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Advancing therapy in suboptimally controlled basal insulin-treated type 2
diabetes: Clinical outcomes with iGlarLixi versus premix BIAsp 30 in the SoliMix
randomized controlled trial
Authors: Julio Rosenstock, MD1, Rifat Emral, MD2, Leobardo Sauque-Reyna, MD3,
Viswanathan Mohan, MD4, Carlos Trescolí, MD5, Saud Al Sifri, MD6, Nebojsa Lalic, MD7,
Agustina Alvarez, MD8, Pascaline Picard, MSc9, Mireille Bonnemaire, MD10, Nacima Demil,
MD11, Rory J. McCrimmon, MBChB12, on behalf of the SoliMix Trial Investigators
Affiliations: 1Dallas Diabetes Research Center at Medical City, Dallas, TX, USA;
2Department of Endocrinology and Metabolic Diseases, Ankara University Faculty of
Medicine, Ankara, Turkey; 3Instituto de Diabetes Obesidad y Nutrición S.C., Cuernavaca,
Morelos, Mexico; 4Dr. Mohan’s Diabetes Specialities Centre & Madras Diabetes Research
Foundation, IDF Centre of Excellence in Diabetes Care & ICMR Centre for Advanced
Research on Diabetes, Chennai, India; 5Hospital Universitario de La Ribera, Alzira, Spain;
6Al Hada Military Hospital, Taif, Saudi Arabia; 7Faculty of Medicine of the University of
Belgrade, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of
Serbia, Belgrade, Serbia; 8Sanofi, Buenos Aires, Argentina; 9IVIDATA Life Sciences,
Levallois-Perret, France; 10Sanofi, Paris, France; 11Diabetes Medical Operation Department,
Sanofi, Chilly-Mazarin, France; 12Division of Systems Medicine, School of Medicine,
University of Dundee, Dundee, UK
Corresponding author: Julio Rosenstock
Address: Dallas Diabetes Research Center at Medical City, 7777 Forest Lane, Suite C-685, Dallas, TX 75230, USA
E-mail: [email protected]
Telephone: (972) 566-7799
CONFIDENTIAL-For Peer Review Only Diabetes Care Publish Ahead of Print, published online June 28, 2021 Diabetes Care Page 2 of 43
Premix RCT primary manuscript peer review 08 June 2021
Clinical trial registration: 2017-003370-13 (EU clinical trials register)
Running Title: Therapy advancement to iGlarLixi vs Premix
Abstract word count: 247 / 250
Word count: 3993 / 4000
Number of references: 31 / 40
Number of figures/tables: 3/1
Supplementary figures/tables: 3/5
Keywords: Premix insulin; basal insulins; Type 2; glycemic control; GLP-1 agonist; hypoglycemia; bodyweight; therapy intensification, GLP-1 RA, fixed-ratio combination
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Abstract
Objective: To directly compare the efficacy and safety of a fixed-ratio combination,
iGlarLixi, with a premix insulin analog (BIAsp 30) as treatment advancement in type 2
diabetes suboptimally controlled on basal insulin plus oral antihyperglycemic drugs (OADs).
Research Design and Methods: SoliMix, a 26-week, open-label, multicenter study,
randomized adults with suboptimally controlled basal insulin-treated type 2 diabetes (HbA1c
≥7.5 % and ≤10 %) to once-daily iGlarLixi or twice-daily BIAsp 30. Primary efficacy
endpoints were non-inferiority in HbA1c reduction (margin 0.3 %) or superiority in
bodyweight change for iGlarLixi versus BIAsp 30.
Results: Both primary efficacy endpoints were met: after 26 weeks, baseline HbA1c (8.6 %)
was reduced by 1.3 % with iGlarLixi and 1.1 % with BIAsp 30, meeting non-inferiority (least
squares [LS] mean difference [97.5% CI]: -0.2 [-0.4, -0.1] %; p<0.001). iGlarLixi was also
superior to BIAsp 30 for bodyweight change (LS mean difference [95% CI] -1.9 [-2.3, -1.4]
kg) and percentage of participants achieving HbA1c <7 % without weight gain and HbA1c <7
% without weight gain and without hypoglycemia (all p<0.001). iGlarLixi was also superior
versus BIAsp 30 for HbA1c reduction (p<0.001). Incidence and rates of ADA Level 1 and 2
hypoglycemia were lower with iGlarLixi versus BIAsp 30.
Conclusions: Once-daily iGlarLixi provided better glycemic control with weight benefit and
less hypoglycemia than twice-daily premix BIAsp 30. iGlarLixi is a more efficacious,
simpler, and well-tolerated alternative to premix BIAsp 30 in suboptimally controlled type 2
diabetes requiring treatment beyond basal insulin plus OAD therapy.
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Premix RCT primary manuscript peer review 08 June 2021
Clinical guidelines recommend a target HbA1c of <7.0 % (<53 mmol/mol) for most non-pregnant adults with type 2 diabetes (1; 2), while recognizing the need to individualize glycemic targets based on patient preference, and treatment efficacy and safety profiles (1; 2).
Most current guidelines advocate a stepwise introduction of pharmacotherapy for people with type 2 diabetes not achieving their individualized glycemic targets. With this approach, advancing basal insulin therapy involves four options: 1) adding rapid-acting insulin progressively to an existing basal insulin regimen; 2) multiple daily premix insulin doses
(basal and prandial insulin co-formulation); 3) adding a daily or weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) to an existing basal insulin regimen; 4) switching to a once-daily fixed-ratio combination (FRC) of basal insulin and GLP-1 RA (2; 3).
Each aforementioned treatment option has been shown to improve glycemic control when used to advance therapy from basal insulin but are also associated with specific adverse effects (4-7). GLP-1 RA therapy can be associated with gastrointestinal (GI) adverse events
(AEs) and resultant adherence issues (4). Basal plus rapid-acting insulin regimens and premix insulin regimens can increase the risks of hypoglycemia and weight gain, whilst requiring multiple daily injections and frequent glucose monitoring that increase treatment burden and may reduce adherence (5-7). Despite this, premix insulins are widely used globally, particularly in Asia, Africa, the Middle East, China and some EU countries (8-11).
Titratable FRCs of basal insulin and a GLP-1 RA can provide a novel alternative therapy advancement option to premix insulin, as tested for the first time in this randomized controlled trial. FRCs combine the complementary mechanisms of action of two individual components in one formulation; basal insulin primarily reduces fasting plasma glucose (FPG) while the GLP-1 RA targets post-prandial glucose (PPG). Overall, GLP-1 RAs act through a glucose-dependent mechanism by which they stimulate insulin secretion while preventing
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glucagon increase (12). Short-acting GLP-1 RAs, specifically target PPG with a predominant
gastric emptying effect, while long-acting GLP-1 RAs, exert their effect predominantly
through pancreatic functions, resulting in a lesser impact on PPG but larger overall reductions
in FPG (12). Two once-daily titratable FRCs of basal insulin and GLP-1 RA are available
which are approved for use in adults with type 2 diabetes. iGlarLixi is an FRC of basal
insulin glargine 100 units/mL (iGlar) and the short-acting GLP-1 RA lixisenatide (Lixi) (13;
14), while IDegLira is an FRC of the basal insulin degludec and the long-acting GLP-1 RA,
liraglutide (15; 16). Both have been shown to provide improved glycemic control versus their
individual components, along with weight-benefits compared with basal insulin and fewer
gastrointestinal AEs compared with their GLP-1 RA component (17-22).
Here we report the results of the first randomized, head-to-head study directly comparing
the efficacy and safety of an FRC (iGlarLixi) with a premix insulin (biphasic insulin aspart
30, BIAsp 30) in adults with type 2 diabetes advancing from basal insulin plus one or two
oral antihyperglycemic drugs (OADs).
Research Design and Methods
Detailed methods have been previously published (23). In brief, SoliMix was an open-
label, multicenter, randomized, 26-week study undertaken to compare the efficacy and safety
of iGlarLixi with BIAsp 30, in adults with suboptimally controlled type 2 diabetes (HbA1c
≥7.5 % [≥58.5 mmol/mol] and ≤10 % [≤85.8 mmol/mol]) despite receiving stable doses of
basal insulin plus OADs (metformin ± sodium-glucose cotransporter-2 [SGLT2] inhibitor)
for 3 months. Exclusion criteria included individuals with type 1 diabetes, BMI of <20 and
≥40 kg/m2, basal insulin dose of <20 U or >50 U at screening, and use of any
antihyperglycemic agent other than basal insulin, metformin, or SGLT2 inhibitors in the 3
months prior to screening.
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Participants were randomized (1:1) to receive once-daily subcutaneous iGlarLixi
(Suliqua®, [Soliqua®], Sanofi, Paris, France) or twice-daily subcutaneous BIAsp 30 (30%
insulin aspart + 70% insulin aspart protamine; NovoMix® 30, Novo Nordisk A/S, Bagsværd,
Denmark). iGlarLixi was injected before a meal using a prefilled disposable SoloSTAR® pen injector. BIAsp 30 was administered subcutaneously twice daily in the morning and before dinner. Participants were switched from their prior basal insulins at randomization; OADs were continued without adjustment. Starting doses of iGlarLixi were based on prior basal insulin doses, according to labelling instructions. If the previous basal insulin dose at randomization was <30 U, the starting dose was 20 dose steps (20 U iGlar, 10 μg Lixi) administered with the 10–40 U pen (2 U:1 μg ratio); if basal insulin was ≥30 to ≤50 U, the starting dose was 30 dose steps (30 U iGlar, 10 μg Lixi) administered with the 30–60 U pen
(3 U:1 μg ratio). Further details are shown in Supplementary Table 1. Starting total daily doses of BIAsp 30 were the same as the participants’ previous basal insulin dose on a unit-to- unit basis and split into two daily doses. Doses of iGlarLixi and BIAsp 30 were recommended for weekly titration based on fasting or premeal self-measured plasma glucose, respectively, to a target of 80–110 mg/dL (4.4–6.1 mmol/L). The recommended dose adjustment algorithms for iGlarLixi and BIAsp 30 were indicated according to label recommendations and are shown in Supplementary Tables 2 and 3.
Rescue therapy use was recommended according to the investigator’s clinical judgment for both arms to correct hyperglycemia persisting beyond prespecified thresholds (HbA1c >8
% or FPG >200 mg/dL from Week 12). Rescue therapy was to be considered in the iGlarLixi group when the maximal dose of 60 dose steps was reached. The use of any additional antihyperglycemic treatment (basal insulin, rapid-acting insulin, third daily injection of premix, or OADs) administered to participants in either group with the objective of rescue was included in the analysis of the proportion of participants requiring rescue therapy.
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This study is registered on the European Union Drug Regulating Authorities Clinical
Trials Database (2017-003370-13), and was conducted in accordance with the ethical
principles of the Declaration of Helsinki, and the International Conference on Harmonisation
guidelines for good clinical practice, and all applicable laws, rules, and regulations.
Study endpoints
The two primary objectives of this study were to demonstrate that, compared with BIAsp
30, iGlarLixi was non-inferior in terms of HbA1c reduction or superior in terms of
bodyweight change from baseline to Week 26. Key secondary efficacy endpoints were
assessed at Week 26, including HbA1c <7 % without weight gain at Week 26, HbA1c <7 %
without weight gain at Week 26 and without hypoglycemia (plasma glucose <70 mg/dL [<3.9
mmol/L]) during the treatment period, and the superiority of iGlarLixi versus BIAsp 30 in
terms of HbA1c reduction from baseline to Week 26. Other secondary exploratory glycemic
endpoints included the proportion of patients reaching HbA1c target <7 % at Week 26, HbA1c
target <7 % without ADA Level 2 hypoglycemia, HbA1c <7 % without weight gain of >1 kg,
and HbA1c <6.5 %. Other secondary endpoints included change in total insulin dose and
change in FPG, from baseline to Week 26.
Safety endpoints were hypoglycemia, AEs, serious AEs (SAEs), AEs leading to treatment
discontinuation, and AEs leading to death. Hypoglycemia was defined by current ADA Level
1 (<70 mg/dL [<3.9 mmol/L] and ≥54 mg/dL [≥3.0 mmol/L]), Level 2 (<54 mg/dL [<3.0
mmol/L]), or Level 3 (severe hypoglycemia). Nocturnal hypoglycemia was also assessed post
hoc using two definitions: between bedtime and waking, and between 00:00–06:00 h.
Statistical analysis
A sample size of 864 randomized participants (432 randomized or 388 evaluable
participants per treatment group) was calculated based on the primary efficacy variables of
HbA1c and weight change from baseline to Week 26. Assuming a drop-out rate of 10%, this
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Premix RCT primary manuscript peer review 08 June 2021 sample size provides over 95% power to demonstrate non-inferiority (margin 0.3 %) of iGlarLixi versus BIAsp 30 for HbA1c reduction or superiority for weight reduction at Week
26. The assumptions made for non-inferiority of HbA1c were a standard deviation (SD) of
1.1 %, a non-inferiority margin of 0.3 % and a zero true difference in HbA1c between treatment groups. Assumptions for superiority testing of iGlarLixi over BIAsp 30 in terms of weight gain included an expected difference of 1 kg between treatment groups and an SD of
3.46 kg for changes from baseline. The two-sided significance level of 0.025 was assumed for each of the above tests.
The primary efficacy endpoints were analyzed using a multiple imputation strategy and an ANCOVA model including screening HbA1c value (<8.0 % vs ≥8.0 %, for the change in bodyweight primary endpoint only), basal insulin dose (<30 U, ≥30 U) and SGLT2 inhibitor use (Yes, No), treatment group, and country as fixed categorical effects, and fixed continuous covariates of baseline values for each primary endpoint (HbA1c and bodyweight).
Continuous secondary efficacy endpoints (e.g. FPG and total daily insulin dose) were analyzed using the same approach as the primary endpoints including the baseline values for the endpoint in question as fixed covariates. Categorical secondary efficacy endpoints (e.g. the first two key secondary endpoints) were analyzed using a logistic regression model adjusting for treatment group randomization strata, and HbA1c and weight baseline covariates.
A multiple testing procedure was pre-specified for analysis of the primary and key secondary efficacy endpoints (Supplementary Figure 1). Following the two primary endpoints, the three key secondary endpoints were assessed using a hierarchical order: superiority of iGlarLixi versus BIAsp 30 in achieving HbA1c <7 % without weight gain; then superiority of HbA1c <7 % without weight gain and without hypoglycemia; then superiority
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of HbA1c reduction. More detailed information pertaining to control for type I error has been
previously published (22).
All efficacy analyses were performed on data from the intention-to-treat (ITT)
population, defined as all randomized participants. The COVID-19 pandemic occurred during
the last few weeks of the study in some countries, making it difficult for some participants to
comply with the protocol. To assess the potential impact of this on the primary and key
secondary efficacy endpoints, sensitivity analyses were performed on a subgroup of the ITT
population who had no major or critical deviations related to the COVID-19 pandemic
situation that could have affected the primary efficacy analysis. Participants who followed the
study visits and assessments without being impacted by the COVID-19 pandemic and its
consequences (e.g. lockdown, sites closed, postponed/incomplete end-of-treatment visit) were
defined as the non-impacted by COVID-19 population. Further sensitivity analyses were
performed for the non-inferiority objective in the per protocol population, defined as all
participants in the ITT population who completed 26 weeks of randomized treatment without
any major protocol violations.
Safety analyses were based on data from the safety population, defined as all
randomized participants who received at least one dose of study drug.
Results
Participant disposition and baseline characteristics
In total, 887 participants from 89 centers in 17 countries were randomized in the
study, of whom 443 were allocated to iGlarLixi and 444 to BIAsp 30. Of the 887 participants
in the ITT population, 403 in the iGlarLixi group and 404 in the BIAsp 30 group were
included in the non-impacted by COVID-19 population. No participants discontinued due to
COVID-19. Overall, participants received treatment with iGlarLixi or BIAsp 30 for a mean
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Premix RCT primary manuscript peer review 08 June 2021 duration of 184 or 181 days, respectively. In total, 844 (95.2%) participants completed the
26-week treatment period; 428 (96.6%) in the iGlarLixi group and 416 (93.7%) in the BIAsp
30 arm (Supplementary Figure 2).
Demographics and baseline characteristics were similar across both treatment groups
(Table 1) and have been reported previously (22). Briefly, the randomized population was primarily white (62.4%) with a mean ± SD age of 59.8 ± 10.2 years, BMI of 29.9 ± 4.9 kg/m2 and duration of type 2 diabetes of 13.0 ± 7.2 years. Metformin was used at baseline in 99.8% of all participants: approximately one quarter were also receiving SGLT2i at baseline in both treatment groups. Basal insulins used at randomization were insulin glargine 100 U/mL
(46%), insulin glargine 300 U/mL (22%), NPH insulin (21%), insulin detemir (7%), and insulin degludec (5%).
Efficacy endpoints
The two primary efficacy endpoints and all three key secondary efficacy endpoints were met. Mean ± SD baseline HbA1c was 8.6 ± 0.7 % (71 ± 7 mmol/mol) in the iGlarLixi group and 8.6 ± 0.7 % (70 ± 7 mmol/mol) in the BIAsp 30 group. At Week 26, mean ± SD
HbA1c had improved to 7.3 ± 1.1 % (56 ± 12 mmol/mol) in the iGlarLixi group and to 7.5 ±
1.0 % (58 ± 11 mmol/mol) in the BIAsp 30 group (Figure 1A and 1B). Statistical non- inferiority (margin 0.3 %) of iGlarLixi over BIAsp 30 was demonstrated for the change in
HbA1c from baseline to Week 26 (LS mean difference [97.5% CI] vs BIAsp 30: -0.2 [-0.4, -
0.1] %; -2.6 [-4.5, -0.9] mmol/mol; p<0.001). Additionally, statistical superiority in HbA1c reduction from baseline to Week 26 of iGlarLixi over BIAsp 30 was demonstrated as part of the key secondary endpoint analysis, on the basis of the hierarchical testing procedure
(Figure 1B).
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At baseline, mean ± SD bodyweight was 80.7 ± 16.5 kg in the iGlarLixi group and
82.2 ± 18.5 kg in the BIAsp 30 group. From baseline to Week 26, mean ± SD bodyweight
decreased to 80.2 ± 16.6 kg for iGlarLixi and increased to 83.4 ± 19.0 kg for BIAsp 30
(Figure 1C). Statistical superiority of iGlarLixi over BIAsp 30 was demonstrated for the
change in bodyweight from baseline to Week 26 (LS mean difference vs BIAsp 30 -1.9 [95%
CI -2.3, -1.4] kg; p<0.001).
Key secondary efficacy endpoints showed that, compared with the BIAsp 30 group, a
significantly greater proportion of participants in the iGlarLixi group reached HbA1c <7 %
(<53 mmol/mol) without weight gain at Week 26, and without weight gain at Week 26 and
without hypoglycemia (<70 mg/dL [<3.9 mmol/L]) during the treatment period (Figure 2).
The percentage of participants who reached HbA1c target <7 % was higher in the iGlarLixi
group than in the BIAsp 30 group (Figure 2, exploratory endpoint). iGlarLixi also
demonstrated higher proportions of HbA1c <7 % target achievement without ADA Level 2
hypoglycemia, HbA1c <7 % without weight gain of >1 kg, and HbA1c <6.5 % than BIAsp 30
(Figure 2, exploratory endpoints).
Mean ± SD FPG at baseline was 151 ± 44 mg/dL (8.4 ± 2.4 mmol/L) in the iGlarLixi
group and 149 ± 41 mg/dL (8.3 ± 2.3 mmol/L) in the BIAsp 30 group. At Week 26, mean ±
SD FPG was 130 ± 44 mg/dL (7.2 ± 2.4 mmol/L) in the iGlarLixi group and 146 ± 51 mg/dL
(8.1 ± 2.8 mmol/L) in the BIAsp 30 group. The LS mean difference (95% CI) between
groups in change from baseline to Week 26 was -16 (-26, -6) mg/dL (-0.9 [-1.5, -0.3]
mmol/L).
After 26 weeks, the increase in LS mean total daily insulin dose was smaller in the
iGlarLixi group than in the BIAsp 30 (Figure 1D). The percentage of participants who
required rescue therapy was low and similar for iGlarLixi (1.8%) and BIAsp 30 (2.3%).
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Detailed data for efficacy endpoints can be found in Supplementary Table 4. All key sensitivity analyses performed on the two primary and key secondary endpoints demonstrated similar results to those observed in the ITT population (Supplementary Table 5).
Safety profile
The proportion of participants with at least one hypoglycemic event was lower in the iGlarLixi group compared with the BIAsp 30 group (OR [95% CI] 0.62 [0.47, 0.81]) (Figure
3). Lower incidence of hypoglycemia with iGlarLixi versus BIAsp 30 was also observed across Level 1 and Level 2 hypoglycemia categories (Figure 3).
Rates of hypoglycemia followed the same pattern as incidence. There was an overall lower rate of any hypoglycemia with iGlarLixi compared with BIAsp 30, as well as lower rates of Level 1 and Level 2 hypoglycemia (Figure 3).
Three severe hypoglycemic episodes (Level 3) were reported: one occurred in the iGlarLixi group and two in the BIAsp 30 group.
In addition, lower incidence (OR [95% CI]: 0.37 [0.16, 0.84]) and event rates (RR
[95% CI]: 0.28 [0.11, 0.71]) of Level 2 nocturnal hypoglycemia (defined as occurring between bedtime and waking) were observed in the iGlarLixi group versus the BIAsp 30 group. Similar patterns were seen when using the between 00:00–06:00 h definition: lower incidence (OR [95% CI]: 0.32 [0.12, 0.90]) and event rates (RR [95% CI]: 0.30 [0.10, 0.88]) were seen with iGlarLixi versus BIAsp 30.
During the 26-week randomized treatment period, the percentage of participants who had at least one AE was slightly higher in the iGlarLixi group (32.6%) compared with the
BIAsp 30 group (27.7%), the difference being mainly due to the higher incidence of GI events in the iGlarLixi group (10.4% vs 2.3%). A large proportion of these GI events were reported in the first week of treatment (Supplementary Figure 3). The most commonly
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reported AE in the iGlarLixi group was nausea (7.7% vs 0% for BIAsp 30), while
nasopharyngitis was the most commonly reported AE in the BIAsp 30 group (2.7% vs 3.2%
for iGlarLixi). In both treatment groups, the majority of participants had AEs considered mild
or moderate in severity. SAEs were reported by a similar proportion of participants in both
treatment groups (2.7% iGlarLixi and 2.9% BIAsp 30). Overall, the rate of study
discontinuation due to an AE was low and similar in both treatment groups (0.9%). There
were two fatal AEs (acute coronary syndrome and cardiac failure/pulmonary edema) during
the study period, both in the BIAsp 30 group. Neither of these fatal AEs were considered
related to study treatment. During the study, no AEs were considered related to COVID-19.
Conclusions
This study is the first RCT comparing an FRC of basal insulin and a GLP-1 RA with
premix insulin. Results from this study provide evidence for the better efficacy and safety of
iGlarLixi compared with premix BIAsp 30 for advancing treatment in adults with
longstanding type 2 diabetes suboptimally controlled by basal insulin plus one or two OADs.
After 26 weeks, iGlarLixi demonstrated both non-inferiority (primary endpoint) and
statistical superiority (key secondary endpoint) to premix BIAsp 30 in HbA1c reduction and
statistical superiority in bodyweight change (primary endpoint). Although the LS mean
difference in HbA1c reduction was modest and may not represent a clinically meaningful
difference in isolation, a greater proportion of participants achieved HbA1c target <7 % (<53
mmol/mol) overall, as well as without weight gain or without weight gain and hypoglycemia
with iGlarLixi versus BIAsp 30, demonstrating the overall clinical benefit of iGlarLixi in
individuals with longstanding type 2 diabetes.
In addition, mean bodyweight decreased from baseline to Week 26 with iGlarLixi and
increased with premix BIAsp 30, with a significant between-group difference. Notably, better
glucose control (HbA1c and FPG) observed with iGlarLixi compared with premix BIAsp 30
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Premix RCT primary manuscript peer review 08 June 2021 was associated with a smaller mean daily insulin dose at Week 26 in the iGlarLixi group compared with the premix BIAsp 30 arm. The between-treatment differences in Week 26
FPG may also have contributed to the greater HbA1c reductions seen with iGlarLixi versus premix BIAsp 30; however, the lack of PPG data does limit our understanding of the cause of the between-treatment HbA1c change difference.
These results align with a previous network meta-analysis (NMA) by Home et al. comparing iGlarLixi versus basal-bolus or premix insulins (24). Results of this NMA estimated greater HbA1c reductions with iGlarLixi versus premix insulin (mean difference of
-0.50 [95% credible interval -0.93, -0.06] %), in addition to favorable bodyweight changes with iGlarLixi compared with premix insulin (-2.2 [-4.6, -0.1] kg) (24).
The improvements in glycemic control and reductions in bodyweight seen with iGlarLixi in this study are consistent with those observed in the LixiLan-L study, which compared efficacy and safety of iGlarLixi versus basal insulin in people with longstanding type 2 diabetes suboptimally controlled by basal insulin ± OAD therapy over 30 weeks (17). In
LixiLan-L, LS mean reduction in HbA1c from baseline was 1.1 %, while weight was reduced by 0.7 kg. Similarly, the glycemic control and bodyweight changes observed for premix
BIAsp 30 in the present study are consistent with previous RCTs of premix BIAsp 30 in adults with type 2 diabetes advancing basal insulin therapy (25-27).
The incidence of hypoglycemia reported in previous RCTs of iGlarLixi and premix
BIAsp 30 is difficult to compare with the current study due to the different definitions and blood glucose thresholds used (17; 26; 27). However, incidence of hypoglycemia in previous
RCTs was generally higher for both treatments (40% for iGlarLixi and ~70% for premix
BIAsp 30) than that observed in the present study (17; 26; 27), possibly due to the absence of sulfonylurea use in this study. It is, therefore, very encouraging that lower incidence and rates of hypoglycemia, including ADA Level 2 nocturnal hypoglycemia between bedtime and
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waking, were still observed with iGlarLixi versus premix BIAsp 30 in the present study,
despite iGlarLixi demonstrating better glycemic control.
Likewise, the overall safety and tolerability profiles of iGlarLixi and premix BIAsp 30
were comparable with those reported in previous studies (17-19; 26; 27), with very low
discontinuation rates due to AEs and no unexpected safety signals identified. The slightly
higher incidence of AEs observed for iGlarLixi versus premix BIAsp 30 in this study was due
to the higher incidence of nausea in the iGlarLixi group. Nausea incidence in this study is in
line with previous reports for FRCs (3.1%–10.4%) (17-22; 28), lower than previously
observed in participants initiating GLP-1 RAs alone (18; 20), and very rarely led to treatment
discontinuation (0.5%). Similarly, for both groups, low rates of SAEs were reported and few
participants required rescue therapy (~2%). No AEs were determined to be COVID-19-
related.
Following beta-cell decline in basal insulin-treated type 2 diabetes, prandial insulin is
often added to control postprandial hyperglycemia (29; 30). An alternative option is adding a
GLP-1 RA to basal insulin. Our results demonstrate that a co-formulation of basal insulin and
GLP-1 RA (iGlarLixi) is more efficacious than a co-formulation of a basal insulin and a
prandial insulin (premix BIAsp 30) when advancing therapy for people with type 2 diabetes
suboptimally controlled on basal insulin alone. In addition to improving clinical outcomes,
the lower incidence of hypoglycemia and the weight benefits observed with iGlarLixi may
improve patient satisfaction, which could improve treatment adherence. Assessment of
patient-reported outcomes from the current study is planned for future analyses. iGlarLixi
may also prove to be a cost-effective alternative to premix with fewer injections and less
glucose monitoring.
A key strength of the present analysis is the evidence base generated by it being the
first randomized head-to-head comparison of the efficacy and safety of an FRC of basal
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Premix RCT primary manuscript peer review 08 June 2021 insulin and a GLP-1 RA versus premix insulin in a clinically relevant population of adults with type 2 diabetes who were suboptimally controlled on basal insulin plus OADs.
Furthermore, it was a global study, including individuals with different ethnicities and from varying healthcare systems, without a glucose monitoring committee enforcing titrations and therefore provides relevant, clinically translatable information.
A potential limitation of this study is its open-label design. However, as the injectables could not be masked, a double-blind study design was impractical. Furthermore, iGlarLixi was tested against the most frequently used premix insulin ratio (30:70) but not against other premix ratios. However, hypoglycemia rates have been shown to be higher with other premix insulin regimens than with premix insulin 30/70 (31), so the benefits of iGlarLixi over other premix insulins could be even greater. A further potential limitation is that the COVID-19 pandemic occurred during the last few weeks of the study in some countries. Systems were put in place to ensure participant safety, retention and data capture.
Sensitivity analyses in a non-impacted by COVID-19 ITT population showed that COVID-19 was unlikely to have influenced the results of any endpoints assessed.
In conclusion, the once-daily FRC, iGlarLixi, is an efficacious and well-tolerated regimen that is simpler for the patient, providing better glycemic control with weight benefit and less hypoglycemia compared with premix BIAsp 30 as an alternative for advancing therapy in people with type 2 diabetes previously suboptimally controlled with basal insulin plus OADs.
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Acknowledgments
The authors thank the study participants, trial staff, and investigators for their participation. We
thank Elisabeth Souhami, MD (Sanofi) for a courtesy review from a medical and scientific
perspective, Mathieu Coudert, MSc (Sanofi) for a courtesy review from a statistical perspective
and Ana Merino-Trigo, PhD (Sanofi) for coordinating the development, facilitating author
discussions, and review of this manuscript. Editorial assistance was provided by Fishawack
Communications Ltd., part of Fishawack Health.
Funding
Sponsorship for this study was funded by Sanofi, Paris, France. Editorial assistance provided
by Fishawack Communications Ltd. was funded by Sanofi.
Author contributions
All named authors meet the International Committee of Medical Journal Editors (ICMJE)
criteria for authorship for this article. All authors participated in the interpretation of the data,
the writing, reviewing, and editing of the manuscript, and had final responsibility for approving
the published version. Julio Rosenstock, MD, and Pascaline Picard, MSc, are the guarantors of
this work and, as such, have full access to all the data in this study and take responsibility for
the integrity of the data and accuracy of the data analysis.
Disclosures
JR has served on advisory panels for Applied Therapeutics, Boehringer Ingelheim, Eli Lilly,
Intarcia, Janssen, Novo Nordisk, Oramed, Sanofi, and Zealand; and has received research
support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly,
Genentech, GlaxoSmithKline, Intarcia, Janssen, Lexicon, Merck, Novo Nordisk, Oramed,
Pfizer and Sanofi.
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RE has acted as an advisor and speaker for AstraZeneca, Boehringer Ingelheim, Lilly, MSD,
Novo Nordisk and Sanofi.
LSR has acted as an advisor and speaker for Novo Nordisk, Sanofi and Boehringer
Ingelheim.
NL has acted as a speaker for Sanofi, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo
Nordisk and Merck.
VM has served on advisory panels and has acted as a speaker for Abbott, Boehringer
Ingelheim, Eli Lilly, Merck (MSD), Novo Nordisk, Sanofi and several Indian pharmaceutical companies. He has also received research grants from some of these companies.
CT has been an investigator in clinical trials for Eli Lilly and Sanofi, and has acted as a speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk and Sanofi.
SAS has acted as an advisor and speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly,
MSD, Novartis, Novo Nordisk, and Sanofi.
ND, AA and MB are employees of Sanofi and may hold shares and/or stock options in the company.
PP is an employee of IVIDATA Life Sciences working as an external contractor on behalf of
Sanofi.
RM has acted as an advisor and speaker for advisory Sanofi and Novo Nordisk.
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References
1. American Diabetes A. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2021. Diabetes Care 2021;44:S73-S84 2. Davies M, D'Alessio D, Fradkin J, Kernan W, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler D, Buse J. Management of hyperglycaemic in type 2 diabetes, 2018. A consensus report by the American Diabetes Assocaition (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018;61:2461-2498 3. American Diabetes A. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2021. Diabetes Care 2021;44:S111-S124 4. Levin PA, Nguyen H, Wittbrodt ET, Kim SC. Glucagon-like peptide-1 receptor agonists: a systematic review of comparative effectiveness research. Diabetes, metabolic syndrome and obesity : targets and therapy 2017;10:123-139 5. Meece J. Basal insulin intensification in patients with type 2 diabetes: A review. Diabetes Ther 2018;9:877-890 6. Vijan S, Hayward RA, Ronis DL, Hofer TP. Brief report: the burden of diabetes therapy: implications for the design of effective patient-centered treatment regimens. J Gen Intern Med 2005;20:479-482 7. 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;29:682-689 8. Chang P. Datamonitor Healtchare – Diabetes type 2 disease analysis report. 2020; 9. Polinski JM, Kim SC, Jiang D, Hassoun A, Shrank WH, Cos X, Rodríguez-Vigil E, Suzuki S, Matsuba I, Seeger JD, Eddings W, Brill G, Curtis BH. Geographic patterns in patient demographics and insulin use in 18 countries, a global perspective from the multinational observational study assessing insulin use: understanding the challenges associated with progression of therapy (MOSAIc). BMC Endocr Disord 2015;15:46-46 10. Aschner P, Gagliardino JJ, Ilkova H, Lavalle F, Ramachandran A, Mbanya JC, Shestakova M, Chantelot JM, Chan JCN. Persistent poor glycaemic control in individuals with type 2 diabetes in developing countries: 12 years of real-world evidence of the International Diabetes Management Practices Study (IDMPS). Diabetologia 2020;63:711-721 11. Ji LN, Lu JM, Guo XH, Yang WY, Weng JP, Jia WP, Zou DJ, Zhou ZG, Yu DM, Liu J, Shan ZY, Yang YZ, Hu RM, Zhu DL, Yang LY, Chen L, Zhao ZG, Li QF, Tian HM, Ji QH, Liu J, Ge JP, Shi LX, Xu YC. Glycemic control among patients in China with type 2 diabetes mellitus receiving oral drugs or injectables. BMC Public Health 2013;13:602 12. Blonde L, Anderson JE, Chava P, Dendy JA. Rationale for a titratable fixed-ratio co-formulation of a basal insulin analog and a glucagon-like peptide 1 receptor agonist in patients with type 2 diabetes. Curr Med Res Opin 2019;35:793-804 13. Soliqua®: US prescribing information [article online], 2019. Available from http://products.sanofi.us/soliqua100-33/soliqua100-33.pdf. Accessed June 2020 14. Suliqua®: EU summary of product characteristics [article online], 2020. Available from https://www.ema.europa.eu/en/medicines/human/EPAR/suliqua. Accessed May 2020 15. Xultophy®: US prescribing information [article online], 2019. Available from https://www.novomedlink.com/content/dam/novonordisk/novomedlink/resources/generaldocume nts/Xultophy%20Prescribing%20Information%20-%20IFU.PDF. Accessed April 2021 16. Xultophy®: EU summary of product characteristics [article online], 2020. Available from https://www.ema.europa.eu/en/documents/product-information/xultophy-epar-product- information_en.pdf. Accessed April 2021 17. Aroda VR, Rosenstock J, Wysham C, Unger J, Bellido D, Gonzalez-Galvez G, Takami A, Guo H, Niemoeller E, Souhami E, Bergenstal RM, LixiLan-L Trial Investigators. Efficacy and safety of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide in type 2 diabetes inadequately
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Premix RCT primary manuscript peer review 08 June 2021 controlled on basal insulin and metformin: The LixiLan-L randomized trial. Diabetes Care 2016;39:1972-1980 18. Rosenstock J, Aronson R, Grunberger G, Hanefeld M, Piatti P, Serusclat P, Cheng X, Zhou T, Niemoeller E, Souhami E, Davies M. Benefits of LixiLan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide, versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled on oral agents: The LixiLan-O randomized trial. Diabetes Care 2016;39:2026-2035 19. Blonde L, Rosenstock J, Del Prato S, Henry R, Shehadeh N, Frias J, Niemoeller E, Souhami E, Ji C, Aroda VR. Switching to iGlarLixi versus continuing daily or weekly GLP-1 RA in type 2 diabetes inadequately controlled by GLP-1 RA and oral antihyperglycemic therapy: The LixiLan-G randomized clinical trial. Diabetes Care 2019;42:2108-2116 20. Gough SC, Bode B, Woo V, Rodbard HW, Linjawi S, Poulsen P, Damgaard LH, Buse JB. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. The lancet Diabetes & endocrinology 2014;2:885-893 21. Buse JB, Vilsbøll T, Thurman J, Blevins TC, Langbakke IH, Bøttcher SG, Rodbard HW. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care 2014;37:2926-2933 22. Linjawi S, Bode B, Chaykin L, Courreges J, Handelsman Y, Lehmann L, Mishra A, Simpson R. The efficacy of IDegLira (insulin degludec/liraglutide combination) in adults with type 2 diabetes inadequately controlled with a GLP-1 receptor agonist and oral therapy: DUAL III randomized clinical trial. Diabetes Ther 2017;8:101-114 23. McCrimmon R, Al Sifri S, Emral R, Mohan V, Sauque-Reyna L, Trescoli C, Lalic N, Alvarez A, Demil N, Coudert M, Shaunik A, Bonnemaire M, Rosenstock J. Advancing therapy with iGlarLixi versus Premix 70/30 in basal insulin-treated type 2 diabetes: Design and baseline characteristics of the SoliMix randomised controlled trial. Diabetes Obes Metab 2021;Online ahead of print; doi:10.1111/dom.14354 24. Home P, Blonde L, Kalra S, Ji L, Guyot P, Brulle-Wohlhueter C, Murray E, Shah R, Sayre T, Shaunik A. Insulin glargine/lixisenatide fixed-ratio combination (iGlarLixi) compared with premix or addition of meal-time insulin to basal insulin in people with type 2 diabetes: A systematic review and Bayesian network meta-analysis. Diabetes Obes Metab 2020;22:2179-2188 25. Liebl A, Prager R, Binz K, Kaiser M, Bergenstal R, Gallwitz B. Comparison of insulin analogue regimens in people with type 2 diabetes mellitus in the PREFER Study: a randomized controlled trial. Diabetes Obes Metab 2009;11:45-52 26. Jin SM, Kim JH, Min KW, Lee JH, Ahn KJ, Park JH, Jang HC, Park SW, Lee KW, Won KC, Kim YI, Chung CH, Park TS, Lee JH, Lee MK. Basal-prandial versus premixed insulin in patients with type 2 diabetes requiring insulin intensification after basal insulin optimization: A 24-week randomized non-inferiority trial. Journal of diabetes 2016;8:405-413 27. Ligthelm RJ, Gylvin T, DeLuzio T, Raskin P. A comparison of twice-daily biphasic insulin aspart 70/30 and once-daily insulin glargine in persons with type 2 diabetes mellitus inadequately controlled on basal insulin and oral therapy: a randomized, open-label study. Endocr Pract 2011;17:41-50 28. Lingvay I, Pérez Manghi F, García-Hernández P, Norwood P, Lehmann L, Tarp-Johansen MJ, Buse JB. Effect of insulin glargine up-titration vs insulin degludec/liraglutide on glycated hemoglobin levels in patients with uncontrolled type 2 diabetes: The DUAL V randomized clinical trial. Jama 2016;315:898-907 29. LaSalle J, Berria R. Insulin therapy in type 2 diabetes mellitus: A practical approach for primary care physicians and other health care professionals. J Am Osteopath Assoc 2013;113:152-163 30. Lin J, Linghor-Smith M, Fan T. Real-world medication persistence and outcomes associated with basal insulin and glucagon-like peptide 1 receptor agonist free-dose combination therapy in patients with type 2 diabetes in the US. Clinicoecon Outcomes Res 2017;9:19-29
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31. Tibaldi J. Intensifying insulin therapy in type 2 diabetes mellitus: Dosing options for insulin analogue premixes. Clin Ther 2011;33:1630-1642
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Tables
Table 1. Abbreviated baseline characteristics (Randomized population) Demographic/clinical characteristic iGlarLixi BIAsp 30 All participants
(n=443) (n=444) (N=887)
Age (years)
Mean ± SD 59.8 ± 10.3 59.8 ± 10.0 59.8 ± 10.2
Median 61 60 61
(Q1, Q3) (52, 67) (54, 67) (53, 67)
Sex, n (%)
Male 224 (50.6) 218 (49.1) 442 (49.8)
Female 219 (49.4) 226 (50.9) 445 (50.2)
BMI (kg/m2)
Mean ± SD 29.7 ± 4.7 30.0 ± 5.1 29.9 ± 4.9
Median 29.1 29.2 29.1
(Q1, Q3) (26.2, 32.9) (26.2, 34.2) (26.2, 33.6)
Duration of type 2 diabetes (years)
Mean ± SD 13.0 ± 7.1 13.0 ± 7.4 13.0 ± 7.2
Median 12.0 12.0 12.0
(Q1, Q3) (7.6, 17.0) (7.2, 17.0) (7.5, 17.0)
Prior basal insulin at baseline*, n (%)
Insulin glargine 100 U/mL 188 (42.4) 219 (49.2) 407 (45.8)
Insulin glargine 300 U/mL 100 (22.6) 92 (20.7) 192 (21.6)
NPH 102 (23.0) 82 (18.4) 184 (20.7)
Insulin detemir 34 (7.7) 31 (7.0) 65 (7.3)
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Insulin degludec 19 (4.3) 21 (4.7) 40 (4.5)
Average basal insulin daily dose (U)†
Mean ± SD 33.8 ± 9.6 33.8 ± 9.9 33.8 ± 9.8
Median 34.0 34.0 34.0
(Q1, Q3) (25.0, 40.0) (24.0, 42.0) (25.0, 40.0)
Average basal insulin daily dose (U/kg)†
Mean ± SD 0.43 ± 0.15 0.43 ± 0.14 0.43 ± 0.14
Median 0.42 0.42 0.42
(Q1, Q3) (0.32, 0.52) (0.32, 0.51) (0.32, 0.52)
Previous non-insulin antihyperglycemic
treatment*, n (%)
Metformin 443 (100.0) 442 (99.5) 885 (99.8)
SGLT2i 104 (23.5) 102 (23.0) 206 (23.2)
Other 1 (0.2) 2 (0.5) 3 (0.3)
Daily metformin dose at baseline (mg)
Mean ± SD 1761 ± 542 1722 ± 549 1741 ± 546
Median 2000 1850 2000
(Q1, Q3) (1500, 2000) (1500, 2000) (1500, 2000)
Diabetes-related complications, n (%)
Diabetic neuropathy 119 (26.9) 127 (28.6) 246 (27.7)
Diabetic retinopathy (incl. proliferative 67 (15.1) 67 (15.1) 134 (15.1)
diabetic retinopathy)
Diabetic nephropathy 45 (10.2) 41 (9.2) 86 (9.7)
Heart failure 11 (2.5) 8 (1.8) 19 (2.1)
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Peripheral artery disease 2 (0.5) 9 (2.0) 11 (1.2)
Ischemic stroke 2 (0.5) 0 2 (0.2)
Full baseline characteristics have been reported previously (22). *A participant can be counted in more than 1 category. †Within the 3 days immediately before randomization. BIAsp 30, biphasic aspart insulin 30 (30% insulin aspart and 70% insulin aspart protamine); BMI, body mass index; iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide-1 receptor agonist, lixisenatide; NPH, neutral protamine Hagedorn insulin; OAD, oral antihyperglycemic drug; Q, quartile; SD, standard deviation; SGLT2i, sodium-glucose cotransporter 2 inhibitor.
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Figure legends
Figure 1. (A) HbA1c over 26 weeks and (B) change in HbA1c, (C) bodyweight and (D) total
insulin daily dose from baseline to Week 26 (ITT population)
Missing data in the primary HbA1c and weight endpoints were imputed through a multiple imputation (MI) strategy under the missing not at random (MNAR) framework, with separate MI process function of treatment completeness. Missing values were imputed 1000 times. †Non-inferiority p value was calculated using a non-inferiority margin of 0.3 %. BIAsp 30, biphasic aspart insulin 30 (30% insulin aspart and 70% insulin aspart protamine); BL, baseline; CI, confidence interval; iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide-1 receptor agonist, lixisenatide; ITT, intention-to- treat; LS, least squares; SE, standard error, SD, standard deviation; W, week.
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Figure 2. Glycemic target achievement and composite secondary efficacy endpoints (ITT population).
*Adjusted odds ratio of iGlarLixi versus BIAsp 30 with associated 2-sided CI (at the specified significance level that is passed from family 1 of the primary objectives), calculated by logistic regression model adjusted for fixed categorical effects of randomization strata (basal insulin dose at screening <30 U and ≥30 U; and SGLT2 inhibitor use [Yes, No] at screening) and treatment group as well as fixed continuous covariates of baseline values for each of the primary endpoints (HbA1c and bodyweight). †Imputed as not having reached HbA1c target (failure, ie. non-responder) in the case of missing HbA1c or weight values at Week 26. ‡Weight gain defined as any increase >0 kg from baseline. §Hypoglycemia defined as plasma glucose <70 mg/dL (<3.9 mmol/L) occurring at any point within the 26-week open-label randomized treatment period.
BIAsp 30, biphasic aspart insulin 30 (30% insulin aspart and 70% insulin aspart protamine); CI, confidence interval; iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide-1 receptor agonist, lixisenatide; ITT, intention-to-treat; n, number of participants; OR, odds ratio. Assessments were done in hierarchical order, starting with the proportion of participants who reached HbA1c <7 % without weight gain.
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Figure 3. (A) Incidence and (B) rates of hypoglycemic events over the 26-week treatment
period (Safety population).
*A participant can have more than one documented event. †Odds ratio for iGlarLixi versus BIAsp 30 and 95% CI based on logistic regression with treatment group (iGlarLixi and BIAsp 30) and randomization strata (HbA1c <8.0 % and ≥8.0 %; basal insulin dose at screening <30 U and ≥30 U; and SGLT2 inhibitor use [Yes, No] at screening) as fixed effects. ‡Rate ratio for iGlarLixi versus BIAsp 30 and 95% CI estimated from a negative binomial regression model with a log-link function, and the log of the time period in which a hypoglycemia episode is considered treatment emergent as offset. The model included fixed effect terms for treatment group (iGlarLixi and BIAsp 30) and randomization strata (HbA1c <8.0 % and ≥8.0 %; basal insulin dose at screening <30 U and ≥30 U; and SGLT2 inhibitor use [Yes, No] at screening).
ADA, American Diabetes Association; BIAsp 30, biphasic aspart insulin 30 (30% insulin aspart and 70% insulin aspart protamine); CI, confidence interval; iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide-1 receptor agonist, lixisenatide; n, number of participants; OR, odds ratio; PPY, per participant-year; RR, rate ratio.
CONFIDENTIAL-For Peer Review Only A C BIAsp 30 iGlarLixi HbA1c (%), mean ± SE 6.5 7.0 7.5 8.0 8.5 9.0 bodyweight, kg n=444 n=443 BL Mean ±SD Week 26
LS mean ± SE change in bodyweight from Baseline baseline to Week 26, kg -0.5 -1.5 -1.0 0.0 0.5 1.0 1.5 2.0 LS meandifference iGlarLixi 02±1. 83.4±19.0 80.2 ±16.6 80.7 ±16.5 -1.9 (-2.3, -1.4)kg;<0.001 -0.7 ±0.2 iGlarLixi (n=443) vs BIAsp30(95% CI); superiority p-value: n=428 n=440 W12 82.2 ±18.5 BIAsp 30 1.2 ±0.2 (n=444) CONFIDENTIAL-For PeerReviewOnly BIAsp 30 iGlarLixi n=414 n=429 W26 Diabetes Care B D 48 52 56 60 64 68 72
insulin dailydose, U
1c (mmol/mol), mean ± SE ± mean (mmol/mol), HbA Mean ±SDtotal baseline HbA Mean ±SD mmol/mol Week 26 Baseline LS mean ± SE change in total insulin LS mean ± SE change in HbA1c from daily dose from baseline to Week 26, U baseline to Week 26, % 10.0 15.0 20.0 25.0 30.0 -1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 5.0 0.0 % 1c vs BIAsp30(97.5%CI);p-value vs BIAsp30(95%CI);p-value LS meandifferenceiGlarLixi LS meandifferenceiGlarLixi LS meandifferenceiGlarLixi -1.3 ±0.1% 97±1. 58.2±23.6 39.7 ± 12.0 -0.2 (-0.4,-0.1)%;<0.001 26.4 ±6.2 10.6 ±1.2 -0.2 (-0.4,-0.1)%;<0.001 iGlarLixi iGlarLixi 8.6 ±0.7 (n=443) (n=442) 1±770±7 71 ±7 vs BIAsp30(95%CI): -12.2 (-14.8,-9.7)U Non-inferiority: Superiority: -1.1 ±0.1% 33.6 ±11.0 22.9 ±1.1 BIAsp 30 BIAsp 30 8.6 ±0.7 (n=444) (n=441) Page 28of43 †
-18.0 -16.0 -14.0 -12.0 -10.0 -8.0 -6.0 -4.0 -2.0 0.0 -20.0
baseline to Week 26, mmol/mol 26, Week to baseline
1c LS mean ± SE change in HbA in change SE ± mean LS from PageiGlarLixi 29 of (n=443)43 Diabetes Care OR (95% CI)*; % (n) p value Favors Favors BIAsp 30 (n=444) (adjusted) BIAsp 30 iGlarLixi Key Secondary Endpoints
27.5 (n=122) Participants who reached HbA1c <7 % 2.83 (1.98, 4.04); †‡ without weight gain 12.4 (n=55) p<0.001
19.4 (n=86) Participants who reached HbA1c <7 % without 3.40 (2.19, 5.28); †§ weight gain and without hypoglycemia 7.0 (n=31) p<0.001
Other target achievement
42.2 (n=187) Participants who reached HbA1c <7 % 1.65 (1.25, 2.19) 31.8 (n=141)
20.3 (n=90) Participants who reached HbA1c <6.5 % 1.95 (1.35, 2.84) 11.9 (n=53)
Participants who reached HbA1c <7 % 39.5 (n=175) without ADA Level 2 hypoglycemia 1.90 (1.42, 2.54) (<54 mg/dL [<3.0 mmol/L]) 26.6 (n=118)
Participants who reached HbA <7 % 31.8 (n=141) 1c 2.26 (1.64, 3.12) without weight gain >1 kg 17.8 (n=79) CONFIDENTIAL-For Peer Review Only 0 20 40 60 80 100 0.1 1 10 % OR (95% CI) A Diabetes Care Page 30 of 43 Relative odds iGlarLixi (n=442) reduction iGlarLixi Incidence, % (n) Favors Favors BIAsp 30 (n=441) vs BIAsp 30 OR† (95% CI) iGlarLixi BIAsp 30
31.2 (n=138) Any hypoglycemic event* 38% 42.4 (n=187) 0.62 (0.47, 0.81)
Level 1 hypoglycemia 25.8 (n=114) (ADA definition: <70 mg/dL [<3.9 mmol/L] 45% 38.5 (n=170) and ≥54 mg/dL [≥3.0 mmol/L]) 0.55 (0.42, 0.74)
6.3 (n=28) Level 2 hypoglycemia 55% (ADA definition: <54 mg/dL [<3.0 mmol/L]) 12.9 (n=57) 0.45 (0.28, 0.73)
0 20 40 60 80 100 0.10 1.00 Incidence, % OR (95% CI)
B Relative rate iGlarLixi (223.15 PY) reduction iGlarLixi Rate, PPY (events) BIAsp 30 (217.85 PY) vs BIAsp 30 Favors Favors RR‡ (95% CI) iGlarLixi BIAsp 30
2.63 (587) Any hypoglycemic event* 33% 3.90 (850) 0.67 (0.49, 0.91)
Level 1 hypoglycemia 2.03 (453) (ADA definition: <70 mg/dL [<3.9 mmol/L] 29% 2.83 (616) and ≥54 mg/dL [≥3.0 mmol/L]) 0.71 (0.52, 0.99)
0.25 (56) Level 2 hypoglycemia 60% (ADA definition: <54 mg/dL [<3.0 mmol/L]) 0.56 (121) 0.40 (0.23, 0.71) CONFIDENTIAL-For Peer Review Only 0 2 4 6 8 10 0.10 1.00 Rate, PPY RR (95% CI) Page 31 of 43 Diabetes Care
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Supplementary Material
Supplementary Figure 1. Diagram of multiplicity testing approach.
1-a: Non-inferiority of iGlarLixi versus BIAsp 30 on HbA1c change from baseline to Week 26; 1-b: Superiority of iGlarLixi versus BIAsp 30 on bodyweight change from baseline to
Week 26; 2a: Proportion of participants reaching HbA1c target <7 % without weight gain at Week 26; 2b: Proportion of participants reaching HbA1c target <7 % without hypoglycemia, and without weight gain at Week 26; 2-c: HbA1c reduction from baseline at Week 26. Alpha will be allocated equally among both primary hypotheses (1-a and 1-b). Test 1-a and 1-b at alpha/2 each; a. If 1-a is significant, alpha/2 is passed from 1-a to 1-b and 1-b is tested at the full alpha level. If significant, the full alpha is passed to test hierarchically 2-a, 2-b and 2-c at full alpha, each.
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b. If 1-a is not rejected, but 1-b is rejected at alpha/2 level, test hierarchically 2-a, 2-b at alpha/2 i. If significant, use a fallback procedure to pass alpha/2 back to 1-a and re-test 1-a at an alpha level. ii. If 1-a is rejected at the alpha level, test 2-c at the full alpha level. Essentially, 1-a, 1-b and 2-a and 2-b are put in a box as a gatekeeper for testing 2-c: 2-c can be tested only if 1-a, 1-b, 2-a and 2-b are all rejected.
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Supplementary Figure 2. Participant disposition
BIAsp 30, biphasic aspart insulin 30 (30% insulin aspart and 70% insulin aspart protamine); iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide-1 receptor agonist, lixisenatide; ITT, intention-to-treat; PP, per protocol.
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Supplementary Figure 3. Onset gastrointestinal adverse events reported over time (Safety population)
AE, adverse events; BIAsp 30, biphasic aspart insulin 30 (30% insulin aspart and 70% insulin aspart protamine); GI, gastrointestinal; iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide-1 receptor agonist, lixisenatide.
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Supplementary Table 1. Starting doses of iGlarLixi from iGlar*
Previous therapy
iGlar iGlar
≥20 U to <30 U ≥30 U to ≤50 U
Starting dose and pen iGlarLixi 20 dose steps
10–40 pen† (20 U iGlar/10 μg Lixi)
iGlarLixi 30 dose steps
30–60 pen† (30 U iGlar/10 μg Lixi)
*If switching from twice-daily basal insulin or insulin glargine 300 U/mL, the total daily dose previously used should be reduced by 20% to choose the starting dose of iGlarLixi; for any other BI, the same dosing should be followed as shown above for iGlar. †Suliqua®, Sanofi, Paris, France. BI, basal insulin; GLP-1 RA, glucagon-like 1 receptor agonist; iGlar, insulin glargine 100 U/mL; iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon- like peptide-1 receptor agonist, lixisenatide; Lixi, lixisenatide; mcg, micrograms; OAD, oral antihyperglycemic drug; U, units.
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Supplementary Table 2. Recommended dose adjustment algorithm for iGlarLixi
Median of fasting SMPG values from the last iGlarLixi* dose adjustments
three measurements (U/day)
>140 mg/dL (>7.8 mmol/L) +4
>110 to ≤140 mg/dL (>6.1 to ≤7.8 mmol/L) +2
Glycemic target: ≥80 to ≤110 mg/dL (≥4.4 to No change
≤6.1 mmol/L)
≥60 and <80 mg/dL (≥3.3 to <4.4 mmol/L) -2
<60 mg/dL (<3.3 mmol/L) or occurrence of ≥2 -2 to -4 or at the investigator’s symptomatic hypoglycemic episodes or 1 severe discretion (or medically qualified hypoglycemic episode (requiring assistance) in the designee) preceding week
*The U/day refers solely to the iGlar component of iGlarLixi. iGlar, insulin glargine 100 U/mL; iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide-1 receptor agonist, lixisenatide; SMPG, self-monitored plasma glucose; U, units.
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Supplementary Table 3. Recommended dose adjustment algorithm for BIAsp 30
Premeal SMPG values* BIAsp 30 dose adjustments
(U/day)
<80 mg/dL (<4.4 mmol/L) –2
Glycemic target: 80–110 mg/dL (4.4–6.1 mmol/L) No change
111–140 mg/dL (6.2–7.8 mmol/L) +2
141–180 mg/dL (7.9–10.0 mmol/L) +4
>180 mg/dL (>10 mmol/L) +6
*Titration was based on the lowest of pre-meal SMPG values of the previous 3 days, using pre-dinner SMPG values for breakfast dose adjustment and pre-breakfast SMPG values for the dinner dose adjustment. The dose was not to be increased if hypoglycemia occurred within these days. BIAsp 30, biphasic aspart insulin 30 (30% insulin aspart and 70% insulin aspart protamine); SMPG, self-monitored plasma glucose; U, units.
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Supplementary Table 4. Primary and secondary efficacy endpoints (ITT population) iGlarLixi BIAsp 30 (n=443) (n=444) Primary efficacy endpoints
HbA1c, % Baseline, mean ± SD 8.61 ± 0.67 8.57 ± 0.65 Week 26, mean ± SD 7.26 ± 1.06 7.48 ± 0.99 Change from baseline to Week 26, mean ± SD -1.36 ± 1.06 -1.09 ± 1.02 LS mean change from baseline to Week 26 ± SE -1.30 ± 0.06 -1.05 ± 0.06 LS mean difference (97.5% CI)* -0.24 (-0.41, -0.08)
p value for non-inferiority† p<0.001
LS mean difference (95% CI)‡ -0.24 (-0.39, -0.10)
p value for superiority§ p<0.001
HbA1c, mmol/mol Baseline, mean ± SD 70.6 ± 7.3 70.2 ± 7.1 Week 26, mean ± SD 55.8 ± 11.5 58.2 ± 10.8 Change from baseline to Week 26, mean ± SD -14.8 ± 11.6 -11.9 ± 11.1 LS mean change from baseline to Week 26 ± SE -14.2 ± 0.7 -11.5 ± 0.7 LS mean difference (97.5% CI)* -2.6 (-4.5, -0.9) p value for non-inferiority† p<0.001 LS mean difference (95% CI)‡ -2.6 (-4.3, -1.1) p value for superiority§ p<0.001 Bodyweight, kg Baseline, mean ± SD 80.7 ± 16.5 82.2 ± 18.5 Week 26, mean ± SD 80.2 ± 16.6 83.4 ± 19.0 Change from baseline to Week 26, mean ± SD -0.6 ± 3.1 +1.3 ± 3.1 LS mean change from baseline to Week 26 ± SE -0.70 ± 0.20 +1.15 ± 0.20 LS mean difference (95% CI)‡ -1.86 (-2.28, -1.43)
p value for superiority† p<0.001 Key secondary efficacy endpoints
§ HbA1c <7 % without weight gain‡
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n (%) 122 (27.5) 55 (12.4)
Odds ratio (95% CI) 2.83 (1.98, 4.04) p value for superiority p<0.001
HbA1c <7 % without weight gain or hypoglycemia (plasma glucose <70 mg/dL [<3.9 mmol/L])‡§
n (%) 86 (19.4) 31 (7.0) Odds ratio (95% CI) 3.40 (2.19, 5.28) p value for superiority p<0.001 Other secondary efficacy endpoints FPG, mmol/L Baseline, mean ± SD 8.37 ± 2.42 8.25 ± 2.28 Week 26, mean ± SD 7.22 ± 2.44 8.10 ± 2.84 Change from baseline to Week 26, mean ± SD -1.12 ± 2.88 -0.16 ± 3.33 LS mean change from baseline to Week 26 ± SE -1.07 ± 0.24 -0.16 ± 0.27 LS mean difference (95% CI) -0.91 (-1.47, -0.34) Total insulin dose, U§ Baseline, mean ± SD 26.4 ± 6.2 33.6 ± 11.0 Week 26, mean ± SD 39.7 ± 12.0 58.2 ± 23.6 Change from baseline to Week 26, mean ± SD 13.4 ± 10.3 24.5 ± 20.8 LS mean change from baseline to Week 26 ± SE 10.6 ± 1.2 22.9 ± 1.1 LS mean difference (95% CI) -12.2 (-14.8, -9.7)
§ HbA1c <7 % n (%) 187 (42.2) 141 (31.8) Odds ratio (95% CI) 1.65 (1.25, 2.19) *Endpoint was assessed at the alpha 0.025 level. †Primary efficacy endpoints, non-inferiority of HbA1c reduction was assessed using a margin of 0.3 %; ‡Endpoint was assessed at the alpha 0.05 level. §Secondary endpoint. BIAsp 30, biphasic aspart insulin 30 (30% insulin aspart and 70% insulin aspart protamine); CI, confidence interval; FPG, fasting plasma glucose; iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide-1 receptor agonist, lixisenatide; ITT, intention-to-treat population; LS, least squares; SD, standard deviation; SE, standard error.
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Supplementary Table 5. Sensitivity analyses of the primary and key secondary efficacy endpoints iGlarLixi BIAsp 30
HbA1c, % PP population n=361 n=344 LS mean difference (95% CI)*† -0.15 (-0.29, -0.01) MMRM analysis n=443 n=444 LS mean difference (95% CI)*† -0.20 (-0.33, -0.07) Penalized multiple imputation n=443 n=444 LS mean difference (95% CI)*† -0.24 (-0.38, -0.09) Multiple imputation for COVID-19 impacted n=443 n=444 participants LS mean difference (95% CI)*† -0.24 (-0.39, -0.09) ANCOVA during the on-treatment period n=443 n=444 LS mean difference (95% CI)*† -0.20 (-0.33, -0.07) Non-impacted by COVID-19 population (n=403) (n=404) LS mean difference (95% CI)*† -0.25 (-0.41, -0.10) Bodyweight, kg MMRM analysis n=443 n=444 LS mean difference (95% CI) -1.87 (-2.28, -1.46) p value for superiority p<0.001 Multiple imputation for COVID-19 impacted n=443 n=444 participants LS mean difference (95% CI) -1.85 (-2.29, -1.41) p value for superiority p<0.001 ANCOVA during the on-treatment period n=443 n=444 LS mean difference (95% CI) -1.89 (-2.31, -1.47) p value for superiority p<0.001 Non-impacted by COVID-19 population (n=403) (n=404) LS mean difference (95% CI) -1.85 (-2.31, -1.40) p value for superiority p<0.001
HbA1c <7 % without weight gain Non-impacted by COVID-19 population (n=403) (n=404)
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n (%) 110 (27.3) 53 (13.1) Odds ratio (95% CI) 2.58 (1.79, 3.73) p value for superiority p<0.001
HbA1c <7 % without weight gain or hypoglycemia (plasma glucose <70 mg/dL [<3.9 mmol/L]) Not-impacted by COVID-19 population (n=403) (n=404) n (%) 76 (18.9) 29 (7.2) Odds ratio (95% CI) 3.16 (2.00, 5.00) p value for superiority p<0.001 All endpoints were assessed at the alpha 0.05 level. *Non-inferiority objective confirmed. †Superiority objective confirmed. PP: same ANCOVA model as described for the primary analysis in the PP population (no imputation necessary since patients with missing HbA1c were excluded from PP). MMRM: MMRM under the missing at random framework was carried out using an adequate contrast at Visit 10 (Week 26), based on ITT population. Penalized multiple imputation: same ANCOVA model as described for the primary analysis with multiple imputation. A penalty of 0.3 % was added to missing HbA1c values in the iGlarLixi group only. Missing related to COVID-19 were not penalized. Multiple imputation for COVID-19 impacted participants: same ANCOVA model as described for the primary analysis in the ITT population, with separate multiple imputation process for COVID-19 impacted and non- impacted patients. Missing data in COVID-19 non-impacted patients were imputed with the same approach as primary analysis (Missing Not At Random). COVID-19 impacted patients were imputed using multiple imputation under the Missing At Random framework. ANCOVA during the on-treatment period: same ANCOVA as primary analysis in the ITT population during the on-treatment period. Only assessments before IMP discontinuation or introduction of the rescue therapy were considered in this analysis. Non-impacted by COVID-19 population: analyzed using the same methodology as primary analysis in the ITT not impacted by COVID- 19 population. ANCOVA, analysis of covariance; BIAsp 30, biphasic aspart insulin 30 (30% insulin aspart and 70% insulin aspart protamine); CI, confidence interval; iGlarLixi, a fixed- ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide-1 receptor agonist, lixisenatide; IMP, investigational medicinal product; ITT, intention-to-treat; LS, least squares; MMRM, mixed effect repeated measure; PP, per protocol.
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Supplementary Materials List of participating investigators Argentina Silvia Ines Orio; Gustavo Frechtel; Patricia Castaño; Jimena Coronel; Lucas Rista Austria Rudolf Prager; Slobodan Peric; Christoph Ebenbichler; Clemens Engel Bulgaria Dimitar Georgiev; Nkolay Botushanov; Yulia Kavarmova-Toneva; Ghassan Farah; Svilen Stanchev; Atanas Milev; Kiril Kirilov; Dimo Dimov; Petya Goicheva; Zahari Nikitov; Antoaneta Zlateva-Nikolaeva; Tundzhay Yozturk; Darina Vasileva; Valentina Zhelyazkova Czech Republic Dana Burdova; Marcela Szabo; Marcela Bacterova; Zuzana Kubikova; Katerina Smolenakova; Romana Urbanova; Jan Vrkoc; Tomas Spousta; Romana Urbanova; Jitka Zemanova; Silvie Lacigova; Dagmar Bartaskova; Jana Kostarova; Klaudia Halova- Karoliova; Jan Skopecek; Peter Gajdos; Tomas Edelsberger; Alica Vesela; Edita Novakova Greece Alexandros Kokkinos; Christos Sampanis; Alexandra Bargiota; Stilianos Tigas India Balamurugan Ramanathan; Paturi Rao; Rakesh Sahay; Manish Gutch; Teju Velkoor; Srinivasa Murthy; Parminder Singh; Viswanathan Mohan; Vasudha Sardesai; Farishta Faraz; Saurabh Agarwal; Pravin Supe; Kingdom of Saudi Arabia Abdulrahman Almaghamsi Kuwait Ebaa Al Ozairi; Monira Al Arouj; Abdullah Bin Nakhi; Dherar Al roudhan Mexico Ricardo Choza Romero; Leobardo Sauque Reyna; Jose Gerardo Gonzalez Gonzalez; Enrique Ortiz Jiminez; Emilia Susana Pelayo Orozco North Macedonia Bekjir Mahmudi; Dusica Stefanovska; Vjosa Xhaferi; Zulkjufli Misimi; Cvetanka Volkanovska Ilijevska; Daniela Doneva; Hasan Taner; Ivana Trajkovska; Natasha Nedevska Minova; Iskra Bitoska Mileva; Ivica Smokovski; Katerina Adamova; Sasha Jovanovska Michevska; Tatjana Milenkovikj; Ljiljana Necevska Romania Mihaela Voitec; Alina Mot; Amorin Popa; Eduard Adamescu Serbia Radivoj Kocic; Sasa Radenkovic; Jelica Bjekic-Macut; Tijana Petrović; Aleksandar Djukic; Ivana Djokic; Jelena Petrovic; Katarina Asanin; Biljana Jojic; Jelena Stojanovic; Marina Anđelic Jelic; Milica Marjanovic Petkovic; Miljanka Vuksanovic; Teodora Beljic Zivkovic; Aleksandra Jotic; Ljiljana Lukic; Marija Macesic; Milica Stoiljkovic; Nebojsa Lalic; Tanja Milicic; Milica Pesic; Sanja Curkovic; Sonja Kostic South Korea Kyung Mook Choi; Nan Hee Kim; Kyung Wan Min; Ji Hyun Lee; Eun-Gyoung Hong; Soon- Jib Yoo; Young Min Cho; Hyuk-Sang Kwon; Sang Yong Kim; In-Kyu Lee Spain Pedro De Pablos; Carlos Trescoli; Ana Silvia Pellitero; Daniel De Luis; Andreea Ciudin; Edelmiro Mendez; Marta Botella Sweden Hans Larnefeldt; Gunnar Strömblad; Ingemar Torstensson Taiwan
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Ching-Chu Chen; Shu-Yi Wang; Kai-Jen Tien; Chen-Ling Huang; Shuen-Fu Weng; Chii- Min Hwu; Horng-Yih Ou Turkey Fahri Bayram; Adil Begüm Bahçecioğlu Mutlu; Rıfat Emral; Fatma Nur Korkmaz; Abdurrahman Çömlekçi; Başak Saydam; Cem Adıyaman; Tevfik Demir; Canan Ersoy; Soner Cander; Emre Gezer; Zeynep Cantürk; Cem Onur Kirac; Levent Kebapcılar; Suleyman Ipekci; Gulay Simsek Bagir; Okan Sefa Bakiner;
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