Slide share soliqua 070320

iGlar and lixisenatide simultaneous versus
sequential administration: comparison of LixiLan
and GetGoal Duo trials
Published in full:
Rosenstock J et al. Propensity score matched comparative analyses
of simultaneously administered fixed
lixisenatide (iGlarLixi) vs sequential administration of insulin glargine
and lixisenatide in uncontrolled type 2 diabetes. Diabetes Obes Metab
2018;20:2821 2829
Presented as posters at EASD 2017:
Rosenstock J et al. Diabetologia 2017;60(Suppl. 1):1 608
ePoster 795
Meier J et al. Diabetologia 2017;60(Suppl. 1):1 608
ePoster 808
Simultaneous versus sequential:
Objective and methods
Rosenstock J et al. Diabetes Obes Metab 2018;20:2821 2829
Objective
To conduct two exploratory analyses to compare indirectly the efficacy and safety of
simultaneous administration of iGlar and lixisenatide as a single-pen, titratable, fixed-
ratio combination (iGlarLixi, LixiLan trials) versus sequential administration of iGlar +
lixisenatide (GetGoal Duo trials) in people with T2D
Methods
Indirect exploratory PSM comparison of simultaneous versus sequential administration
iGlar + lixisenatide (GetGoal Duo-1) versus iGlarLixi (LixiLan-O) in insulin-naïve
patients with OAD failure
iGlar + lixisenatide (GetGoal Duo-2) and iGlarLixi (LixiLan-L) in patients with basal
insulin failure
Baseline covariates for PSM included age, race, BMI, HbA1c, FPG, diabetes duration,
and OAD/metformin use
BMI, body mass index; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; PSM, propensity-score matching; OAD, oral antidiabetes drug;
T2D, type 2 diabetes

HbA1c
The mean change from baseline in HbA1c with simultaneous iGlarLixi was significantly
greater compared with iGlar + lixisenatide for both PSM comparisons
iGlarLixi iGlar + lixisenatide
0
10
20
30
40
50
60
70
80
90
100
79%
51%
p<0.0001
p<0.0001
62%
33%
LixiLan-O LixiLan-LGetGoal
Duo-1
GetGoal
Duo-2
n indicates the number of patients included in analysis (mITT population); there were small variations in the number of patients meeting the criteria for inclusion
in LixiLan and GetGoal Duo mITT populations based on variable measured
HbA1c, glycated hemoglobin; mITT, modified intent-to-treat; PSM, propensity-score matching; SD, standard deviation
Change in weight and dose
Weight reduction was greater with iGlarLixi compared with iGlar + lixisenatide; the difference
was significant for LixiLan-O versus GetGoal Duo-1
Patients given iGlar + lixisenatide had a higher mean insulin dose compared with those
given iGlarLixi for both PSM comparisons; baseline insulin dose was significantly different
between LixiLan-L and GetGoal Duo-2
n indicates the number of patients included in analysis (mITT population); there were small variations in the number of patients meeting the criteria for inclusion
in LixiLan and GetGoal Duo mITT populations based on variable measured. *No LS mean difference or p-value has been included for the comparison of the final
mean iGlar dose at end of treatment period in LixiLan-L versus GetGoal Duo-2 as mean insulin doses showed significant difference at baseline (66 32 U vs 35
9 U; p<0.0001)
LS, least squares; mITT, modified intent-to-treat; PSM, propensity-score matching

Time to control
Time (95% CI) to first HbA1c value <53 mmol/mol (<7.0%)
LixiLan-O versus GetGoal Duo-1 LixiLan-L versus GetGoal Duo-2
iGlarLixi
iGlar + lixisenatide
The median time to achieve target HbA1c:
LixiLan-O versus GetGoal Duo-1: 57 versus 58 days for iGlarLixi and iGlar + lixisenatide
LixiLan-L versus GetGoal Duo-2: 85 versus 192 days for iGlarLixi and iGlar + lixisenatide (p<0.0001)
For LixiLan-O versus GetGoal Duo-1, after the median time, more patients reached target HbA1c sooner
with iGlarLixi compared with iGlar + lixisenatide (p=0.005)
The likelihood of achieving glycemic control was significantly higher with iGlarLixi versus iGlar +
lixisenatide (LixiLan-O vs GetGoal Duo-1: HR 1.6, 95% CI: 1.1 2.3; LixiLan-O vs GetGoal Duo-2: HR 2.2,
95% CI: 1.8 2.8)
CI, confidence interval; HbA1c, glycated hemoglobin; HR, hazard ratio; NE, non-evaluable
Adverse events
LixiLan-O vs GetGoal Duo-1 LixiLan-L vs GetGoal Duo-2
iGlarLixi
(n=87)
iGlar +
lixisenatide
(n=87)
iGlarLixi
(n=239)a
iGlar +
lixisenatide
(n=241)b
AE, n (%) 52 (59.8) 62 (71.3)b 130 (54.4) 179 (74.3)b
Serious AE, n (%) 2 (2.3) 5 (5.7) 15 (6.3) 8 (3.3)
AE leading to death, n (%) 1 (1.1) 0 1 (0.4) 1 (0.4)
AE leading to discontinuation, n (%) 6 (6.9) 5 (5.7) 10 (4.2) 12 (5.0)
Gastrointestinal AEs
Diarrhea 7 (8.0) 4 (4.6) 12 (5.0) 16 (6.6)
Leading to discontinuation 0 0 0 0
Nausea 8 (9.2) 18 (20.7) 24 (10.0) 65 (27.0)
Leading to discontinuation 1 (1.1) 1 (1.1) 4 (1.7) 3 (1.2)
Vomiting 1 (1.1) 9 (10.3) 8 (3.3) 21 (8.7)
Leading to discontinuation 0 2 (2.3) 0 4 (1.7)
a n=241 pairs were matched based on randomized patients regardless of their protocol adherence; however, two patients in the iGlarLixi cohort did not meet the
safety population criteria (did not receive at least one dose of study drug)
b Symptomatic hypoglycemia was included in the AE listing for GetGoal Duo-1 and GetGoal Duo-2
c
AE, adverse event

LixiLan-O versus GetGoal-1: percentage of patients with a symptomatic hypoglycemia event
was lower for iGlarLixi versus iGlar + lixisenatide; no events of severe symptomatic
hypoglycemia occurred
LixiLan-L versus GetGoal-2: despite greater HbA1c reductions with iGlarLixi, similar
proportions experienced symptomatic hypoglycemia events in both arms; two events (0.8%)
of severe hypoglycemia occurred with iGlarLixi versus no events with iGlar + lixisenatide
Hypoglycemia
HbA1c, glycated hemoglobin
Conclusions
iGlarLixi resulted in lower final HbA1c levels and a higher percentage of patients
achieving target HbA1c (<53 mmol/mol [<7.0%]) compared with sequential iGlar
+ lixisenatide
Significant body weight reduction occurred with iGlarLixi compared with iGlar +
lixisenatide in the LixiLan-O and GetGoal Duo-1 analysis, but not in the analysis
of LixiLan-L and GetGoal Duo-2
This suggests that mitigation of insulin-associated weight gain may be more
pronounced in patients newly initiating basal insulin compared with patients
who have already experienced insulin-associated weight gain
Indirect PSM comparisons suggest that early simultaneous treatment with a
titratable, fixed-ratio combination of basal insulin and a short-acting GLP-1 RA
may be more effective, with better gastrointestinal tolerability and with the
potential for more weight loss, than a sequential approach of adding a GLP-1
RA in patients with uncontrolled T2D newly initiating or intensifying basal insulin
therapy
LixiLan-L
primary
analysis
conclusions
LixiLan-O
primary
analysis
conclusionsGLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycated hemoglobin;
PSM, propensity-score matching; T2D, type 2 diabetes

1
Comparison of iGlarLixi and basal-bolus regimen
Efficacy and Safety of iGlarLixi, Fixed-Ratio Combination of
Insulin Glargine and Lixisenatide, Compared with Basal-Bolus
Regimen in Patients with Type 2 Diabetes: Propensity Score
Matched Analysis
IGlarlixi VS Basal Bolus
Tabak A et al. Diabetes Ther 2019
2
iGlarLixi and basal-bolus regimen:
Objective and methods
Tabak A et al. Diabetes Ther 2019
Objective
Membandingkan efikasi dan safety iGlarLixi dengan basal-bolus insulin pada
patients dengan T2DM yang tidak terkontrol dengan basal insulin
Methods
Propensity-score matching digunakan utk memilih pasien yang mendapat iGlarLixi
di LixiLan-L atau basal bolus di GetGoal Duo-2, berdasarkan umur, jenis kelamin,
ras, lama sakit diabetes, and baseline BMI, HbA1c, FPG, dosis insulin , dan
penggunaan metformin
Endpoints dilihat pada minggu 24 untuk iGlarLixi dan minggu 26 untuk basal bolus,
yaitu :
HbA1c dan weight change
HbA1c <7% (53 mmol/mol), tanpa kenaikan Berat badan dan significant
Hypoglycaemia event rates dilihat pada minggu 30 untuk iGlarLixi dan minggu 26
untuk basal bolus; dosis insulin diukur pada akhir minggu 30 untuk iGlarLixi dan
minggu 26 untuk basal bolus
BMI, body mass index; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; T2D, type 2 diabetes

3
4
HbA1c
*The change from baseline in HbA1c and weight were analysed using an MMRM with treatment groups and randomization strata (HbA1c
mmol/mol)] at screening and metformin use) as fixed effects, and visit (Week 12 and Week 24/26), baseline by visit interaction, and treatment by visit interaction
as covariates
CI, confidence interval; HbA1c, glycated haemoglobin; MMRM, mixed-effect model with repeated measures; SE, standard error
Penurunan HbA1c lebih
besar pada kelompok
Iglarlixi (1.02%)
dibandingkan kelompok
basal bolus (0.74%)

5
weight change
*The change from baseline in HbA1c and weight were analysed using an MMRM with treatment groups and randomization strata (HbA1c
mmol/mol)] at screening and metformin use) as fixed effects, and visit (Week 12 and Week 24/26), baseline by visit interaction, and treatment by visit interaction
as covariates
CI, confidence interval; HbA1c, glycated haemoglobin; MMRM, mixed-effect model with repeated measures; SE, standard error
Terjadi penurunan berat
badan sebanyak 0.62 kg
pada Kelompok iGlarLixi
dan kenaikan berat
badan 0.70 kg pada
kelompok basal bolus
6
Proportions reaching individual endpoints
0
iGlarLixi (n=194) Basal bolus (n=194)
Hypoglycaemia was defined as documented symptomatic hypoglycaemia (plasma glucose concentration <54 mg/dL [3 mmol/L])
*p<0.01 from Cochran Mantel Haenszel test for the weighted difference between treatment groups in all categories (randomization strata of HbA1c [<8.0%,
HbA1c, glycated haemoglobin
The proportions of patients reaching individual endpoints were higher with
iGlarLixi compared with basal bolus
Proporsi pasien yang
mencapai target individual
endpoint secara konsisten
lebih tinggi pada kelompok
Iglarlixi Vs Basal Bolus

7
Proportions reaching composite endpoints
Hypoglycaemia was defined as documented symptomatic hypoglycaemia (plasma glucose concentration <54 mg/dL [3 mmol/L])
*p<0.01 from Cochran Mantel Haenszel test for the weighted difference between treatment groups in all categories (randomization strata of HbA1c [<8.0%,
HbA1c, glycated haemoglobin
The proportions of patients reaching composite endpoints were higher with
iGlarLixi compared with basal bolus
iGlarLixi (n=194) Basal bolus (n=194)
Proporsi pasien yang
mencapai target
individual endpoint
secara konsisten lebih
tinggi pada kelompok
Iglarlixi Vs Basal Bolus
8
Hypoglycaemia and insulin dose
iGlarLixi (n=194) Basal-bolus (n=195)
Hypoglycaemia was defined as documented symptomatic hypoglycaemia
mmol/L])
*p-values were estimated from Poisson regression with treatment as a
fixed factor and log value of patient-years of exposure as an offset variable
iGlarLixi
(n=194)
Basal
bolus
(n=194)
Baseline, mean (SD) 39 (8) 38 (11)
Week 30/26, mean (SD) 49 (11) 53 (23)
LS mean (SE) change from
baseline
9 (1) 14 (1)
LS mean treatment difference ±
SE (95% CI)
5 ± 1
(2, 8)
p-value 0.0003
Hypoglycaemia events per patient-year Average daily insulin dose
Observed cases are used for this analysis. Based on MMRM with
treatment groups and randomization strata (HbA1c
mmol/mol)] at screening and metformin use) as fixed effects, and visit
(Week 2, Week 6, Week 12, and Week 30/26), baseline by visit
interaction, and treatment by visit interaction as covariates
CI, confidence interval; HbA1c, glycated haemoglobin; LS, least squares;
MMRM, mixed-effect model with repeated measures; SD, standard
deviation; SE, standard error
Rate terjadinya
hipoglikemia lebih
rendah pada iglarlixi
dibandingkan basal
bolus
Insulin dosis lebih
rendah pada iglalixi
dibandingkan Basal
Bolus

9
Kesimpulan
Treatment dengan iGlarLixi berhubungan dengan
penurunan berat badan, penurunan HbA1c lebih besar, dan
lebih sedikit kejadian hypoglycaemia dibandingkan dengan
basal-bolus regimen
iGlarLixi berhubungan dengan lebih banyak pasien yang
mencapai target HbA1c <7% [53 mmol/mol]) dan composite
endpoints
Hal ini dapat dicapai dengan injeksi 1 kali sehari (iglarlixi)
versus multiple injeksi untuk basal-bolus insulin
Pada pasien T2DM tidak terkontrol dengan basal insulin,
intensifikasi dengan iGlarLixi memiliki efikasi lebih,
ditoleransi baik dan lebih simple dibandingkan dengan
switching ke basal bolus
HbA1c, glycated haemoglobin; T2D, type 2 diabetes

LixiLan-L
SAID.SQA.19.04.0145/(04/19)
Hanya Metformin yang dilanjutkan pada fase run-in
DESIGN: Randomized, open-label, parallel-group, 30-week treatment trial
6-week
run-in phase
Insulin glargine 100 U/mL (iGlar) Metformin
Dosis insulin disesuaikan untuk mencapai GD Puasa
target (80 to 100 mg/dL) and capped to 60 U/day pada kedua
groups
iGlarLixi Metformin
30-minggu treatment period
Pasien Diabetes tipe 2
dengan
Basal insulin >6 bulan
Dosis stabil 15 40 U/d
± OADs
HbA1c 10%
GD puasa 200
mg/dL n=367
7% HbA1c %
GD Puasa
Dosis iGlar
n=369
Inisiasi iGlar
dan atau titrasi
FPG, fasting plasma glucose; HbA1c, glycated hemoglobin
OAD, oral antidiabetic drug; U, unit
Aroda VR, et al. Diabetes Care 2016;39:1972 80

iGlarLixi adalah self-injected, diberikan 1x sehari, pemberian dalam 1 jam (0 60
min) sebelum sarapan
Setelah 2 minggu dalam dosis stabil, dosis di titrasi sekali dalam seminggu untuk
mencapai target puasa SMPG of 4.4 to 5.6 mmol/L (80 to 100 mg/dL), mencegah
hipoglikemia.
Pasien di
random ke
iGlarLixi
PEN B
Dosis iGlar dari 30 U hingga 60 U; dosis awal 30 U
PEN A
Dosis iGlar dari 10 hingga 40 U; dosis awal 10 U per hari
Dosis iGlar
U/day
sebelum
randomisasi
Dosis iGlar
<30 U/day
sebelum
randomisasi
SMPG, self-measured plasma glucose
For statistical analysis of the study endpoints, a step-down
testing procedure was applied to control for type 1 error
PPG, postprandial glucose
PRIMARY
Superioritas dari iGlarLixi dibandingkan iGlar 100 U/mL dalam perubahan HbA1c pada minggu ke 30
SECONDARY
Superioritas dari iGlarLixi dibandingkan iGlar pada:
2 jam perjalanan glukosa plasma
Berat badan
7-point SMPG
Persentase pada pasien dengan HbA1c <7% dan tanpa peningkatan berat badan
Dosis iGlar
Persentase pada pasien dengan HbA1c <7% dan tanpa peningkatan berat badan dan/atau tanpa hipoglikemi simptomatik
Gula darah Puasa
Tambahan secondary endpoints termasuk:
Persentase responden dengan HbA1c <7% dan
Persentase pasien dengan HbA1c <7%, tanpa kenaikan berat badan pada minggu 30 and tidak ada resiko hipoglikemia
simptomatik
SAFETY
Didokumentasi hipoglikemi simptomatik
Kejadian efek samping

iGlarLixi
(n=367)
iGlar
(n=369)
Usia (years) 59.6 (9.4) 60.3 (8.7)
Wanita (%) 55.0 51.5
Caucasian/Black (%) 92/5 92/6
Berat badan (kg) at Baseline 87.7 (14.5) 87.1 (14.8)
BMI (kg/m2) at Baseline 31.3 (4.3) 31.0 (4.2)
Durasi Diabetes (years) 12.0 (6.6) 12.1 (6.9)
Durasi penggunaan Basal Insulin (years) 3.1 (3.1) 3.3 (3.1)
Jenis Basal insulin at Screening (%)
iGlar 64 65
Detemir 13 15
NPH 23 20
OAD use at Screening (%)
None 5 5
Metformin 46 52
Sulfonylurea (SU) 4 4
DPP-4 inhibitor 1 1
Metformin + SU 37 32
Metformin + DPP-4 inhibitor 5 5
BMI, body mass index; DPP-4, dipeptidyl peptidase 4;
NPH, neutral protamine Hagedorn insulin; SU, sulfonylurea
iGlarLixi
(n=367)
iGlar
(n=369)
HbA1c (%)
Screening 8.5 8.5
Baseline 8.1 8.1
FPG, mmol/L
Screening 7.9 8
Baseline 7.3 7.4
iGlar dose (U)
Start of run in 27.3 27.7
End of run in 35.0 35.2

6.0
6.5
7.0
7.5
8.0
8.5
9.0
0.62
iGlar
HbA1c selama studi (%)
Modified intent-to-treat population
*Weighted average of proportion difference between treatment groups
BL, baseline; CI, confidence interval; HbA1c, glycated hemoglobin; LS, least squares; LOCF, last observation carried forward; S, screening;
SE, standard error
LS mean difference
95% CI, p-value
0.52 ( 0.633 to 0.397)
p<0.0001
iGlarLixi
6.0
6.5
7.0
7.5
8.0
8.5
9.0
Week
iGlarLixi
iGlar
6.9%
7.5%
S BL 8 12 24 30 30
LOCF
1.13LS mean change
HbA1c <7% HbA1c
25.5%*
95% CI:
18.9% 32.1%
p<0.0001
19.8%*
95% CI:
13.9% 25.6%
p<0.0001
iGlarLixi
iGlar
55
34
30
14
0
10
20
30
40
50
60
70
Target HbA1c minggu ke 30
2
1
1
2
3
0
BL 4 8 12 18 24 30 30
LOCF
Time (weeks)
iGlarLixi
iGlar
+0.7 kg
0.7 kg
Body weight (kg) change
from baseline to Week 30
-85.1
-70.2
-25.1
-8.4
95% CI: 70.7 to 52.9
p<0.0001
61.8*
2-hr PPGa (mg/dL) Excursiona (mg/dL)
60.0
95% CI: 70.1 to 50.0
Modified intent-to-treat population; ANCOVA for PPG analyses; MMRM for body weight analyses
aStandardized liquid breakfast meal
*LS mean difference vs iGlar
ANCOVA, analysis of covariance; CI, confidence interval; LOCF, last observation carried forward; LS, least squares; MMRM, mixed-effect model with
repeated measures; PPG, postprandial glucose; SE, standard error

Safety population
E/p-y, event/patient-year; GI, gastrointestinal
Documented symptomatic
hypoglycemia
E/p-y 0.02 < 0.01
iGlarLixi
(n = 469)
iGlar
(n = 467)
Nausea 38 (10.4) 2 (0.5)
Discontinuation 4 (1.1) 0
Vomiting 13 (3.6) 2 (0.5)
Discontinuation 2 (0.4) 0
Diarrhea 16 (4.4) 10 (2.7)
Discontinuation 0 0
All data are n (%)
Efek samping GI
iGlarLixi
iGlar
40
42.5
0
10
20
30
40
50
34.2
31.7
19.9
13.4
18.6
0
10
20
30
40
50
60
70
9.0
HbA1c <7% tanpa peningkatan
berat badan di minggu ke 30
HbA1c <7% tanpa peninmgkatan
berat badan di minggu 30 dan
Tanpa hipoglikemia
didokumentasi
HbA1c <7%
tanpa hipoglikemi
didokumentasi
20.8%*
95% CI: 15.0 to 26.7
p<0.0001 13.2%*
95% CI: 7.1 to 19.3
10.9%*
95% CI: 5.9 to 16.0
p<0.0001
mITT population
*Weighted average of proportion difference between
treatment groups; No p-value available as comparison not
specified in step-down testing procedure
iGlarLixi (n=366)
iGlar (n=365)

0
5
10
15
20
25
30
35
40
45
50
Week
Aroda V, et al. ADA 2016 congress, scientific sessions webcast. Available at:
http://professional.diabetes.org/webcasts-ss2016, last accessed 10 May 2017
Average daily Insulin dose (U)
1 2 3 4 5 6 7 8 9 101112 15 18 21 24 27 30 30
LOCF
Run-in
start Randomization
-4
mITT population
iGlarLixi (n=366)
iGlar (n=365)
iGlar dose (U)
iGlarLixi
(n=365)
iGlar
(n=365)
Start of run-in 28 29
End of run-in 35 35
Week 30 (LOCF) 46 47
*LS mean change in HbA1c from baseline to Week 30.
Proportion of patients affected by documented symptomatic hypoglycemia
- vs iGlar-treated groups.
Mean change in weight from baseline to Week 30.
Proportion of patients who discontinued iGlarLixi treatment as a result of gastrointestinal (GI)
treatment-emergent adverse events.
1. Aroda VR et al. Diabetes Care. 2016;39:1972-1980.
Penurunan HbA1c yang signifikan pada minggu ke 30 1.1%*
Similar Hipoglikemia 40.0 vs 42.5%
Tanpa peningkatan berat badan 0.7 kg
Efek samping GI yang lebih rendah dibandingkan dengan
lixisenatide, yang menyebabkan penghentian pengobatan
1.1%§

1
LixiLan-O primary
methods and results
Published in full:
Rosenstock JR et al. 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
LixiLan-O
Iglarlixi memperlihatkan statistical superiority dibanding insulin glargine
100 units/mL atau lixisenatide pada penurunan HbA1c pada pasien DM tipe
2 yang sebelumnya mendapat metformin OAD lain, dengan profil safety
sebanding dengan insulin glargine 100 units/mL dan lixisenatide1
2
aStop OAD ke-2/titrasi metformin hingga paling tidak 2000 mg/hari atau dosis maximal yg ditoleransi hari sebelum
randomisasi)
4-weeka
run-in
phase
Lixi + metformin
iGlar + metformin
iGlar dose adjusted to self-monitored FPG target
(80 100 mg/dL) and capped to 60 U/day in the
iGlarLixi and iGlar groups
iGlarLixi + metformin
30-week treatment period
10
20
Up to
2-week
screening
LixiLan-O: Pasien DM Tipe 2 yang tidak terkontrol dengan OAD
(NCT02058147)
Rosenstock J et al. Diabetes Care 2016;39:2026 2035
DESIGN: Randomized, open-label, active controlled, 3-arm parallel-group trial
Pasien DM tipe 2 dengan:
Metformin saja atau kombinasi
dengan OAD ke-2
HbA1c:
7.0% 9.0% (jika dgn 2 OAD)
7.5% 10% (jika dgn
metformin saja )
n = 234
n = 469
n = 467
FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; OAD, oral antidiabetic drug; T2D, type 2 diabetes

3
Objectives and endpoints
PRIMARY
Perubahan HbA1c di minggu 30:
Superiority of iGlarLixi over Lixisenatide AND
Non-inferiority of iGlarLixi over iGlar (non inferiority margin: 0.3%)
Once shown, superiority can be tested (included in testing hierarchy)
SECONDARY
Efek iGlarLixi vs iGlar dan lixisenatide pada:
Ekskursi glukosa 2 jam pp dan 2 jam PP
Berat badan
7-point SMPG
GDP
Persentase responder yang mencapai
Persentase responder yang mencapai HbA1c <7% tanpa kenaikan berat badan
Persentase responder yang mencapai HbA1c <7% tanpa documented, symptomatic hypoglycemia
Persentase responder yang mencapai HbA1c <7% tanpa kenaikan berat badan, dan documented, symptomatic
hypoglycemia
Dosis iGlar
SAFETY
Documented, symptomatic hypoglycemia
Insidens adverse events
Rosenstock J, et al. Diabetes Care 2016;39:2026 35
For statistical analysis of the study endpoints, a step-down
testing procedure was applied to control for type 1 error
PPG, postprandial glucose
4
Sanofi data on file, CSR HOE901/AVE0010-EFC12404 v1:pages 78, 80
iGlarLixi
(n=469)
iGlar
(n=467)
Lixisenatide
(n=234)
All
(N=1170)
Age (years) 58.2 (9.5) 58.3 (9.4) 58.7 (8.7) 58.4 (9.3)
Male/female (%) 47.3/52.7 50.7/49.3 56.8/43.2 50.6/49.4
Caucasian/Black (%) 88.9/7.0 90.1/7.1 92.3/5.1 90.1/6.7
Diabetes duration (years) 8.9 (5.5) 8.7 (5.6) 8.9 (6.3) 8.8 (5.7)
BMI (kg/m2) 31.6 (4.4) 31.7 (4.5) 32.0 (4.4) 31.7 (4.4)
% P kg/m2 62.9 61.7 67.9 63.4
HbA1c (%) at screening 8.2 (0.7) 8.2 (0.7) 8.3 (0.7) 8.2 (0.7)
HbA1c (%) at randomization 8.1 (0.7) 8.1 (0.7) 8.2 (0.7) 8.1 (0.7)
% Patients with HbA1c 55.9 55.7 56.0 55.8
FPG, mmol/L (mg/dL) 9.9 (178) 9.8 (176) 9.8 (176) 9.8 (177)
Metformin dose (baseline) (mg) 2246 (457) 2245 (445) 2267 (427) 2250 (446)
Second OAD use at screening (%) 58.4 57.8 56.8 57.9
Sulfonylurea 55.2 53.3 52.6 53.9
Glinide 0.6 2.1 2.1 1.5
SGLT-2 inhibitor 0.4 0.4 0 0.3
DPP-4 inhibitor 2.6 2.4 2.1 2.4
BMI, body mass index; DPP-4, dipeptidyl peptidase 4
SGLT-2, sodium-glucose cotransporter 2
Demographics and baseline characteristics

5
LixiLan-O: Algoritme titrasi
iGlarLixi adalah terapi injeksi yang diberikan 1x sehari, pemberian dalam 1jam sebelum sarapan
Setelah 2 minggu dalam dosis stabil, dosis dititrasi sekali seminggu untuk mencapai GDP 80 sampai 100
mg/dL), mencegah hipoglikemia
Semua pasien
dirandom mulai
dengan PEN A
PEN B (ratio of 3 U : 1 µg)
Dosis iGlar dari 30 U hingga 60 U; digunakan untuk pasien
yang menggunakan dosis 41 60 U
PEN A (ratio of 2 U : 1 µg)
Dosis iGlar dari 10 hingga 40 U; dosis awal 10 U per hari
SMPG, self-measured plasma glucose
6
LixiLan-O: Key Result
HbA1c reduction
1.6
1.3
0.9
-1.8
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
LSmeanchange(%)
iGlarLixi
iGlar
Lixisenatide
p<0.0001
p<0.0001
Patients at target HbA1c
74
5659
40
33
19
0.0
20.0
40.0
60.0
80.0
100.0
HbA1c <7%
Proportionofpatients
(%)
14.3*
40.6*
16.4*
36.4*
0.3
1.1
2.3
-3.0
-2.0
-1.0
0.0
1.0
2.0
LSmeanchange(kg)
Weight change
1.4*
95% CI: 1.9, 0.9
2.0
95% CI: 1.4, 2.6
Baseline 89.4 89.8 90.8
Hypoglycemia §
25.6
23.6
6.4
0.0
10.0
20.0
30.0
40.0
50.0
Patients with
events (%)
No. of events
per patient
year
1.4 1.2
0.3
0.0
1.0
2.0
3.0
4.0
5.0
FPG change
3.5
3.3
1.5
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
LSmeanchange
(mmol/L)
0.2
95% CI: 0.4, 0.04
2.0
95% CI: 2.2, 1.7
hypoglycemia dL
§ One event of severe hypoglycemia was reported during the study and occurred in the iGlar group
2-hour PPG
reduction
2.4
95% CI: 2.8, 2.0
1.1
95% CI: 1.6, 0.6
5.7
3.3
4.6
-6.0
-5.0
-4.0
-3.0
-2.0
-1.0
0.0
LSmeanchange
(mmol/L)

7
Profil 7-point SMPG
5
6
7
8
9
10
11
12
13
Mean±SE
Baseline
Week 30
mmol/L mg/dL
234
216
198
180
162
144
126
108
90
Pre-breakfast 2-hour
post-breakfast
Pre-lunch Pre-dinner 2-hour
post-dinner
Bedtime2-hour
post-lunch
mITT population
Mean change in 7-point SMPG
iGlarLixi (n=468)
iGlar (n=466)
Lixisenatide (n=233)
Penurunan Glukosa harian
(seven-point SMPG) lebih
besar pada kelompok Iglarlixi
dibandingan Iglar dan lixi
8
Rata rata dosis insulin harian
0
5
10
15
20
25
30
35
40
45
50
Mean±SE
Week
Average daily Insulin dose (U)
40 U
1 2 3 4 5 6 7 8 9 10 11 12 15 18 21 24 27 30 30
LOCF
Sanofi data on file, CSR HOE901/AVE0010-EFC12404 v1:pages 109 10
mITT population
iGlarLixi (n=468)
iGlar (n=466)
Dosis insulin harian
sama antara iglarlixi
dan iglar

9
Pasien mencapai composite endpoints
31.8
18.9
27.9
26.2
0
10
20
30
40
50
60
70
80
Proportionofpatients(%) HbA1c <7% with
no body weight gain
HbA1c <7% with
no body weight gain and
no documented
18.1%*
95% CI: 12.2 to 24.0
p<0.0001
15.2%*
95% CI: 8.1 to 22.4
13.0%*
95% CI: 7.5 to 18.5
p<0.0001
5.6%*
95% CI: 1.3 to 12.6
mITT population
*Weighted average of proportion difference between treatment groups
No p-value available as comparison not specified in step-down testing procedure
43.2
25.1
iGlarLixi (n=468)
iGlar (n=466)
Lixisenatide (n=233)
Lebih banyak pasien yang
mencapai composite
endpoint pada Iglarlixi
dibanding iglar dan lixi
10
Profil safety
Patients, n (%), with iGlarLixi
(n=469)
iGlar
(n=467)
Lixisenatide
(n=233)
TEAE
Any 267 (56.9%) 227 (48.6%) 157 (67.4%)
Serious 18 (3.8%) 19 (4.1%) 9 (3.9%)
Leading to Death 2 (0.4%) 3 (0.6%) 1 (0.4%)
Leading to Discontinuation 12 (2.6%) 9 (1.9%) 21 (9.0%)
GI TEAEs
Nausea 45 (9.6%) 17 (3.6%) 56 (24.0%)
discontinuation 2 (0.4%) 0 6 (2.6%)
Vomiting 15 (3.2%) 7 (1.5%) 15 (6.4%)
Diarrhea 42 (9.0%) 20 (4.3%) 21 (9.0%)
Safety population
Data analyses are descriptive
TEAE, treatment emergent adverse event
Mual dan muntah lebih
jarang terjadi pada igalrlixi
dibanding Lixisenatide

11
Kesimpulan
Tercapainya Primary endpoint yaitu superiority iGlarLixi dalam menurunkan HbA1c
versus iGlar dan Lixisenatide
iGlarLixi dikombinasi dengan metformin:
Penurunan HbA1c dari 8.1% menjadi 6.5%
menurunkan 2h-PPG dan ekskursi glucosa
Mencegah kenaikan berat badan ( 0.3 kg) dan selisih perubahan berat badan dengan
kelompok Iglar adalah 1.4 kg (p<0.0001)
Sebanyak 74% pasien mencapai HbA1c <7%
43% HbA1c <7% tanpa kenaikan berat badan
32% HbA1c <7%, tanpa kenaikan berat badan dan documented hypoglycemia
12
Kesimpulan
insiden kelompok
iGlarLixi dan iGlar dan lebih rendah pada kelompok Lixisenatide
Secara umum, iGlarLixi dapat ditoleransi dengan profil safety sama dengan
kelompok iGlar dan Lixisenatide
Mual dan muntah lebih jarang terjadi pada igalrlixi dibanding Lixisenatide

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