual hyperglycemia, and macrovascular complications [47]. In our study, the INSIGHT algorithm revealed similar glycemic control without hypoglycemia and weight gain compared with the EDITION algorithm. Simple titration adjusting basal insulin 1 unit/day might turn every fasting SMBG data point into actionable data for patients struggling with burdensome regimens [28]. In addition, although not evaluated in our study, HCPs also preferred the INSIGHT algorithm over the EDITION algorithm in the Canadian TITRATION study [20].
This study has several limitations. First, this study was an open-label trial. As the investigators and participants were aware of the treatment allocation, this might cause bias in the assessment or reporting of outcomes. However, because the investigators did not intervene other than instructing the titration algorithm, it would have been minimized in this pragmatic, randomized trial. Second, since the duration of the study was short, the long-term effects of the INSIGHT algorithm on diabetes-related outcomes could not be evaluated compared with the EDITION algorithm.
In conclusion, the self-titration of Gla-300 using the INSIGHT algorithm was effective and safe, with similar glycemic control, less weight gain, and greater patient satisfaction, in Korean individuals with uncontrolled T2DM compared with that using the EDITION algorithm. Further research is needed to ascertain whether overcoming barriers to insulin therapy using the INSIGHT algorithm results in sustained glycemic control and improvement in diabetes-related outcomes in patients with T2DM.
Supplementary materials related to this article can be found online at https://doi.org/10.4093/dmj.2020.0274.
Supplementary Table 1.
Insulin dose titration algorithms
dmj-2020-0274-suppl1.pdf
Supplementary Table 2.
Definition of hypoglycemic events
dmj-2020-0274-suppl2.pdf
Supplementary Table 3.
PRECIS-2 scores for nine domains
dmj-2020-0274-suppl3.pdf
Supplementary Table 4.
CONSORT 2010 checklist
dmj-2020-0274-suppl4.pdf

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Conception or design: J.H.B., Y.M.C.

Acquisition, analysis, or interpretation of data: J.H.B., C.H.A., Y.S.Y., S.J.M., S.H.K., H.S.J., K.S.P., Y.M.C.

Drafting the work or revising: J.H.B., Y.M.C.

Final approval of the manuscript: J.H.B., C.H.A., Y.S.Y., S.J.M., S.H.K., H.S.J., K.S.P., Y.M.C.

FUNDING

This study was supported by Sanofi-Aventis Korea.

Acknowledgements
We acknowledge Kyunghee Kim, Jeong Hwa Oh, and Kyungjoo Yun for conducting this clinical trial.
Fig. 1.
Study design. The participants were randomly assigned to either the Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment (INSIGHT) or EDITION group and self-titrated the dose of insulin glargine 300 units/mL according to each algorithm for 12 weeks. NIAHA, noninsulin antihyperglycemic agents; NPH, neutral protamine Hagedorn; SMBG, self-monitoring of blood glucose. aIn group 2, one individual was excluded owing to the withdrawal of informed consent.
dmj-2020-0274f1.jpg
Fig. 2.
The proportion of individuals with type 2 diabetes mellitus achieving a fasting self-monitoring of blood glucose value ≤5.6 mmol/L without hypoglycemia at week 12. Data are presented as proportion (%). The analysis was performed according to the intention-to-treat principle (n=129). P values <0.05 were regarded as statistically significant. INSIGHT, Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment.
dmj-2020-0274f2.jpg
Fig. 3.
Changes in (A) 7-point self-monitoring of blood glucose (SMBG) values and (B) the area under the curve (AUC) from week 0 to week 12. Data are presented as mean and standard error of the mean. The analysis was performed according to the intention-to-treat principle (n=129). P values <0.05 were regarded as statistically significant. INSIGHT, Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment. There was a significant decrease in SMBG levels from week 0 to week 12 in athe abovementioned groups and the bINSIGHT group.
dmj-2020-0274f3.jpg
Fig. 4.
Changes in (A) total daily insulin dose (TDD) and (B) body weight from week 0 to week 12. Data are presented as mean and standard error of the mean. The analysis was performed according to the intention-to-treat principle (n=129). P values <0.05 were regarded as statistically significant. INSIGHT, Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment.
dmj-2020-0274f4.jpg
dmj-2020-0274f5.jpg
Table 1.
Baseline characteristics of the study participants
Characteristic INSIGHT (n=65) EDITION (n=64) P value
Age, yr 63.7±8.8 64.5±10.2 0.658
 Range, yr 36–77 22–86
Men/Women 35/30 28/36 0.332
Body weight, kg 67.3±10.5 65.1±11.3 0.255
Body mass index, kg/m2 25.5±2.8 25.1±3.0 0.415
 Range, kg/m2 20.6–33.3 19.5–35.0
Fasting plasma glucose, mmol/L 7.8±2.1 8.0±2.3 0.704
HbA1c, % 8.4±0.7 8.4±0.8 0.758
Prior basal insulin treatment 59 (90.8) 58 (90.6) 0.999
 Total insulin dose, units/day 26.9±13.0 25.9±12.9 0.651
NIAHA
 Metformin 61 (93.8) 51 (81.2) 0.057
 Sulfonylurea 35 (55.4) 35 (54.7) 0.999
 Glinides 0 2 (3.1) 0.469
 Thiazolidinediones 0 1 (1.6) 0.934
 DPP-4 inhibitors 30 (46.2) 31 (48.4) 0.934
 GLP-1 receptor agonists 3 (4.6) 2 (3.1) 0.999
 SGLT2 inhibitors 5 (7.7) 6 (9.4) 0.979
 α-Glucosidase inhibitors 1 (1.5) 1 (1.6) 0.999
Hypertension 44 (66.7) 43 (67.2) 0.999
Hyperlipidemia 52 (80.0) 55 (85.9) 0.508

Values are presented as mean±standard deviation or number (%).

INSIGHT, Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment; HbA1c, glycosylated hemoglobin; NIAHA, noninsulin antihyperglycemic agent; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter 2.

  • 1. U.S. Food and Drug Administration: Prescribing information for TOUJEO 2019. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/206538s012lbl.pdf (cited 2021 May 25).
  • 2. Shiramoto M, Eto T, Irie S, Fukuzaki A, Teichert L, Tillner J, et al. Single-dose new insulin glargine 300U/ml provides prolonged, stable glycaemic control in Japanese and European people with type 1 diabetes. Diabetes Obes Metab 2015;17:254-60.ArticlePubMedPDF
  • 3. Becker RH, Dahmen R, Bergmann K, Lehmann A, Jax T, Heise T. New insulin glargine 300 units · mL-1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 units · mL-1. Diabetes Care 2015;38:637-43.ArticlePubMedPDF
  • 4. Riddle MC, Bolli GB, Ziemen M, Muehlen-Bartmer I, Bizet F, Home PD, et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1). Diabetes Care 2014;37:2755-62.ArticlePubMedPDF
  • 5. Yki-Jarvinen H, Bergenstal R, Ziemen M, Wardecki M, Muehlen-Bartmer I, Boelle E, et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care 2014;37:3235-43.ArticlePubMedPDF
  • 6. Bolli GB, Riddle MC, Bergenstal RM, Ziemen M, Sestakauskas K, Goyeau H, et al. New insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naïve people with type 2 diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab 2015;17:386-94.ArticlePubMedPMCPDF
  • 7. Terauchi Y, Koyama M, Cheng X, Takahashi Y, Riddle MC, Bolli GB, et al. New insulin glargine 300 U/ml versus glargine 100 U/ml in Japanese people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs: glucose control and hypoglycaemia in a randomized controlled trial (EDITION JP 2). Diabetes Obes Metab 2016;18:366-74.PubMedPMC
  • 8. Home PD, Bergenstal RM, Bolli GB, Ziemen M, Rojeski M, Espinasse M, et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 1 diabetes: a randomized, phase 3a, open-label clinical trial (EDITION 4). Diabetes Care 2015;38:2217-25.ArticlePubMedPDF
  • 9. Matsuhisa M, Koyama M, Cheng X, Takahashi Y, Riddle MC, Bolli GB, et al. New insulin glargine 300 U/ml versus glargine 100 U/ml in Japanese adults with type 1 diabetes using basal and mealtime insulin: glucose control and hypoglycaemia in a randomized controlled trial (EDITION JP 1). Diabetes Obes Metab 2016;18:375-83.PubMedPMC
  • 10. Ma RC, Chan JC. Type 2 diabetes in East Asians: similarities and differences with populations in Europe and the United States. Ann N Y Acad Sci 2013;1281:64-91.ArticlePubMedPMCPDF
  • 11. Yagihashi S, Inaba W, Mizukami H. Dynamic pathology of islet endocrine cells in type 2 diabetes: β-Cell growth, death, regeneration and their clinical implications. J Diabetes Investig 2016;7:155-65.ArticlePubMedPDF
  • 12. Chiu KC, Cohan P, Lee NP, Chuang LM. Insulin sensitivity differs among ethnic groups with a compensatory response in beta-cell function. Diabetes Care 2000;23:1353-8.ArticlePubMedPDF
  • 13. Chiu KC, Chuang LM, Yoon C. Comparison of measured and estimated indices of insulin sensitivity and beta cell function: impact of ethnicity on insulin sensitivity and beta cell function in glucose-tolerant and normotensive subjects. J Clin Endocrinol Metab 2001;86:1620-5.PubMed
  • 14. Cho YM. Incretin physiology and pathophysiology from an Asian perspective. J Diabetes Investig 2015;6:495-507.PubMed
  • 15. Gerstein HC, Yale JF, Harris SB, Issa M, Stewart JA, Dempsey E. A randomized trial of adding insulin glargine vs. avoidance of insulin in people with type 2 diabetes on either no oral glucose-lowering agents or submaximal doses of metformin and/or sulphonylureas: the Canadian INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) Study. Diabet Med 2006;23:736-42.ArticlePubMed
  • 16. Garber AJ, Handelsman Y, Grunberger G, Einhorn D, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm: 2020 executive summary. Endocr Pract 2020;26:107-39.ArticlePubMed
  • 17. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2020. Diabetes Care 2020;43(Suppl 1):S98-110.
  • 18. International Diabetes Federation Clinical Guidelines Task Force. Global guideline for type 2 diabetes. Brussels: IDF; 2012.
  • 19. Kim MK, Ko SH, Kim BY, Kang ES, Noh J, Kim SK, et al. 2019 Clinical practice guidelines for type 2 diabetes mellitus in Korea. Diabetes Metab J 2019;43:398-406.ArticlePubMedPMCPDF
  • 20. Yale JF, Berard L, Groleau M, Javadi P, Stewart J, Harris SB. TITRATION: a randomized study to assess 2 treatment algorithms with new insulin glargine 300 units/mL. Can J Diabetes 2017;41:478-84.ArticlePubMed
  • 21. Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009;94:709-28.ArticlePubMed
  • 22. Bradley C. Handbook of psychology and diabetes. Chur: Harwood; 1994. Chapter 7, Diabetes treatment satisfaction questionnaire. p. 111-32.
  • 23. Bradley C. Diabetes treatment satisfaction questionnaire: change version for use alongside status version provides appropriate solution where ceiling effects occur. Diabetes Care 1999;22:530-2.ArticlePubMedPDF
  • 24. Loudon K, Treweek S, Sullivan F, Donnan P, Thorpe KE, Zwarenstein M. The PRECIS-2 tool: designing trials that are fit for purpose. BMJ 2015;350:h2147.ArticlePubMed
  • 25. Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c332.ArticlePubMedPMC
  • 26. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet 2014;383:1068-83.ArticlePubMed
  • 27. Fonseca VA, Haggar MA. Achieving glycaemic targets with basal insulin in T2DM by individualizing treatment. Nat Rev Endocrinol 2014;10:276-81.ArticlePubMedPDF
  • 28. Russell-Jones D, Pouwer F, Khunti K. Identification of barriers to insulin therapy and approaches to overcoming them. Diabetes Obes Metab 2018;20:488-96.ArticlePubMedPDF
  • 29. Russell-Jones D, Dauchy A, Delgado E, Dimitriadis G, Frandsen HA, Popescu L, et al. Take control: a randomized trial evaluating the efficacy and safety of self-versus physician-managed titration of insulin glargine 300U/mL in patients with uncontrolled type 2 diabetes. Diabetes Obes Metab 2019;21:1615-24.ArticlePubMedPMCPDF
  • 30. Davies M, Storms F, Shutler S, Bianchi-Biscay M, Gomis R; ATLANTUS Study Group. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care 2005;28:1282-8.PubMed
  • 31. Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26:3080-6.PubMed
  • 32. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 2008;51:408-16.ArticlePubMedPMCPDF
  • 33. Khunti K, Damci T, Meneghini L, Pan CY, Yale JF; SOLVE Study Group. Study of Once Daily Levemir (SOLVE): insights into the timing of insulin initiation in people with poorly controlled type 2 diabetes in routine clinical practice. Diabetes Obes Metab 2012;14:654-61.ArticlePubMed
  • 34. Khunti K, Caputo S, Damci T, Dzida GJ, Ji Q, Kaiser M, et al. The safety and efficacy of adding once-daily insulin detemir to oral hypoglycaemic agents in patients with type 2 diabetes in a clinical practice setting in 10 countries. Diabetes Obes Metab 2012;14:1129-36.ArticlePubMed
  • 35. Meneghini LF, Mauricio D, Orsi E, Lalic NM, Cali AMG, Westerbacka J, et al. The Diabetes Unmet Need with Basal Insulin Evaluation (DUNE) study in type 2 diabetes: achieving HbA1c targets with basal insulin in a real-world setting. Diabetes Obes Metab 2019;21:1429-36.ArticlePubMedPMCPDF
  • 36. Peyrot M, Rubin RR, Lauritzen T, Skovlund SE, Snoek FJ, Matthews DR, et al. Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care 2005;28:2673-9.ArticlePubMedPDF
  • 37. Peyrot M, Barnett AH, Meneghini LF, Schumm-Draeger PM. Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study. Diabet Med 2012;29:682-9.ArticlePubMedPMCPDF
  • 38. Khunti K, Millar-Jones D. Clinical inertia to insulin initiation and intensification in the UK: a focused literature review. Prim Care Diabetes 2017;11:3-12.ArticlePubMed
  • 39. Brown RJ, Wijewickrama RC, Harlan DM, Rother KI. Uncoupling intensive insulin therapy from weight gain and hypoglycemia in type 1 diabetes. Diabetes Technol Ther 2011;13:457-60.ArticlePubMedPMC
  • 40. Davies MJ, Gagliardino JJ, Gray LJ, Khunti K, Mohan V, Hughes R. Real-world factors affecting adherence to insulin therapy in patients with type 1 or type 2 diabetes mellitus: a systematic review. Diabet Med 2013;30:512-24.ArticlePubMed
  • 41. Ho PM, Rumsfeld JS, Masoudi FA, McClure DL, Plomondon ME, Steiner JF, et al. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med 2006;166:1836-41.ArticlePubMed
  • 42. Currie CJ, Peyrot M, Morgan CL, Poole CD, Jenkins-Jones S, Rubin RR, et al. The impact of treatment noncompliance on mortality in people with type 2 diabetes. Diabetes Care 2012;35:1279-84.ArticlePubMedPMCPDF
  • 43. Patel S, Abreu M, Tumyan A, Adams-Huet B, Li X, Lingvay I. Effect of medication adherence on clinical outcomes in type 2 diabetes: analysis of the SIMPLE study. BMJ Open Diabetes Res Care 2019;7:e000761.ArticlePubMedPMC
  • 44. Miya A, Nakamura A, Miyoshi H, Cho KY, Nagai S, Kurihara Y, et al. Satisfaction of switching to combination therapy with lixisenatide and basal insulin in patients with type 2 diabetes receiving multiple daily insulin injection therapy: a randomized controlled trial. J Diabetes Investig 2018;9:119-26.ArticlePubMedPDF
  • 45. Young-Hyman D, de Groot M, Hill-Briggs F, Gonzalez JS, Hood K, Peyrot M. Psychosocial care for people with diabetes: a position statement of the American Diabetes Association. Diabetes Care 2016;39:2126-40.ArticlePubMedPMCPDF
  • 46. Polonsky WH, Hajos TR, Dain MP, Snoek FJ. Are patients with type 2 diabetes reluctant to start insulin therapy?: an examination of the scope and underpinnings of psychological insulin resistance in a large, international population. Curr Med Res Opin 2011;27:1169-74.ArticlePubMed
  • 47. Boels AM, Vos RC, Hermans TG, Zuithoff NP, Muller N, Khunti K, et al. What determines treatment satisfaction of patients with type 2 diabetes on insulin therapy?: an observational study in eight European countries. BMJ Open 2017;7:e016180.ArticlePubMedPMC

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      Efficacy and Safety of Self-Titration Algorithms of Insulin Glargine 300 units/mL in Individuals with Uncontrolled Type 2 Diabetes Mellitus (The Korean TITRATION Study): A Randomized Controlled Trial
      Diabetes Metab J. 2022;46(1):71-80.   Published online June 16, 2021
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    Efficacy and Safety of Self-Titration Algorithms of Insulin Glargine 300 units/mL in Individuals with Uncontrolled Type 2 Diabetes Mellitus (The Korean TITRATION Study): A Randomized Controlled Trial
    Image Image Image Image Image
    Fig. 1. Study design. The participants were randomly assigned to either the Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment (INSIGHT) or EDITION group and self-titrated the dose of insulin glargine 300 units/mL according to each algorithm for 12 weeks. NIAHA, noninsulin antihyperglycemic agents; NPH, neutral protamine Hagedorn; SMBG, self-monitoring of blood glucose. aIn group 2, one individual was excluded owing to the withdrawal of informed consent.
    Fig. 2. The proportion of individuals with type 2 diabetes mellitus achieving a fasting self-monitoring of blood glucose value ≤5.6 mmol/L without hypoglycemia at week 12. Data are presented as proportion (%). The analysis was performed according to the intention-to-treat principle (n=129). P values <0.05 were regarded as statistically significant. INSIGHT, Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment.
    Fig. 3. Changes in (A) 7-point self-monitoring of blood glucose (SMBG) values and (B) the area under the curve (AUC) from week 0 to week 12. Data are presented as mean and standard error of the mean. The analysis was performed according to the intention-to-treat principle (n=129). P values <0.05 were regarded as statistically significant. INSIGHT, Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment. There was a significant decrease in SMBG levels from week 0 to week 12 in athe abovementioned groups and the bINSIGHT group.
    Fig. 4. Changes in (A) total daily insulin dose (TDD) and (B) body weight from week 0 to week 12. Data are presented as mean and standard error of the mean. The analysis was performed according to the intention-to-treat principle (n=129). P values <0.05 were regarded as statistically significant. INSIGHT, Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment.
    Graphical abstract
    Efficacy and Safety of Self-Titration Algorithms of Insulin Glargine 300 units/mL in Individuals with Uncontrolled Type 2 Diabetes Mellitus (The Korean TITRATION Study): A Randomized Controlled Trial
    Characteristic INSIGHT (n=65) EDITION (n=64) P value
    Age, yr 63.7±8.8 64.5±10.2 0.658
     Range, yr 36–77 22–86
    Men/Women 35/30 28/36 0.332
    Body weight, kg 67.3±10.5 65.1±11.3 0.255
    Body mass index, kg/m2 25.5±2.8 25.1±3.0 0.415
     Range, kg/m2 20.6–33.3 19.5–35.0
    Fasting plasma glucose, mmol/L 7.8±2.1 8.0±2.3 0.704
    HbA1c, % 8.4±0.7 8.4±0.8 0.758
    Prior basal insulin treatment 59 (90.8) 58 (90.6) 0.999
     Total insulin dose, units/day 26.9±13.0 25.9±12.9 0.651
    NIAHA
     Metformin 61 (93.8) 51 (81.2) 0.057
     Sulfonylurea 35 (55.4) 35 (54.7) 0.999
     Glinides 0 2 (3.1) 0.469
     Thiazolidinediones 0 1 (1.6) 0.934
     DPP-4 inhibitors 30 (46.2) 31 (48.4) 0.934
     GLP-1 receptor agonists 3 (4.6) 2 (3.1) 0.999
     SGLT2 inhibitors 5 (7.7) 6 (9.4) 0.979
     α-Glucosidase inhibitors 1 (1.5) 1 (1.6) 0.999
    Hypertension 44 (66.7) 43 (67.2) 0.999
    Hyperlipidemia 52 (80.0) 55 (85.9) 0.508
    Table 1. Baseline characteristics of the study participants

    Values are presented as mean±standard deviation or number (%).

    INSIGHT, Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment; HbA1c, glycosylated hemoglobin; NIAHA, noninsulin antihyperglycemic agent; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter 2.

    Bae JH, Ahn CH, Yang YS, Moon SJ, Kwak SH, Jung HS, Park KS, Cho YM. Efficacy and Safety of Self-Titration Algorithms of Insulin Glargine 300 units/mL in Individuals with Uncontrolled Type 2 Diabetes Mellitus (The Korean TITRATION Study): A Randomized Controlled Trial. Diabetes Metab J. 2022;46(1):71-80.
    Received: Nov 24, 2020; Accepted: Feb 04, 2021
    DOI: https://doi.org/10.4093/dmj.2020.0274.

    Diabetes Metab J : Diabetes & Metabolism Journal
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