Diabetes Ther (2018) 9:1469–1476 https://doi.org/10.1007/s13300-018-0450-0 ORIGINAL RESEARCH Similar Intrapatient Blood Glucose Variability with LY2963016 and Lantus Insulin Glargine in Patients with Type 1 (T1D) or Type 2 Diabetes, Including a Japanese T1D Subpopulation . . . Hiroshi Nishiyama Tomotaka Shingaki Yumi Suzuki Liza L. Ilag Received: March 20, 2018 / Published online: May 31, 2018 The Author(s) 2018 Results: Overall, evaluations of all three indices ABSTRACT showed that intrapatient blood glucose vari- ability was similar between LY IGlar and IGlar Introduction: LY2963016 insulin glargine (LY throughout the study periods both in the IGlar) and Lantus (IGlar), both with identical overall populations of patients with T1D and primary amino acid sequences, were compared T2D and also in the subgroup of Japanese in two phase 3 studies for intrapatient blood patients with T1D. glucose variability. Conclusion: Intrapatient blood glucose vari- Methods: ELEMENT-1 was a 52-week study in ability between LY IGlar and IGlar was shown to patients with type 1 diabetes (T1D), which be similar in patients with T1D or T2D. included Japanese patients, and ELEMENT-2 Clinical Trial Registration: NCT01421147 was a 24-week study in non-Japanese patients (ELEMENT-1) and NCT01421459 (ELEMENT-2). with type 2 diabetes (T2D). In ELEMENT-1, 535 Funding: Eli Lilly and Company (Indianapolis, patients with T1D were evaluable (268 LY IGlar IN, USA); Boehringer-Ingelheim (Ridgeﬁeld, CT, and 267 IGlar). Of these, 100 were Japanese USA); Eli Lilly Japan K.K. (Kobe, Japan) and Nippon patients (49 LY IGlar and 51 IGlar). In ELE- Boehringer Ingelheim Co., Ltd. (Tokyo, Japan). MENT-2, 756 patients with T2D were evaluable (376 LY IGlar and 380 IGlar). We evaluated and Keywords: Blood glucose variability; Insulin compared intrapatient blood glucose variability glargine; Japanese subgroup; LY2963016; Type of LY IGlar and IGlar in these studies from three 1 diabetes; Type 2 diabetes different perspectives: intrapatient between-day fasting blood glucose variability, intrapatient Abbreviations between-day daily mean blood glucose vari- ANCOVA Analysis of covariance ability, and intrapatient within-day blood glu- FBG Fasting blood glucose cose variability. IGlar Lantus insulin glargine Enhanced digital features To view enhanced digital LOCF Last observation carried forward features for this article go to https://doi.org/10.6084/ LS Least-squares m9.ﬁgshare.6280895. LY IGlar LY2963016 insulin glargine PD Pharmacodynamics H. Nishiyama (&) T. Shingaki Y. Suzuki PK Pharmacokinetics Eli Lilly Japan, K.K., Kobe 651-0086, Japan e-mail: email@example.com SD Standard deviation SMBG Self-monitored blood glucose L. L. Ilag T1D Type 1 diabetes Eli Lilly and Company, Indianapolis 46285, USA 1470 Diabetes Ther (2018) 9:1469–1476 variability, the intrapatient perspective needs to T2D Type 2 diabetes be further assessed. Additionally, differences between Asians and Caucasians in, for example, genetic susceptibility to diabetes and underly- INTRODUCTION ing pathophysiology, body mass index, diet, insulin dose requirements, and postprandial LY2963016 insulin glargine (LY IGlar) is the ﬁrst hyperglycemia, have been suggested/reported biosimilar insulin to receive marketing autho- [14, 15]. Given these differences, blood glucose rization in the European Union  and Japan variability data in such a subpopulation is of  and was authorized as the ﬁrst follow-on clinical interest not only in Japan but also in insulin in the USA . LY IGlar has an identical other East Asian countries. The ELEMENT-1 primary amino acid sequence and the same study included a Japanese subpopulation as an pharmaceutical form and strength as Lantus East Asian subpopulation and thus allowed for a insulin glargine (IGlar; recombinant DNA ori- separate analysis. Accordingly, the aim of this gin; Sanoﬁ-Aventis, Paris, France) . LY IGlar study was to evaluate and compare the intrap- and IGlar have been shown to have similar atient variability of daily blood glucose values pharmacokinetic (PK) and pharmacodynamic in patients treated with LY IGlar and IGlar in (PD) properties [5, 6]. Randomized phase 3 the overall population of patients with T1D and clinical trials in patients with type 1 diabetes in the subgroup of Japanese patients in ELE- (T1D; ELEMENT-1) or type 2 diabetes (T2D; MENT-1, and in the overall population of ELEMENT-2) further demonstrated that LY IGlar patients with T2D in ELEMENT-2. and IGlar have similar efﬁcacy, safety, and immunogenicity proﬁles [7–9]. In both ELE- MENT-1 and ELEMENT-2, the change in gly- METHODS cated hemoglobin (HbA1c) from baseline to the 24-week endpoint was used to demonstrate the Study Design equivalence of efﬁcacy between LY IGlar and IGlar [7, 8]. In this report, data from ELEMENT-1 and ELE- To show similarity of the two products, it is MENT-2 were analyzed. Detailed study methods important to make comparisons from both and results for the primary endpoints for both inter- and intrasubject perspectives . For LY studies have been reported [7, 8] as well as those IGlar and IGlar, similarity in both inter- and for the subgroup analysis of Japanese patients in intrasubject PK/PD parameters has been shown ELEMENT-1 . ELEMENT-1 was a 52-week in three biopharmaceutical studies conducted open-label study of patients with T1D being in healthy subjects . Reports from ELEMENT- treated with basal and bolus insulin; it included 1 and ELEMENT-2 showed similarity of gly- a 24-week treatment period and a 28-week cemic control between LY IGlar and IGlar based extension period . ELEMENT-2 was a 24-week on HbA1c [7, 8], which is a good indicator of double-blind study of patients with T2D who interpatient (i.e., population average) glycemic were insulin-naive or previously treated with control but is not an appropriate indicator of IGlar . In both studies, patients were ran- intrapatient glycemic control [11–13]. Patients domized to LY IGlar or IGlar treatment. The with the same HbA1c value may have small or initial dose was equivalent to their prestudy large ﬂuctuations in blood glucose proﬁles over insulin dose, except that patients with T2D who time, as HbA1c does not reﬂect daily or were insulin-naive started with 10 units of LY between-day variations in blood glucose levels. IGlar or IGlar. The LY IGlar or IGlar dose was Therefore, previously reported comparisons of titrated on the basis of daily blood glucose levels LY IGlar and IGlar based on HbA1c have shown [7, 8]. Both of these studies were conducted in that they are similar in glycemic control from accordance with the International Conference an interpatient perspective, but considering the on Harmonization Guidelines for Good Clinical limitations of HbA1c in reﬂecting blood glucose Practice and the Declaration of Helsinki , Diabetes Ther (2018) 9:1469–1476 1471 and all patients provided written informed as covariate. The analyses described in this consent [7, 8]. This article is based on previously manuscript were prespeciﬁed in the study pro- conducted studies and does not contain any tocol and/or statistical analysis plan. studies with human participants or animals performed by any of the authors. RESULTS Outcomes In ELEMENT-1, 535 patients with T1D were included in the analysis (268 LY IGlar and 267 Intrapatient blood glucose variability with LY IGlar). Of these, 100 were Japanese patients (49 IGlar and IGlar was assessed and compared LY IGlar and 51 IGlar). In ELEMENT-2, 756 using three measures of variability derived from patients with T2D were included in the analysis 7-point self-monitored blood glucose (SMBG) (376 LY IGlar and 380 IGlar). No Japanese proﬁles (premeal for each meal, postmeal for patients were included in ELEMENT-2. breakfast and lunch, bedtime, and 03:00 h), Least-squares (LS) means of intrapatient which were collected three times in the 2-week between-day FBG variability in both treatment period before each clinic visit. Patients visited groups ranged from 36.3 to 46.7 mg/dL in the the clinic at weeks 0 (baseline), 2, 6, 12, 18, 24, overall population of patients with T1D, and 30, 36, 44, and 52 in ELEMENT-1 and at weeks 0 from 33.2 to 56.3 mg/dL in the subgroup of (baseline), 2, 12, and 24 in ELEMENT-2. Japanese patients. There were no statistically The three measures of variability analyzed signiﬁcant differences at any visit or at endpoint were intrapatient between-day FBG variability, (LOCF) in patients with T1D, except for two intrapatient between-day daily mean blood visits (weeks 6 and 52) in the overall popula- glucose variability, and intrapatient within-day tion, where the values were signiﬁcantly lower blood glucose variability. Intrapatient between- in the LY IGlar group compared with the IGlar day FBG variability for each visit was calculated group (Fig. 1a, b). In the population with T2D, as the standard deviation (SD) of the three LS means of intrapatient between-day FBG morning premeal blood glucose values. Intrap- variability in both treatment groups ranged atient between-day daily mean blood glucose from 13.7 to 18.4 mg/dL, and no statistically variability for each visit was calculated as the SD signiﬁcant differences were observed at any visit of the three daily means of the 7-point SMBG or at endpoint (LOCF) (Fig. 1c). proﬁles. Intrapatient within-day blood glucose LS means of intrapatient between-day daily variability for each visit was calculated as the mean blood glucose variability in both treat- mean of the three SDs of the 7-point SMBG ment groups ranged from 15.6 to 21.5 mg/dL in proﬁles. the overall population with T1D and from 22.1 to 30.8 mg/dL in the subgroup of Japanese Statistical Analysis patients. There were no statistically signiﬁcant differences between treatment groups at any visit or at endpoint (LOCF) in patients with T1D The analysis population was comprised of all randomized patients who took at least one dose (Fig. 2a, b). In the population with T2D, LS means of intrapatient between-day daily mean of study drug. If the measurement for a visit was missing, the previous non-missing measure- blood glucose variability in both treatment ment was analyzed using last observation car- groups ranged from 9.8 to 14.0 mg/dL, and no ried forward (LOCF) methodology. HbA1c is statistically signiﬁcant differences were shown in the NGSP value as recommended by observed at any visit or at endpoint (LOCF) the Japan Diabetes Society . Each measure- (Fig. 2c). ment was analyzed using an analysis of covari- LS means of intrapatient within-day blood ance model with country, time of basal insulin glucose variability in both treatment groups injection (daytime, evening/bedtime), and ranged from 44.1 to 56.7 mg/dL in the overall population with T1D and from 49.1 to 64.8 mg/ treatment as ﬁxed effects, and baseline HbA1c 1472 Diabetes Ther (2018) 9:1469–1476 Fig. 1 Intrapatient between-day FBG variability. a All signiﬁcance was observed at these visits or endpoints. patients with T1D. b Japanese patients with T1D. ANCOVA analysis of covariance, BL baseline, FBG fasting c Patients with T2D. Intrapatient between-day FBG blood glucose, IGlar Lantus insulin glargine, LOCF last variability calculated using standard deviation of FBG from observation carried forward, LS least-squares, LY IGlar SMBG (standard deviation of 3 values per visit) (bar LY2963016 insulin glargine, N number of patients with graph; left axis). To display dispersion, mean FBG is also data, SMBG self-monitored blood glucose, T1D type 1 shown (line graph; right axis). Treatment comparisons at diabetes, T2D type 2 diabetes each visit were analyzed using ANCOVA: *p \ 0.05 LY IGlar vs IGlar. For a and b, data from weeks 2, 18, 30, 44, and week 24 (LOCF) are not shown. No statistical dL in the subgroup of Japanese patients. There Intrapatient between-day FBG variability were no statistically signiﬁcant differences showed day-to-day variability of FBG, which between treatment groups at any visit or at was used as part of dose adjustment algorithms endpoint (LOCF) in patients with T1D (Fig. 3a, in both ELEMENT-1 and ELEMENT-2, as it is b). In the population with T2D, LS means of used in actual clinical settings. Intrapatient intrapatient within-day blood glucose variabil- between-day daily mean blood glucose vari- ity in both treatment groups ranged from 32.1 ability and intrapatient within-day blood glu- to 40.0 mg/dL, and no statistically signiﬁcant cose variability were calculated using all differences were observed at any visit or at measurements from 7-point SMBG proﬁles to endpoint (LOCF) (Fig. 3c). show day-to-day and within-day variability in blood glucose, respectively. All three measures of intrapatient blood glucose variability after DISCUSSION treatment with LY IGlar were similar to those with IGlar in the overall populations of patients This is the ﬁrst report of comparisons of intra- with T1D and T2D and in the subgroup of patient blood glucose variability between LY Japanese patients with T1D. IGlar and IGlar using data from the ELEMENT-1 In the LY IGlar development program, phase and ELEMENT-2 studies. In this analysis, intra- 1 studies with healthy volunteers showed simi- patient blood glucose variability was assessed larities of both inter- and intrasubject PK and and compared using three measures: intrapa- PD between LY IGlar and IGlar in an experi- tient between-day FBG variability, intrapatient mental setting using euglycemic clamps . between-day daily mean blood glucose vari- Similarity of average interpatient glycemic ability, and intrapatient within-day blood glu- control (i.e., HbA1c) with LY IGlar and IGlar has cose variability. also been reported in ELEMENT-1 and Diabetes Ther (2018) 9:1469–1476 1473 Fig. 2 Intrapatient between-day daily mean BG variability. not shown. No statistical signiﬁcance was observed at these a All patients with T1D. b Japanese patients with T1D. visits or endpoints. ANCOVA analysis of covariance, BG c Patients with T2D. Intrapatient between-day daily mean blood glucose, BL baseline, IGlar Lantus insulin glargine, BG variability calculated using standard deviation of daily LOCF last observation carried forward, LS least-squares, mean BG from 7-point SMBG proﬁles (standard deviation LY IGlar LY2963016 insulin glargine, N number of of 3 values per visit) (bar graph; left axis). To display patients with data, SMBG self-monitored blood glucose, dispersion, daily mean BG is also shown (line graph; right T1D type 1 diabetes, T2D type 2 diabetes axis). Treatment comparisons at each visit were analyzed using ANCOVA; not signiﬁcant at all visits. For a and b, data from weeks 2, 18, 30, 44, and week 24 (LOCF) are Fig. 3 Intrapatient within-day BG variability. a All 18, 30, 44, and week 24 (LOCF) are not shown. No patients with T1D. b Japanese patients with T1D. statistical signiﬁcance was observed at these visits or c Patients with T2D. Intrapatient within-day daily mean endpoints. ANCOVA analysis of covariance, BG blood BG variability calculated using mean of daily BG standard glucose, BL baseline, LOCF last observation carried deviations from 7-point SMBG proﬁles (mean of 3 values forward, LS least-squares, N number of patients with per visit) (bar graph; left axis). To display dispersion, daily data, SMBG self-monitored blood glucose, T1D type 1 mean BG is also shown (line graph; right axis). Treatment diabetes, T2D type 2 diabetes comparisons at each visit were analyzed using ANCOVA; not signiﬁcant at all visits. For a and b, data from weeks 2, 1474 Diabetes Ther (2018) 9:1469–1476 ELEMENT-2 [7, 8]; however, average interpa- intrapatient blood glucose variability provides tient HbA1c values cannot be used to appro- additional support for the similarity of LY IGlar priately estimate intrapatient glycemic control and IGlar. [11–13]. Assessment of intrapatient blood glu- cose variability of LY IGlar and IGlar using data from ELEMENT-1 and ELEMENT-2 (conducted ACKNOWLEDGEMENTS in settings more similar to that of regular clin- ical practice than the biopharmaceutical studies mentioned above) indicated that intrapatient Funding. The studies were funded by Eli glycemic control was also similar between LY Lilly and Company (Indianapolis, IN, USA) and IGlar and IGlar. In combination with the simi- Boehringer-Ingelheim (Ridgeﬁeld, CT, USA). Eli larity in interpatient average glycemic control Lilly Japan K.K. (Kobe, Japan) and Nippon reported previously, comprehensive similarity Boehringer Ingelheim Co., Ltd. (Tokyo, Japan) in glycemic control has been demonstrated for funded the article processing charges. LY IGlar and IGlar in patients with T1D or T2D. Since blood glucose variability captures Medical Writing Assistance. The authors ﬂuctuations in daily glucose proﬁles, it is also acknowledge the assistance of Michelle Carey, considered a predictor of hypoglycemia . of Syneos Health, with the preparation of this Even though HbA1c has been used as the pri- article. This assistance was funded by Eli Lilly mary measure of glycemic control, it only and Company (Indianapolis, IN, USA). reﬂects long-term (over 1–2 months) average blood glucose levels. HbA1c cannot capture Authorship. All named authors meet the shorter-term ﬂuctuations and is only weakly International Committee of Medical Journal associated with the risk of severe hypoglycemia Editors (ICMJE) criteria for authorship for this . The results from this analysis further sup- article, had full access to all of the data in this study, take complete responsibility for the port the similarity of glycemic control achieved with LY IGlar and IGlar in both the short (as integrity of the data and accuracy of the data measured by blood glucose variability) and the analysis, and have given their approval for this long term (as measured by HbA1c). version to be published. One limitation of this analysis is that the Prior Presentation. This work was previ- blood glucose variability measures were derived ously published as an abstract presented at the from 7-point SMBG proﬁles, which only provide 60th Annual Meeting of the Japan Diabetes snapshots of glucose concentrations, unlike Society, Nagoya, Japan, May 2017 (III-P-168). continuous glucose monitoring, which captures blood glucose levels over time . Even Disclosures. Hiroshi Nishiyama is an though the studies were designed to collect data employee of Eli Lilly Japan K.K. and has com- at the times when maximum and minimum pany stock options. Tomotaka Shingaki is an blood glucose were likely to be observed, actual employee of Eli Lilly Japan K.K. Yumi Suzuki is maximum and minimum values may not have an employee of Eli Lilly Japan K.K. Liza L. Ilag is been captured. an employee of Eli Lilly and Company and has company stock options. CONCLUSIONS Compliance with Ethics Guidelines. This article is based on previously conducted studies Intrapatient blood glucose variability was simi- and does not contain any studies with human lar between LY IGlar and IGlar in patients with participants or animals performed by any of the T1D or T2D. In addition, the intrapatient blood authors. glucose variability measures were also similar between LY IGlar and IGlar in a subgroup of Japanese patients with T1D. This analysis of Diabetes Ther (2018) 9:1469–1476 1475 and Lantus, in subjects with type I diabetes mellitus Data Availability. The data sets analyzed (T1DM). Diabetes. 2014;63(Suppl. 1):A228. during the current study are not publicly avail- able. Lilly provides access to the individual 6. Linnebjerg H, Lam EC, Seger ME, et al. Comparison patient data from studies on approved medici- of the pharmacokinetics and pharmacodynamics of LY2963016 insulin glargine and EU- and US-ap- nes and indications as deﬁned by the sponsor- proved versions of Lantus insulin glargine in heal- speciﬁc information on http:// thy subjects: three randomized euglycemic clamp clinicalstudydatarequest.com. Researchers need studies. Diabetes Care. 2015;38(12):2226–33. to have an approved research proposal submit- 7. Blevins TC, Dahl D, Rosenstock J, et al. Efﬁcacy and ted through http://clinicalstudydatarequest. safety of LY2963016 insulin glargine compared com. Access to the data will be provided in a with insulin glargine (Lantus ) in patients with secure data sharing environment after signing a type 1 diabetes in a randomized controlled trial: the data sharing agreement. ELEMENT 1 study. Diabetes Obes Metab. 2015;17(8):726–33. Open Access. This article is distributed 8. Rosenstock J, Hollander P, Bhargava A, et al. Similar under the terms of the Creative Commons efﬁcacy and safety of LY2963016 insulin glargine Attribution-NonCommercial 4.0 International and insulin glargine (Lantus ) in patients with type License (http://creativecommons.org/licenses/ ¨ 2 diabetes who were insulin-naıve or previously treated with insulin glargine: a randomized, dou- by-nc/4.0/), which permits any non- ble-blind controlled trial (the ELEMENT 2 study). commercial use, distribution, and reproduction Diabetes Obes Metab. 2015;17(8):734–41. in any medium, provided you give appropriate credit to the original author(s) and the source, 9. 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Diabetes Therapy – Springer Journals
Published: May 31, 2018
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