Similar HbA1c reduction and hypoglycaemia with variable- vs fixed-time dosing of basal insulin peglispro in type 1 diabetes: IMAGINE 7 study

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1 Received: 1 July 2016 Accepted: 3 July 2016 DOI /dom ORIGINAL ARTICLE Similar HbA1c reduction and hypoglycaemia with variable- vs fixed-time dosing of basal insulin peglispro in type 1 diabetes: IMAGINE 7 study S. Garg 1 J.-L. Selam 2 A. Bhargava 3 N. Schloot 4 J. Luo 5 Q. Zhang 5 J. G. Jacobson 5 B. J. Hoogwerf 5 1 Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora 2 Diabetes Research Center, Tustin, California 3 Iowa Diabetes and Endocrinology Research Center, Des Moines, Iowa 4 Lilly Deutschland GmbH, Bad Homburg, Germany 5 Eli Lilly and Company, Indianapolis, Indiana Corresponding Author: Byron J. Hoogwerf, MD, Lilly Corporate Center, Indianapolis, IN (hoogwerf_byron_james@lilly.com). Aims: To compare 24-hour fixed-time basal insulin peglispro (BIL) dosing with 8- to 40-hour variable-time BIL dosing for glycaemic control and safety in patients with type 1 diabetes. Primary outcome was non-inferiority of BIL variable-time dosing compared with fixed-time dosing for glycated haemoglobin (HbA1c) change after 12-week treatment (margin = 0.4%). Materials and methods: This Phase 3, open-label, randomized, cross-over study (N = 212) was conducted at 20 centres in the United States. During the 12-week lead-in phase, patients received BIL daily at fixed-times. Two 12-week randomized cross-over treatment phases followed, where patients received BIL dosed at either fixed- or variable-times. During the 4-week safety follow-up, patients received conventional insulins. Results: During the lead-in period, least-squares mean HbA1c decreased from 7.5% to 6.8%. For BIL, variable-time dosing was non-inferior to fixed-time dosing for HbA1c change [leastsquares mean difference = 0.06%, 95% confidence interval ( 0.01, 0.13)]. In both regimens, HbA1c increased slightly during the cross-over periods, but remained significantly below baseline. Variable- and fixed-time dosing regimens had similar rates of total hypoglycaemia ( and events/patient/30 days, P =.947) and nocturnal hypoglycaemia ( and events/patient/30days, P =.060). Comparable proportions of patients achieved HbA1c < 7.0% with variable- [91 (54.5%)] and fixed-time dosing [101 (60.5%)]. Conclusions: Treatment with BIL allows patients to use flexible dosing intervals from 8 to 40 hours. Glycaemic efficacy (HbA1c), glycaemic variability and hypoglycaemia are similar to fixed-time dosing, suggesting that BIL could potentially provide flexibility in dosing for patients who miss their daily basal insulin. KEYWORDS basal insulin peglispro, continuous glucose monitoring, variable-time dosing 1 INTRODUCTION For people with diabetes, balancing work and family responsibilities can result in variable daily schedules, which in turn are often Portions of this work were previously presented at the Annual Scientific Session of the American Diabetes Association, Boston, Massachusetts, USA, June 2015 and the European Association for the Study of Diabetes, Stockholm, Sweden, September associated with variability in insulin dosing times. Daily basal insulin dosing times, which usually occur in the evening, may vary on weekends, holidays or when other life events intervene. Further disruption to insulin dosing can occur when an evening dose is forgotten altogether. When an insulin dose is missed, questions may arise about what to do the following morning. Furthermore, glycaemic variability may limit the ability to maximally titrate basal insulin and may be associated with increased risk for complications of type 1 diabetes (T1D) 1 3 and hypoglycaemic unawareness. 4,5 This study Diabetes Obes Metab 2016; 18 (Suppl. 2): wileyonlinelibrary.com/journal/dom 2016 John Wiley & Sons Ltd 43

2 44 GARG ET AL. was designed to address the impact of variable-time dosing (at prescribed intervals) vs evening fixed-time dosing with basal insulin peglispro (BIL) on measures of glycaemic control including glycated haemoglobin (HbA1c), hypoglycaemia and glycaemic variability. BIL is a novel insulin with a half-life greater than 24 hours as determined by pharmacokinetic/pharmacodynamics (PK/PD) studies. 6,7 Moreover, Phase 2 and 3 clinical trials have demonstrated that there is less glycaemic variability during treatment with BIL, compared to treatment with glargine or isophane insulin (NPH) To provide clinical support for the stability and efficacy of BIL, we compared fixed-time evening basal insulin dosing with variabletime basal insulin dosing (intervals of 8 2to40 2 hours) on glycaemic control and variability as assessed by HbA1c, fasting blood glucose (FBG), 9-point self-monitored blood glucose (SMBG) profiles and within- and between-day glycaemic variability in patients with T1D. The study design does not represent a dosing regimen that would likely occur in clinical practice; the design models what might happen if a patient missed an evening dose of basal insulin and followed it with the same dose the next morning. 2 MATERIALS AND METHODS This Phase 3, multicentre, outpatient, open-label, randomized, crossover study was conducted from early 2013 to April 2014 at 20 sites within the United States, including Puerto Rico. The study was approved by local Ethical Review Boards and conducted in accordance with Good Clinical Practice guidelines of the International Conference on Harmonisation. All patients provided written informed consent. Trial registration: NCT Adults with T1D (World Health Organization criteria 16 ) were eligible if their duration of diabetes was 1 year, they had HbA1c <9.0% and body mass index 35.0 kg/m 2, and had been treated with conventional insulins for at least 90 days prior to enrollment. Patients were excluded if they had triglycerides >4.5 mmol/l, had more than 1 episode of severe hypoglycaemia or two or more emergency room visits or hospitalizations due to poor glucose control within 6 months before study entry, or had cardiac disease, serum creatinine >221 μmol/l or obvious signs of liver disease or hepatitis. The study began with a 12-week lead-in period, during which all patients (N = 212) received BIL doses at a fixed interval, once daily in the evening. This was done so patients could achieve stable HbA1c levels. Patients were then randomized 1:1 using an interactive voice or web response system to one dosing regimen for 12 weeks and then crossed over to the alternate dosing regimen for another 12 weeks. After 36 weeks total of BIL treatment, patients were switched back to their usual treatment with conventional insulins for a 4-week safety follow-up (Figure S1, Supporting Information). Patients in the fixed-time dosing regimen administered their insulin dose once daily in the evening. Patients in the variable-time dosing regimen administered their insulin dose in the morning on Mondays, Wednesdays and Fridays and in the evening on Tuesdays, Thursdays, Saturdays and Sundays (dosing intervals: 8 2 hours to 40 2 hours). The basal insulin dosing algorithm (Table S1) was modified from Bartley et al 17 and Bolli et al 18 and was used during the lead-in period and for both BIL treatment regimens during the randomization periods. Bolus doses were also titrated throughout the study using insulin-dosing algorithms adapted from Riddle et al 19 and Bergenstal et al 20 based on SMBG values. 2.1 Study objectives The primary objective was to demonstrate non-inferiority of variabletime dosing of BIL compared with fixed-time dosing of BIL for HbA1c change after 12 weeks of therapy (margin = 0.4%). Secondary efficacy objectives of this study which were compared between treatment regimens at 12 weeks included 9-point SMBG, FBG, change in FBG, between-day intra-patient variability in FBG and SMBG, fasting serum glucose (FSG) (central laboratory measurement), HbA1c change, basal, bolus and total insulin doses, the ratio of mealtime (bolus) insulin to total insulin, 3 AM to pre-breakfast blood glucose (BG) excursion, proportion of patients with HbA1c <7.0% and with HbA1c 6.5% and hypoglycaemia. HbA1c was also assessed at other time points. Objectives assessed across the full 36 weeks of treatment included weight change, antibodies to BIL, triglycerides and total, low-density lipoprotein (LDL)-, and high-density lipoprotein (HDL)- cholesterol. In addition, a subset of patients participated in a continuous glucose monitoring (CGM) substudy designed to elucidate the impact of BIL on glucose profiles when administered with fixed-time dosing compared to variable-time dosing, as well as within- and between-day glucose variability, especially during the nocturnal time period. The primary objective of this substudy was to compare fixedtime vs variable-time dosing for the duration of nocturnal (midnight to 06:00 hours) hypoglycaemia as measured by total minutes with blood glucose 3.9 mmol/l after 12 weeks of treatment. Statistical methods A total of 144 patients completing both randomized treatment periods was estimated to provide >90% statistical power to demonstrate non-inferiority of variable-time BIL dosing to fixed-time BIL dosing for change in HbA1c during 12 weeks of treatment, with the assumption of no difference between the two treatment regimens, an SD of 1.1%, within-patient correlation of 0.5 and a non-inferiority margin of 0.4% by using two-sided significance alpha level of.05. With the estimated dropout rate of 15% during both randomized treatment periods, a total of 170 randomized patients were needed. Assuming 15% screen failure and additional 10% drop out during the lead-in period, we planned to screen 223 patients for this study. CGM was conducted on a subset of patients. Forty-seven patients provided additional written informed consent to participate in the CGM substudy. Six-day CGM profiles were obtained during the last week of the leadin period and each of the 12 week randomization periods. All analyses were conducted by SAS (9.2, Cary, North Carolina). For the comparison between the two dosing regimens of BIL, the analyses were based on all randomized patients who took 1 dose of study drug. Unless otherwise specified, all tests of statistical

3 GARG ET AL. 45 significance were evaluated at a nominal level of.05 using two-tailed test procedures; confidence intervals (CIs) were computed as twotailed using a 95% significance level. For continuous outcomes with repeated measurements, a mixed model for repeated measurements analysis using restricted maximum likelihood was used. For categorical variables, Prescott s exact test was used for comparisons between treatment regimens. All negative binomial regressions estimated group means instead of least-squares (LS) means, using the delta method to estimate the standard error (SE) of the group mean 21 ; group mean was defined as the mean response in the treatment group. No multiplicity test adjustment was made for the Type I error. For the measures such as HbA1c, body weight and safety endpoints during 36 weeks of treatment starting from the lead-in period, analyses were conducted on all patients who took at least one dose of BIL in the whole study. The change from baseline for continuous variables was analyzed using mixed model repeated measures and categorical variables were descriptively summarized. Between-group differences are presented as LS mean differences with 95% CIs. Baseline and endpoint values are presented as LS mean SE unless otherwise indicated. 3 RESULTS Baseline characteristics are shown in Table 1. Mean age was years, with mean duration of diabetes being years. Most patients (96%) were white and 12% were of Hispanic or Latino ethnicity. A total of 262 patients were screened; 212 were enrolled. Thirty patients discontinued treatment during the lead-in period; 10 dropped out of the study altogether and 20 opted to enter the 4-week safety follow-up period, during which patients returned to conventional insulin treatment. Adverse events (15 patients) and patient withdrawal (10 patients) were the most common reasons for discontinuation during the 12-week lead-in phase (Figure S2). During the 12-week lead-in with fixed-time BIL treatment, LS mean HbA1c decreased from 7.5% to 6.8% (P <.001; Figure 1A) and 107 (58.8%) patients achieved HbA1c < 7% while 55 (30.2%) patients achieved HbA1c < 7% without nocturnal hypoglycaemia. In addition, 68 (37.4%) patients had HbA1c 6.5% and 36 (19.8%) had HbA1c 6.5% without nocturnal hypoglycaemia. After the lead-in period, 182 patients were randomized to receive BIL with either 12 weeks of fixed-time dosing followed by 12 weeks of variable-time dosing or 12 weeks of variable-time dosing followed by 12 weeks of fixed-time dosing. Of these 182 patients, 10 discontinued early. The most common reason for discontinuation was patient withdrawal (four patients). A total of 197 patients entered the 4-week follow-up period (Figure S2). Variable-time dosing was non-inferior to fixed-time dosing for the primary objective of change in HbA1c [LS mean difference = 0.06%, 95% CI ( 0.01, 0.13), the upper limit of the 95% CI of 0.13 is less than the pre-specified non-inferiority margin of 0.4%, Figure 1B]. HbA1c increased slightly during the two 12-week randomized treatment periods, but remained significantly below the baseline mean of 7.5% (P.001, Figure 1). TABLE 1 Baseline patient characteristics 1 All patients (N = 212) CGM subgroup (N = 37) Age, years Sex, male, n (%) 114 (53.8) 24 (64.9) Race, n (%) American Indian or Alaskan Native 1 (0.5) Asian 3 (1.4) 1 (2.7) Black or African American 4 (1.9) Multiple 1 (0.5) White 203 (95.8) 36 (97.3) Hispanic or Latino ethnicity 26 (12.3) 2 (5.4) BMI, kg/m Weight, kg Duration of diabetes, years HbA1c % mmol/mol Fasting serum glucose (laboratory) mmol/l mg/dl LDL-cholesterol mmol/l mg/dl HDL-cholesterol mmol/l mg/dl Triglycerides mmol/l mg/dl Alanine aminotransferase, U/L Aspartate aminotransferase, U/L BMI, body mass index; CGM, continuous glucose monitoring; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein. 1 Values are mean standard deviation unless otherwise indicated. The majority of patients in both groups had HbA1c <7.0% after 12 weeks of randomized treatment [91 patients (54.5%) for variabletime dosing and 101 patients (60.5%) for fixed-time dosing]. More than a quarter of patients in both groups had HbA1c <7.0% with no nocturnal hypoglycaemia [47 patients (28.1%) for variable-time dosing and 48 patients (28.7%) for fixed-time dosing]. There were no differences between these two groups for either measure (P =.313 and.901, respectively). Measures of total, nocturnal and severe hypoglycaemia were also similar in the full patient population (Table 2). More than one third of patients achieved HbA1c 6.5% after 12 weeks of randomized treatment [57 patients (34.1%) in each treatment regimen, P =.258], while almost one in five achieved HbA1c 6.5 with no nocturnal hypoglycaemia [34 patients (20.4%) for variable-time dosing and 31 patients (18.6%) for fixed-time dosing]. FBG, derived from the mean values of all fasting SMBG measurements in the last week of each randomized treatment period, was higher for patients during variable-time dosing, with LS mean between-

4 46 GARG ET AL. TABLE 2 Outcomes after 12 weeks of treatment Fixed-time (N = 177) LS mean SE Variable-time (N = 180) LS mean SE Betweengroup P- value 1 HbA1c % mmol/mol FSG (laboratory) mmol/l mg/dl FBG (9-point SMBG) mmol/l mg/dl Within-day variability (9-point SMBG) mmol/l mg/dl Between-day variability (9-point SMBG) mmol/l FIGURE 1 Glycated haemoglobin (HbA1c) over time. (A) HbA1c over the course of the 36-week trial and 4-week follow-up period for all patients (white circles). During the 12-week lead-in period (Weeks 12 to 0), all patients received fixed-time (evening) dosing of basal insulin peglispro (BIL). At Week 0, patients were randomized to fixedor variable-time dosing with BIL, and crossed over to the alternate treatment regimen at Week 12. At Week 24, patients were returned to conventional insulin treatment for a 4-week follow-up period. The final value on the graph (labelled Study Endpoint) represents HbA1c at the end of the 4-week safety follow-up period for most patients. For patients who did not complete the full 36-week trial, it represents HbA1c at last treatment visit. (B) Change in HbA1c during 12 weeks of treatment. Fixed-time dosing (black circles) vs variabletime dosing (white squares). The least-squares (LS) mean difference between dosing regimens was 0.06%, 95% confidence interval (CI) = 0.01 to 0.13, P =.095. group difference of 0.46 mmol/l. FSG was comparable for both regimens (Table 2), with an LS mean between-group difference of 0.06 mmol/l. Glycaemic variability was assessed by examining within- and between-day variability in 9-point SMBG profile, between-day variability in FBG and glucose excursions from bedtime to 3 AM, from bedtime to next day fasting and from 3 AM to next day fasting. Glycaemic variability was similar between dosing regimens for all variability measures except bedtime to 3 AM excursion (Table 2). Basal and bolus insulin doses were similar in the two regimens after 12 weeks of randomized treatment, as was the ratio of bolus insulin to total insulin (Table 2). Weight decreased slightly but significantly during 36-weeks of BIL treatment, and returned to approximately baseline level after patients were returned to treatment with conventional insulins (Table 3). Blood glucose values, as assessed by 9-point SMBG measurements conducted on two non-consecutive days during the week prior to Week 12, were generally similar between the two dosing regimens. However, blood glucose was higher 2 hours after breakfast, before lunch and at 3 AM with variable-time dosing at 12 weeks (P <.05) (Figure 2). mg/dl Between-day FBG variability mmol/l mg/dl Bedtime to 3 AM excursion mmol/l mg/dl Bedtime to next day fasting excursion mmol/l mg/dl AM to next day fasting excursion mmol/l mg/dl Basal insulin dose, unit/kg Bolus insulin dose, unit/kg Proportion of bolus to total insulin Total hypoglycaemia rate Nocturnal hypoglycaemia rate 2 Severe hypoglycaemia rate FBG, fasting blood glucose; FSG, fasting serum glucose; HbA1c, glycated haemoglobin; LS, least-squares; SMBG, self-monitored blood glucose. 1 Between group comparison. 2 Group mean SE, events/patient/30 days. 3 Aggregate rate SE, events/patient/100 years. Demographics and baseline characteristics in the CGM subpopulation were comparable to the overall study population (Table 1). Five patients discontinued during the 12-week lead-in phase; 39 patients completed both randomized treatment periods. The two treatment regimens were comparable for time spent per 24-hours in hypoglycaemia, euglycaemia and hyperglycaemia, as well as the amount of time spent in nocturnal hypoglycaemia (Figure S3). Lipids changed significantly during 36-week treatment (Table 3). Triglycerides increased significantly, but returned to baseline concentrations after patients returned to treatment with conventional insulins (Table 3).

5 GARG ET AL. 47 TABLE 3 Outcomes after 36 weeks and at study endpoint Baseline (N = 212) mean SD 36-weeks 1 (N = 163) Study endpoint 3 (N = 210) LS mean SE P-value 2 LS mean SE P-value 2 Weight, kg < ALT, IU/L < AST, IU/L < HDL-cholesterol mmol/l < mg/dl LDL-cholesterol mmol/l mg/dl Triglycerides mmol/l < mg/dl ALT, alanine aminotransferase; AST, aspartine aminotransferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LS, least-squares. 1 Twelve-week lead-in period plus two 12-week treatment periods. 2 Comparison with baseline value. 3 Last measurement in the study, although most were from the 4-week safety follow-up, some were last treatment visit. FIGURE 2 Nine-point self-monitored blood glucose. Least-squares (LS) means of 9-point self-monitored blood glucose (SMBGs) collected twice during the last week of each randomized treatment period. Fixed-time dosing (black circles) vs variable-time dosing (white squares). Blood glucose was significantly higher with the variable-time dosing regimen 2 hours after breakfast, before the midday meal and at 3 AM. PC, post-cibum (after food); HS, hora somni (at bedtime). **P <.01, *P <.05. common types of adverse events were infections and infestations (Table S2). Individual adverse events that occurred in more than 5% of patients were nasopharyngitis (15.6%), upper respiratory tract infection (14.2%), hypoglycaemia (11.3%), influenza (6.1%), sinus congestion (6.1%) and sinusitis (5.2%). The most common serious adverse event was hypoglycaemia [24 patients (11.3%); Table S2]. A total of 17 patients discontinued due to adverse events during the 36-weeks of BIL treatment (Figure S2). Fifteen patients discontinued during the lead-in period: four for injection site swelling, and one each for injection site pain, injection site hypertrophy, injection site nodule, lipohypertrophy, atrial fibrillation, palpitations, abdominal discomfort, weight increased, hypoglycaemia and lower extremity mass. For one patient who discontinued due to adverse event, the cause is unknown due to data collection error. Two patients discontinued during the randomized treatment period (one each for weight decreased and hypoglycaemia). Changes in HDL- and LDL-cholesterol during 36 weeks of BIL treatment and to study endpoint were small but statistically significant. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) both increased significantly during 36-week treatment with BIL (P <.001). After return to conventional insulin, AST was similar to baseline value (P =.551); ALT concentration decreased but was still significantly above baseline (P =.009; Table 3). During this study, 10 patients (4.8%) experienced ALT 3 the upper limit of normal (ULN), and 2 (1%) had ALT 5 ULN; 5 (2.4%) patients experienced AST 3 ULN and 2 (1%) had AST 5 ULN. During the study, no patient met the criteria for Hy s law, an algorithm used to identify severe drug-induced liver damage. 22 Injection site reactions were commonly reported treatmentemergent adverse events (TEAEs) over 36 weeks of BIL treatment [injection site swelling: 10 patients (4.7%), lipohypertrophy: 9 patients (4.2%), injection site hypertrophy: 1 patient (0.5%)]. The most 4 CONCLUSIONS This study demonstrates that the basal insulin, BIL, with a flat PK and PD profile 6,7 can be given at intervals of up to 40 hours without any deterioration of glucose control as measured by HbA1c. In fact, the difference in HbA1c after 12 weeks of treatment with each regimen was less than 0.1%. Variable- and fixed-time dosing with BIL treatment also had similar glycaemic variability and hypoglycaemia rates as well as times spent in different glucose ranges in the subset of patients who had CGM. These data are consistent with what would be expected of the long half-life observed for BIL in PK studies. 6,7 Furthermore, in other studies, glycaemic variability was lower with BIL than with comparator insulins (insulin glargine and NPH). 8 11,13 15,23 Reduction of glycaemic variability may not only allow more effective titration of basal insulin and improved glycaemic efficacy compared to insulin glargine

6 48 GARG ET AL. or NPH but may also reduce nocturnal hypoglycaemia and perhaps reduce the risk or delay the onset of long-term health concerns. 1 5 Of note, the study cohort was comprised of T1D patients with a mean duration of diabetes of 20 years in whom more than half achieved an HbA1c of less than 7% after 12 weeks of therapy (lead-in period) and for most patients this was maintained for the next 24 weeks. Higher levels of HbA1c within 4 weeks of discontinuing BIL (Figure 1A) suggest that these observations were likely related to BIL s flat PK/PD profile. Variable dosing intervals have also been examined with insulin degludec in patients with T1D. 24 The degludec study did not have a lead-in period, so patients were switched directly from their prestudy insulin to variable-time dosed degludec (8-40 hours), fixed-time dosed degludec (24 hours) or fixed-time dosed glargine. Patients were treated for 26 weeks, and at endpoint, variable-timed dosing with degludec was non-inferior to fixed-time dosing with degludec and to fixed-time dosing with glargine for reduction in HbA1c. HbA1c reduction was similar between the 2 degludec treatment arms at 26 weeks with a 0.01% difference compared to the 0.06% observed in the current study. However, differences in laboratory-measured fasting glucose between flexible- and fixed-time dosing with degludec was reported as 0.95 mmol/l and this difference was numerically greater than the 0.06 mmol/l LS mean difference reported for laboratory-measured FSG and the 0.46 mmol/l reported for fasting SMBG in the current study. Measures of glycaemic variability between degludec fixed vs flexible-dosing were not reported. 24 In this study, SMBG profiles revealed numerically higher glucose values at four of the nine time points: 03:00, fasting, 2-hour postbreakfast and pre-lunch (P = NS), with variable-time dosing compared to fixed-time dosing. These differences were consistent with prestudy PK modelling for variable dose timing (data not shown). In spite of these differences, the highest mean post-prandial value with flexible dosing was less than 9 mmol/l. This value is comparable to the highest mean post-prandial values observed in patients with T1D in treat-to-target studies of other insulins, and is well within American Diabetes Association recommendations. 28 Cross-over designs are not widely used in clinical efficacy trials because of the need in typical efficacy trials to demonstrate either greater or comparable efficacy between different antihyperglycaemic agents. However, cross-over designs are optimal designs to efficiently answer questions such as differences in dosing regimens using the same medication. Although BIL has a prolonged duration of action, the use of 12-week treatment periods was adequate to mitigate any concerns about carry over effects from one treatment arm to the next. Because of the use of a single basal insulin, concerns about attribution of any adverse effects are not confounded by the crossover design. The use of a 12-week lead-in period allowed patients to achieve stable glycaemic measures before randomization, and therefore the requirement for further titration-up of basal insulin dose during the randomized cross-over period was minimized and the impact of different basal insulin regimens under stable doses can be assessed. Thus, mean HbA1c values were similar at the beginning (and throughout the study) of each randomization period. Limitations of this study include lack of comparator insulin for both efficacy and safety concerns and comparatively short durations of treatment for the primary analyses. These limitations are mitigated by the extensive data from other BIL trials with durations of weeks in which greater glycaemic efficacy was demonstrated in six comparator trials, including two in T1D, with an insulin glargine comparator In this study, LS mean HbA1c after 12 weeks (6.8%) and 36 weeks (7.0%) of therapy is comparable to the BIL-treated patients in other T1D trials: 7.1% and 7.4%, respectively, at 26 and 78 weeks in IMAGINE 1 (n = 295) 14 and 7.4% at 52 weeks in IMAG- INE 3 (n = 664). 10 Finally, the observations of the lipid changes and increases in ALT and AST in this study are consistent with changes observed in studies of comparing BIL to conventional insulins in patients previously treated with insulin. 10,11,14,23,29 Each of these variables returned to baseline or near baseline during the 4 weeks off study drug in this and previous studies. 10,11,14,23,29 In conclusion, treatment with BIL allows patients to use flexible dosing intervals from 8 to 40 hours with similar glycaemic efficacy (HbA1c) glycaemic variability, and hypoglycaemia when compared with fixed-time dosing with BIL. These data suggest that patients who miss evening doses of basal insulin due to variable work schedules or travel across time zones may be allowed flexibility in dosing when using BIL as their basal insulin. Study Investigators Study Investigators were Aurora Alcantara, Timothy Bailey, Anuj Bhargava, Thomas Blevins, Anna Chang, Satish Garg, David Huffman, James Lane, David Liljenquist, Hiralal Maheshwari, Ronald Mayfield, Wendell Miers, Paul Norwood, Kerem Ozer, John Reed, Angel Comulada, Rivera, Julio Rosenstock, Jean-Louis Selam, Alan Wynne, and Daniel Weiss. Funding information This study was funded by Eli Lilly and Company. Conflicts of interest Dr. Garg serves as a speaker or consultant for Medtronic, Roche, Eli Lilly and Company, Lexicon, Novo-Nordisk and Sanofi. He has received research grants from Eli Lilly and Company, Halozyme, Novo Nordisk, Merck, MannKind, Lexicon, Medtronic, T1D Exchange, NIDDK, JDRF and Sanofi. He does not own stocks or equity in any device or pharmaceutical company. Dr. Selam is a speaker for Novo Nordisk, a consultant for Sanofi and received research support from Eli Lilly and Company. Dr. Bhargava conducts or has conducted research studies in the interest of diabetes for Novo Nordisk, Eli Lilly and Company, AbbVie, MannKind Corporation, Intarcia, Orexigen Therapeutics, Inc., Sanofi-Aventis, Jaeb, Merck, GlaxoSmithKline, University of Oxford, Bristol Myers Squibb, Boehringer Ingelheim Pharmaceuticals, Inc., Duke University Medical Center, Medtronic, Astra Zeneca and Halozyme. He serves on Advisory Boards for Abbott and Janssen. He also is a speaker for Astra- Zeneca, Janssen and sanofi. Dr. Schloot is guest scientist at Institute of Clinical Diabetology, German Diabetes Center at Heinrich-Heine University Duesseldorf, Germany. Drs. Schloot, Luo, Zhang, Jacobson and Hoogwerf are full-time employees and minor stockholders of Eli Lilly and Company.

7 GARG ET AL. 49 Author contributions BJH designed the study. SG, J-LS and AB collected data. JL and QZ performed statistical analyses. JGJ drafted the manuscript. SG, J-LS, AB, NS, JL, QZ, JGJ and BJH contributed to interpretation of the data and critically reviewed the manuscript. All authors approved the final version of the manuscript. REFERENCES 1. Trence DL, Hirsch IB. Motherhood, apple pie, hemoglobin A(1C), and the DCCT. Endocr Pract. 2012;18: Nalysnyk L, Hernandez-Medina M, Krishnarajah G. Glycaemic variability and complications in patients with diabetes mellitus: evidence from a systematic review of the literature. Diabetes Obes Metab. 2010;12: Bragd J, Adamson U, Backlund LB, Lins PE, Moberg E, Oskarsson P. Can glycaemic variability, as calculated from blood glucose self-monitoring, predict the development of complications in type 1 diabetes over a decade? Diabetes Metab. 2008;34: Kilpatrick ES, Rigby AS, Goode K, Atkin SL. 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Lipid changes during basal insulin peglispro, insulin glargine, or NPH treatment in 6 IMAGINE trials. Diabetes Obes Metab. 2016;18: SUPPORTING INFORMATION Additional Supporting Information may be found online in the supporting information tab for this article. How to cite this article: Garg S, Selam J-L, Bhargava A, Schloot N, Luo J, Zhang Q, Jacobson JG and Hoogwerf BJ. Similar HbA1c reduction and hypoglycaemia with variable- vs fixed-time dosing of basal insulin peglispro (BIL) in type 1 diabetes: IMAGINE 7 study, Diabetes Obes Metab 2016, 18 (Suppl. 2), DOI: /dom.12740