Que poden aportar les noves insulines?
Nuevas insulinas basales
Dr. Javier Escalada
Consultor. Departamento de Endocrinología y Nutrición. Clínica Universidad de Navarra
18 Congrés de la Societat Catalana d'Endocrinologia i Nutrició 13 de Noviembre de 2015
Conflictos de interés
Francisco Javier Escalada
En relación con el tema: Conferencias para Lilly, Novonordisk y Sanofi y pertenece a comités
asesores de Sanofi.
New Basal Insulin Formulations
• Introducción
• Mecanismo de acción, duración, variabilidad
• Estudios pivotales – Control glucémico
• HbA1c • Glucemia basal
– Hipoglucemias – Peso – Dosis de insulina
• Seguridad
– Cardiovascular – No cardiovascular
New Basal Insulin Formulations
• Introducción
• Mecanismo de acción, duración, variabilidad
• Estudios pivotales – Control glucémico
• HbA1c • Glucemia basal
– Hipoglucemias – Peso – Dosis de insulina
• Seguridad
– Cardiovascular – No cardiovascular
Tattersall RB. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed.
Blackwell Science: Malden, MA; 2003:1.1-1.22; Drugs@ FDA;
http://diabetes.webmd.com/news/20071018/pfizer-quits-inhaled-insulin-exubera.
1920 1930 1940 1960 1970 1980 2000 2010 1990 1950
Insulin discovered (1921)
First human treatment with bovine insulin (1922)
Protamine and protamine zinc insulins developed (1936)
NPH insulin developed (1946)
Lente (zinc) insulins developed (1952)
Synthetic human insulin developed (1965)
Recombinant human insulin developed (1979)
Insulin pump developed (1978?)
Insulin pen developed (1981)
Insulin lispro approved in US (1996)
Insulin aspart and insulin glargine approved in US (2000)
Insulin
glulisine (2004)
Insulin detemir approved in US (2005)
Inhaled insulin (2006) 2014
2013
Degludec (2013)
In development: Glargine U-300 Pegylated Lispro
2014
Milestones in Insulin Development
Characteristics of Available Basal Insulin Analogs
Benefits over NPH
•Longer duration of action
•Less variability
•Less weight gain
•Less hypoglycemia
Simon ACR. Diabetes Technol Ther. 2011;13(suppl 1):S103-108. Grunberger G. Diab Obes Metab. 2013;15(suppl 1):1-5.
Room for Improvement
•More consistent 24+ hour coverage
•Flat time-action profile
•Less day-to-day variability
•Less weight gain
•Less hypoglycemia
•More suppression of hepatic glucose production
*p<0.05 between treatments
Riddle MC, et al. Diabetes Care. 2003;26:3080-86
GLARGINA U-100
DEGLUDEC GLARGINA U-300
PEGILADA LISPRO
New Basal Insulin Formulations
• Glargine U-300
• Degludec
• *Pegylated Lispro
* Not FDA Approved
No head-to-head trials
Estudios frente a Glargina U-100
New Basal Insulin Formulations
• Introducción
• Mecanismo de acción, duración, variabilidad
• Estudios pivotales – Control glucémico
• HbA1c • Glucemia basal
– Hipoglucemias – Peso – Dosis de insulina
• Seguridad
– Cardiovascular – No cardiovascular
NH
O
OH
O NH
O
OH
O
L-γ-Glu
DesB30 insulin
Glutamic acid ‘spacer’
DesB30 T
Des(B30) LysB29(γ-Glu Nε-hexadecandioyl) human insulin
s s s
s
A1
B1
A21 s s
T Y G E E C Y C C N L Q L S I S Q V I N C
P T Y Y F F F G G G R E E C C V L L A V L H S L H Q N V K
NH
O
OH
O NH
O
Hexadecandioyl Fatty diacid side chain
Insulin degludec: rationally designed, beyond sequence modification
Insulin degludec injected
Phenol from the vehicle diffuses quickly, and hexamers link up via single side-chain contacts
Long multi-hexamers
assemble
Phenol
Zn2+
Subcutaneous depot
Zinc diffuses slowly causing individual hexamers to disassemble, releasing
monomers
Monomers are absorbed from the depot into the circulation
Jonassen et al. Pharm Res 2012;29:2104–14
Insulin degludec: from injection to slow release from the subcutaneous depot
IDeg half-life (25.4 hours) is twice that of IGlar (12.5 hours)
0
1
2
3
4
5
0 4 8 12 16 20 24
GIR
(m
g/k
g/m
in)
Time since injection (hours)
IDeg 0.8 U/kg
IDeg 0.6 U/kg
IDeg 0.4 U/kg
IDeg glucose-lowering profile
1
10
100
0 24 48 72 96 120
*
IDeg 0.8 U/kg
IGlar 0.8 U/kg
Insulin c
oncentr
ation
(% o
f m
axim
um
)
Half-life
Time since injection (hours)
*Insulin glargine was undectable after 48 hours. CV, coefficient of variation; GIR, glucose infusion rate; IDeg, insulin degludec; IGlar, insulin glargine; T1D, type 1 diabetes Heise et al. Diabetes Obes Metab 2012;14:944–50; Heise et al. Diabetologia 2011;54(Suppl. 1):S425; Heise et al. Diabetes Obes Metab 2012;14:859–64
IDeg has a flat glucose-lowering profile with a half-life twice as long as IGlar
Steinstraesser A et al. Diabetes Obes Metab. 2014;16:873-6; Becker RHA et al. Diabetes Care. 2014 Aug 22. pii: DC_140006. [Epub ahead of print] PD, pharmacodynamic; PK, pharmacokinetic Data on file
Menor superficie del depot (1/2)
U300 Lantus®
Reducción de volumen (2/3)
30 U insulina:
• G-100: 0,3 ml • G-300: 0,1 ml
U300 es una nueva insulina basal de duración prolongada que ofrece beneficios PK/PD adicionales
0 6 12 18 24 30 36
3
Euglycemic clamp study in T1DM in steady state (8 days’ treatment)
Time, h
3
2
1
0
140
120
100
160
0 6 12 18 24 30 36
U300 0.4 U/kg
Lantus® 0.4 U/kg
20
10
0
0 6 12 18 24 30 36
Insulin concentration, µU/mL
Glucose infusion rate, mg/kg/min
Blood glucose, mg/dL
25
15
5
Becker RHA et al. Diabetes Care. 2014 Aug 22. pii: DC_140006. [Epub ahead of print]
LLOQ
Clamp level
Clamp level +18 mg/dL (1 mmol/L)
Tight blood glucose control (≤105 mg/dL) was maintained for approximately 5 h longer (median of 30 h) with Gla-300 compared with Gla-100.
La liberación más controlada y gradual con U300 vs Lantus resulta en un perfil PK más constante y prolongado y un efecto reductor de la
glucosa durante más de 24 horas
For perspective, the hydrodynamic size of BIL is ≥ albumin4
1. Humalog®. US prescribing information 2011; 2. Beals JM et al. Diabetologia 2012;55(Suppl):abs 42; 3. Beals JM et al. Oral presentation 42 at the 48th Annual Meeting of the European Association for the Study of Diabetes, Berlin, Germany, October 1-5, 2012; 4. Meloun B et al. FEBS Lett 1975;58:134-7
BIL: a novel basal insulin analog with a large hydrodynamic size
1. Kaminskas LM et al. J Controlled Release 2013;168:200-8; 2. Kaminskas LM, Porter CJ. Adv Drug Del Rev 2011;63:890-900; 3. Kaminskas LM et al. J Control Release 2009;140:108-16; 4. Charman SA et al. Pharm Res 2001;18:1620-6
INJECTION: Rapid
dissociation from
hexamers to large
monomersLymph capillary
Blood capillary
Hypothesis: the large hydrodynamic size of BIL may allow slow absorption of monomers predominantly via the lymphatic system
1. Sinha VP et al. Diabetes 2012;61(Suppl 1):abs 1063-P; 2. Sinha VP et al. Poster 1063-P presented at ADA, 2012 3. Sinha VP et al. Diabetes Obes Metab 2014;16:344-50
The flat GIR profiles at steady state mirrored the flat PK profile at steady state3
5
4
3
2
1
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (h)
5
4
3
2
1
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (h)
Day 1
Glucose infusion rate (mg/min/kg)
Day 14
Glucose infusion rate (mg/min/kg)
BIL 4.5 nmol/kg (0.50 U/kg), n=8BIL 6.0 nmol/kg (0.67 U/kg), n=8BIL 9.0 nmol/kg (1.00 U/kg), n=8
BIL 3.0 nmol/kg (0.33 U/kg), n=8
Mean GIR profiles following single and multiple once-daily SC doses of BIL in patients with T2DM
Glu
co
se in
fusio
n r
ate
(mg
/min
/kg
)
Time (h) 0 4 8 12 16 20 24 28 32 36
Insulin glargine 0.8 U/kg Insulin glargine 0.5 U/kg BIL 0.1 nmol/kg (0.01 U/kg) BIL 0.5 nmol/kg (0.06 U/kg) BIL 3.0 nmol/kg (0.33 U/kg) BIL 6.0 nmol/kg (0.67 U/kg) BIL 9.0 nmol/kg (1.00 U/kg) BIL 13.0 nmol/kg (1.44 U/kg) BIL 20.0 nmol/kg (2.22 U/kg)
0
1
2
3
4
5
The GIR profiles mirrored the PK profiles following single SC doses of BIL and glargine in healthy subjects1,2
1. Moore MC et al. Diabetes 2014;63:494-504; 2. Beals JM et al. Diabetologia 2012;55(Suppl):abs 42; 3. Beals JM et al. Oral presentation 42
presented at EASD, 2012; 4. Linnebjerg H et al. Diabetologia 2012;55(Suppl):abs 922; 5. Linnebjerg H et al. Poster 922 presented at EASD, 2012
Lipolysis
No weight gain /
moderate weight loss
Low renal
clearance
Endogenous insulinPreferential
hepatic action1
Adipocytes
Muscle
Kidney2-5
Decreased renal clearance
Glucose utilization: fasting state
FFA utilization: fasting state
Risk of hypoglycemia
BIL
Decreased peripheral activity
Hypothesis: based on preclinical data, BIL may more closely mimic that of endogenous insulin due to a greater hepatic vs peripheral activity
profile
Variability
0
40
80
120
160
200 Ideg IGlar
Area under the GIR curve (time interval, hours)
Day-t
o-d
ay v
ari
ability
(coeff
icie
nt of
vari
ation %
)
Variability in glucose-lowering effect over 24 hours at steady state
IDeg variability is four-fold lower than IGlar
*Insulin glargine was undectable after 48 hours. CV, coefficient of variation; GIR, glucose infusion rate; IDeg, insulin degludec; IGlar, insulin glargine; T1D, type 1 diabetes Heise et al. Diabetes Obes Metab 2012;14:944–50; Heise et al. Diabetologia 2011;54(Suppl. 1):S425; Heise et al. Diabetes Obes Metab 2012;14:859–64
IDeg has a flat glucose-lowering profile with a four-times lower day-to-day variability
Todas las medidas de la variabilidad glucémica intradiaria e interdiaria fueron numéricamente inferiores en los participantes que recibieron Gla-300 que en los que recibieron Gla-100
Población con MCG; †Combinada las 2 últimas semanas de tratamiento en cada periodo (semanas 7-8 y semanas 15-16), grupos de inyección combinados por la mañana y por la noche
DE: desviación estándar; DET: variabilidad de la desviación estándar total; DEintra: variabilidad intradiaria; DEmd: variabilidad entre las medias diarias; DEinter: variabilidad interdiaria (para
el mismo momento del día)
-7,4
-5,4
-14,3
-7,2
-15
-13
-11
-9
-7
-5
-3
-1
SDT SDw SDdm SDb
% d
ifere
nci
a e
n v
aria
bili
dad
A favor de Gla-300
Valor absoluto;media (DE) (mg/dl)
DET DEintra DEmd DEinter
Gla-100 76,1 (2,7) 61,4 (1,8) 41,4 (2,5) 71,3 (2,9)
Gla-300 70,5 (2,4) 58,1 (2,1) 35,5 (1,7) 66,2 (2,3)
Valor de P 0,1259 0,2286 0,052 0,1568
DET DEintra DEmd DEinter
Bergenstal et al. Diabetes Tech Ther 2015; 17 (Suppl1): A16-17 (abstract no. 39).
Medidas de la variabilidad glucémica: últimas 2 semanas de tratamiento† Estudio de
MCG en T1
Between-day FBG variability was significantly lower
with BIL compared with insulin glargine in T1DM
Rosenstock J et al. Diabetes Care 2013;36:522-8
Between-day FBG variability after 8 weeks of treatment in T1DM
Be
twe
en
-da
y F
BG
SD
(m
g/d
L)
P<.001Baseline
Insulin glargine, Week 8
BIL, Week 8
0
10
20
30
40
50
60
70
Insulin glargine BIL
In T2DM patients, between-day FBG variability was
similar for BIL and insulin glargine at the end of
treatment
Bergenstal RM et al. Diabetes Care 2012;35:2140-7
0
5
10
15
20
25
Insulin glargine BIL
Be
twe
en
-da
y F
BG
SD
(m
g/d
L)
Between-day FBG variability after 12 weeks of treatment in T2DM
New Basal Insulin Formulations
• Introducción
• Mecanismo de acción, duración, variabilidad
• Estudios pivotales – Control glucémico
• HbA1c • Glucemia basal
– Hipoglucemias – Peso – Dosis de insulina
• Seguridad
– Cardiovascular – No cardiovascular
Type 1 diabetes Type 2 diabetes
BB Basal–bolus
Met ± TZD, n=1006 Garber, 2012; Lancet
ONCE LONG Basal start
Met ± DPP-4, n=1030 Zinman, 2012; Diabetes Care Rodbard, 2013; Diabet Med
BB T1 LONG Basal–bolus
n=629 Heller, 2012; Lancet
Bode, 2013; Diabet Med
FLEX T1 Flexible basal therapy
n=493 Mathieu, 2013; J Clin Endocrinol Metab
EARLY Basal start
Met ± SU/TZD, n=458 Philis-Tsimikas, 2013; Diabetes Obes Metab
LOW VOLUME U200 Basal start
Met ± DPP-4, n=460 Gough, 2013; Diabetes Care
ONCE ASIA Basal start
Met ± SU/-gluc, n=435 Onishi, 2013; J Diabetes Investig
FLEX BOT
Met ± OADs, n=687 Meneghini, 2013; Diabetes Care
BB T1 Basal–bolus
n=456 Davies, 2014; Diabetes Obes Metab
vs. insulin detemir vs. DPP-4 inhibitors and T1D vs. insulin glargine T2D
-gluc, alpha glucosidase inhibitor; BB, basal–bolus; BOT, basal–oral therapy; DPP-4, dipeptidyl peptidase-4 inhibitor; TZD, thiazolidinedione
Insulin degludec once daily (BEGIN) All studies with active comparator
Black box denotes both treatment arms switching to NPH for 1 week then resuming IDeg or IGlar to allow for antibody measurement
Zinman et al. Diabetes Care 2012;35:2464–71; Rodbard et al. Diabet Med 2013;30:1298–304
IDeg OD IGlar OD
FPG
(mg/d
L)
150
0
90
138
198
162
102
66
114
186 174
126
78
59
43
55
75
67
51
35
71
63
47
39
HbA
1c (m
mol/m
ol)
5,0
5,5
6,0
6,5
7,0
7,5
8,0
8,5
9,0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
HbA
1c (
%)
3
4
5
6
7
8
9
10
11
0 4 8 12 16 20 24 28 32 36 40 44 48 52
FPG
(m
mol/
L)
HbA1c FPG
52 56 60 64 68 72 76 80 84 88 92 96 100 104
0.0
Treatment difference:
non-inferior
26
Extension
Treatment difference:
0.12%-points (ns)
65 79 91 104 Time (weeks)
Core
52 56 60 64 68 72 76 80 84 88 92 96 100 104
0
Treatment difference:
–0.43 mmol/L, p=0.005
26
Core Extension
Treatment difference:
–0.38 mmol/L, p=0.019
65 79 91 104 Time (weeks)
0
Insulin-naïve T2D: results BEGIN ONCE LONG – 2 years
Mejora GB -0.38 mmol/L (6,8 mg/dL) (p=0.019)
Garber et al. Lancet 2012;379:1498–507
IDeg OD + IAsp IGlar OD + IAsp
0
90
144
114
180
162
126
72
FPG
(mg/d
L)
0
45
60
50
75
70
55
40
HbA
1c (m
mol/m
ol)
65
35 3,0
4,0
5,0
6,0
7,0
8,0
9,0
10,0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
FPG
(m
mol/
L)
5,0
5,5
6,0
6,5
7,0
7,5
8,0
8,5
9,0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
HbA
1c (
%)
HbA1c FPG
0.0
Treatment difference:
non-inferior
0.0
Treatment difference: –0.29 mmol/L (ns)
26 26 Time (weeks) Time (weeks)
Basal–bolus in T2D: results BEGIN BB T2D
Black box denotes both treatment arms switching to NPH for 1 week then resuming IDeg or IGlar to allow for antibody measurement
Heller et al. Lancet 2012;379:1489–97; Bode et al. Diabet Med 2013;30:1293–7
IDeg OD IGlar OD
FPG
(mg/d
L)
168
216
120
192
144
96
HbA
1c (m
mol/m
ol)
59
43
55
75
67
51
35
71
63
47
39
4
5
6
7
8
9
10
11
12
0 4 8 12 16 20 24 28 32 36 40 44 48 52
FPG
(m
mol/
L)
5,0
5,5
6,0
6,5
7,0
7,5
8,0
8,5
9,0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
HbA
1c (
%)
HbA1c FPG
52 56 60 64 68 72 76 80 84 88 92 96 100 104
0.0
Treatment difference:
non-inferior
26
Core Extension
Treatment difference:
–0.04%-points (ns)
65 79 91 104 Time (weeks)
52 56 60 64 68 72 76 80 84 88 92 96 100 104
0
Treatment difference:
–0.33 mmol/L (ns)
26
Core Extension 0
Treatment difference:
–0.29 mmol/L (ns)
65 79 91 104 Time (weeks)
0
Basal–bolus in T1D: results BEGIN BB T1D – 2 years
extn, extension; non-inf., non-inferior; wks, weeks
* Data depict results for IDeg Flexible vs. IGlar
Trial
Population/ comparator
Duration (wks)
Efficacy Hypoglycaemia
Non-inf. HbA1c
FPG mmol/L [mg/dL]
Total
Nocturnal
ONCE LONG (core and extn)
Insulin naïve, T2D 104 -0.38
[-6.84] 16% 43%
BB Previously treated with insulin, T2D
52 -0.29
[-5.22] 18% 25%
FLEX* Insulin naïve and insulin treated, T2D
26 -0.42
[-7.56] 3% 23%
LOW VOLUME Insulin naïve, T2D 26 -0.42
[-7.56] 14% 36%
ONCE ASIA Insulin naïve, T2D 26 -0.09
[-1.62] 18% 38%
T1 BB LONG (core and extn)
Type 1 104 -0.29
[-5.22] 2% 25%
T1 FLEX*
(core and extn) Type 1 52
-1.07 [-19.26]
9% 25%
No significant difference
Insulin degludec significantly better
Phase 3a summary: IDeg vs Iglar
EDITION 1
EDITION 2
EDITION 3
EDITION JP 1
EDITION JP 2
EDITION 4
DM2
DM2
DM2
DM2
DM1
DM1
Tto previo: Basal-bolo
Tto previo: Basal + ADOs
Tto previo: ADOs (insulin-naïve)
Tto previo: Basal + ADOs (Japón)
Tto previo: Basal-bolo (Japón)
Tto previo: Basal-bolo
Riddle et al. Diabetes Care 2014;37(10):2755-62; Yki-Jarvinen et al. Diabetes Care 2014 Sep 5. pii: DC_140990. [Epub
ahead of print]; Bolli et al (abstract). ADA 2014, Diabetes 2014; Tesauch et al (abstract). ADA 2014, Diabetes 2014; Matsuhisa
et al (abstract) ADA 2014, Diabetes 2014.
Programa de estudios EDITION. Glargina U-300 vs Glargina U-100 Análisis de eficacia, tolerancia y seguridad en diferentes poblaciones
Diseño de los estudios y características basales
Tratamiento del estudio
EDITION 1 EDITION 2 EDITION 3 META-ANALYSIS
U300 vs Lantus®
(+AIR+Met) U300 vs Lantus®
(+Met+ADOs*) U300 vs Lantus®
(+Met+ADOs†) N/A
Número participantes U300 Lantus®
404 403
404 407
439 439
1247 1249
Tratamiento hipoglucemiante previo
Insulina Basal + insulina en las comidas +
ADOs
Insulina basal + ADOs
Insulin naive + ADOs
N/A
Criterios de inclusión Dosis de insulina HbA1C
Edad, años
≥42 U 7–10%
≥18
≥42 U 7–10%
≥18
7–11% ≥18
N/A
Media al inicio U300 Lantus® U300 Lantus® U300 Lantus® U300 Lantus®
IMC, kg/m2 Edad, años Duración diabetes, años HbA1C, %
36.6 60.1 15.6 8.15
36.6 59.8 16.1 8.16
34.8 57.9 12.7 8.26
34.8 58.5 12.5 8.22
32.8 58.2 10.1 8.51
33.2 57.2 9.6
8.57
34.7 58.7 12.7 8.31
34.8 58.5 12.6 8.32
*Use of sulfonylureas were prohibited within 2 months prior to screening and during the study †Except sulfonylureas, glinides and other OADs not approved for use with insulin AIR, análogo de insulina rápida
Ritzel R et al. Poster presentation at EASD 2014; Abstract 963 Available at: http://www.easdvirtualmeeting.org/resources/18908 Accessed September 2014
Análisis agrupado EDITION 1, 2 y 3: Se evaluó el control glucémico y las hipoglucemias durante 6 meses en una amplia población heterogénea
con DM2
Datos en archivo, informe final del EDITION 1, pág. 72; informe final del EDITION 2, pág. 73; informe final del EDITION 3, pág. 83; informe final del EDITION JP 2, pág. 86; informe final del EDITION 4, pág. 88; informe final del EDITION JP 1, pág. 80 Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43; Bolli GB et al. Diabetes Obes Metab. 2015 Jan 14. doi: 10.1111/dom.12438. [Pub. electrónica antes de impresión]; Terauchi Y et al. Presentación en póster en la reunión de la EASD 2014; abstract 976; Home PD et al. Presentación en póster en la reunión de la ADA 2014; abstract 80-LB; Matsuhisa M et al. Presentación en póster en la reunión de la EASD 2014; abstract 975
-0,83
-0,57
-1,42
-0,45 -0,40
-0,30
-0,83
-0,56
-1,46
-0,55
-0,44 -0,43
-1,5
-1
-0,5
0
Cam
bio
med
io d
e m
ínim
os
cuad
rad
os
en la
H
bA
1c
des
de
el in
icio
, %
Gla-100 Gla-300
EDITION 3
Inicio IB
EDITION JP 2
Cambio IB
EDITION 1
BB
EDITION 2
Cambio IB EDITION 4 EDITION JP 1
Diferencia media de mínimos cuadrados:
0,00 % (0,11 a 0,11)
Diferencia media de mínimos cuadrados:
-0,01 % (-0,14 a 0,12)
Diferencia media de mínimos cuadrados:
0,04 % (-0,09 a 0,17)
Diferencia media de mínimos cuadrados:
0,10 %
(-0,08 a 0,27)
Diferencia media de mínimos cuadrados:
0,04 % (-0,10 a 0,19)
Diferencia media de mínimos cuadrados:
0,13 % (-0,03 a 0,29)
33
Criterio de valoración principal: no inferioridad en el cambio en la HbA1c con Gla-300 frente a Gla-100 en el mes 6
T2
T1
GLARGINA U-300 HbA1c: se alcanzó el criterio de valoración principal en todos los ensayos
53
58
63
68
7,0
7,5
8,0
8,5
HbA1c (mmol/mol) Media ± EE
HbA1c (%) Media ± EE
Gla-100 Gla-300
90
110
130
150
170
5,0
6,0
7,0
8,0
9,0
10,0
Glucosa plasmática en ayunas
medida en el laboratorio
mmol/l Media ± EE
mg/dl Media ± EE
M12 M9 M6 S12 MB
M12 MB S12 M6 M9
Población ITm (Gla-300, n = 404; Gla-100, n = 400)
MB, momento basal; IC, intervalo de confianza; MC, mínimos cuadrados; M6, mes 6; M9, mes 9; M12, mes 12; EE, error estándar; S12, semana 12
• Gla-300 produjo reducciones más sostenidas de la HbA1c a los 12 meses comparado con Gla-100
Diferencia de medias de MC (IC 95%) entre los grupos
−0,17 (−0,30 a −0,05) %
(p = 0,007)
EDITION 1, 1 año: control glucémico y dosis de insulina
Primary end point in all studies: change from baseline in HbA1c
http://www.clinicaltrials.gov, accessed 4/10/2014
HbA1c, glycosylated hemoglobin; LPV, last patient visit; NPH, neutral protamine Hagedorn; OAM, oral antidiabetic medication; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
The BIL Phase 3 program
Lunt H et al. 967-P. American Diabetes Association’s 75th Scientific Sessions; Boston, MA; June 5 - 9, 2015 Chang AM et al. 972-P. European Association for the Study of Diabetes 51st Annual Meeting; Stockholm, Sweden; September 14-18, 2015
The BIL Phase 3 program
DM2: insulina basal + prandial
(IMAGINE 4): -0.20%
DM1: insulina basal + prandial
(IMAGINE 3): -0.22%
Basal insulin peglispro is superior to insulin glargine in reducing HbA1c in insulin-naïve patients with type 2 diabetes treated with oral antihyperglycaemic drugs: IMAGINE 2 BIL-treated patients had statistically superior HbA1c change at week 52 compared to GL-treated patients (-1.6 vs -1.3%; Δ=-0.3% [95% CI: -.40, -.19]).
Trescoli C et al. 971-P. European Association for the Study of Diabetes 51st Annual Meeting; Stockholm, Sweden; September 14-18, 2015
The BIL Phase 3 program
DM2: insulina basal + ADOs (tto previo con insulina basal; IMAGINE 5)
New Basal Insulin Formulations
• Introducción
• Mecanismo de acción, duración, variabilidad
• Estudios pivotales – Control glucémico
• HbA1c • Glucemia basal
– Hipoglucemias – Peso – Dosis de insulina
• Seguridad
– Cardiovascular – No cardiovascular
Black box denotes both treatment arms switching to NPH for 1 week then resuming IDeg or IGlar to allow for antibody measurement
Zinman et al. Diabetes Care 2012;35:2464–71; Rodbard et al. Diabet Med 2013;30:1298–304
IDeg OD IGlar OD
Confirmed hypoglycaemia Nocturnal confirmed hypoglycaemia
18% lower rate with IDeg (ns)
Core Extension
16% lower rate with IDeg (ns)
Core Extension
43% lower rate with IDeg, p=0.002
0
1
2
3
4
5
0 13 26 39 52
Confirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per
patient)
0
1
2
3
4
5
52 65 78 91 104
Confirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per p
atie
nt)
Time (weeks)
0,0
0,2
0,4
0,6
0,8
1,0
0 13 26 39 52 Noctu
rnal confirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per
patient)
Time (weeks)
0,0
0,2
0,4
0,6
0,8
1,0
52 65 78 91 104
Noctu
rnal c
onfirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per p
atie
nt)
36% lower rate with IDeg, p=0.038
Insulin-naïve T2D: results BEGIN ONCE LONG – 2 years
Nocturna -36 a -43%
Garber et al. Lancet 2012;379:1498–507
IDeg OD + IAsp IGlar OD + IAsp
Confirmed hypoglycaemia Nocturnal confirmed hypoglycaemia
18% lower rate with IDeg, p=0.0359
Time (weeks)
25% lower rate with IDeg, p=0.0399
Time (weeks)
0
2
4
6
8
10
12
14
16
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Confirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per
patient)
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1,6
1,8
2,0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Noctu
rnal confirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per
patient)
Basal–bolus in T2D: results BEGIN BB T2D
Nocturna -25% Confirmada -18%
Black box denotes both treatment arms switching to NPH for 1 week then resuming IDeg or IGlar to allow for antibody measurement
Heller et al. Lancet 2012;379:1489–97; Bode et al. Diabet Med 2013;30:1293–7
IDeg OD IGlar OD
Confirmed hypoglycaemia Nocturnal confirmed hypoglycaemia
Core Extension
25% lower rate with IDeg, p=0.021
Core Extension
25% lower rate with IDeg, p=0.02
0
10
20
30
40
50
60
70
80
0 13 26 39 52
Confirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per
patient)
0
10
20
30
40
50
60
70
80
52 65 78 91 104 Confirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per p
atie
nt)
7% higher rate with IDeg (ns)
2% higher rate with IDeg (ns)
0
2
4
6
8
10
12
0 13 26 39 52
Noctu
rnal confirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per
patient)
Time (weeks)
0
2
4
6
8
10
12
52 65 78 91 104
Noctu
rnal c
onfirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per p
atie
nt)
Time (weeks)
Basal–bolus in T1D: results BEGIN BB T1D – 2 years
Nocturna -25%
extn, extension; non-inf., non-inferior; wks, weeks
* Data depict results for IDeg Flexible vs. IGlar
Trial
Population/ comparator
Duration (wks)
Efficacy Hypoglycaemia
Non-inf. HbA1c
FPG mmol/L [mg/dL]
Total
Nocturnal
ONCE LONG (core and extn)
Insulin naïve, T2D 104 -0.38
[-6.84] 16% 43%
BB Previously treated with insulin, T2D
52 -0.29
[-5.22] 18% 25%
FLEX* Insulin naïve and insulin treated, T2D
26 -0.42
[-7.56] 3% 23%
LOW VOLUME Insulin naïve, T2D 26 -0.42
[-7.56] 14% 36%
ONCE ASIA Insulin naïve, T2D 26 -0.09
[-1.62] 18% 38%
T1 BB LONG (core and extn)
Type 1 104 -0.29
[-5.22] 2% 25%
T1 FLEX*
(core and extn) Type 1 52
-1.07 [-19.26]
9% 25%
No significant difference
Insulin degludec significantly better
Phase 3a summary: IDeg vs IGlar
0
20
40
60
80
100
BL to M6 BL to W8 W9 to M6 BL to M6 BL to W8 W9 to M6
Principal criterio de valoración secundario
-21 %, P = 0,0045
Gla-100 Gla-300
Part
icip
ante
s c
on ≥
1 h
ipoglu
cem
ias c
onfirm
adas (≤70
mg/d
l [3,9
mm
ol/l])
y/o
hip
oglu
cem
ias s
evera
s (
%)
Riddle MC et al. Diabetes Care. 2014;37:2755-62; Yki-Järvinen H et al. Diabetes Care. 2014;37:3235-43; datos en archivo, saf_hypo_ph2_3 pág. 221, 275-6; Bolli GB et al. Diabetes Obes Metab. 2015 Jan 14. doi: 10.1111/dom.12438. [Pub. electrónica antes de impresión]; Bolli GB et al. Presentación en póster en la reunión de la EASD 2014; abstract 947; datos en archivo, saf_hypo_ph2_3, pág. 222, 276; Terauchi Y et al. Presentación en póster en la reunión de la EASD 2014; abstract 976
Población por IDTm en el principal criterio de valoración secundario; población de seguridad para otros datos; BL: basal; M6: mes 6; S8: semana 8; S9: semana 9; RR: riesgo relativo
RR 0,93 (0,88 a 0,99)
RR 0,86 (0,78 a 0,94)
RR 0,96 (0,89 a 1,04)
RR 0,78 (0,68 a 0,89)
RR 0,79 (0,64 a 0,98)
RR 0,79 (0,67 a 0,93)
En cualquier momento
(24 h)
Nocturnas (00:00-05:59 h)
0
20
40
60
80
100
BL to M6 BL to W8 W9 to M6 BL to M6 BL to W8 W9 to M6
Principal criterio de valoración secundario
-23 %, P = 0,0038
RR 0,90 (0,83 a 0,98)
RR 0,78 (0,69 a 0,89)
RR 0,91 (0,82 a 1,02)
RR 0,71 (0,58 a 0,86)
RR 0,53 (0,39 a 0,72)
RR 0,77 (0,60 a 0,97)
En cualquier momento
(24 h)
Nocturnas (00:00-05:59 h)
0
20
40
60
80
100
BL to M6 BL to W8 W9 to M6 BL to M6 BL to W8 W9 to M6
Principal criterio de valoración secundario
-11 %, P = 0,454 RR 0,88 (0,77 a 1,01)
RR 0,83 (0,66 a 1,03)
RR 0,86 (0,74 a 1,00)
RR 0,76 (0,59 a 0,99)
RR 0,74 (0,48 a 1,13)
RR 0,89 (0,66 a 1,20)
En cualquier momento
(24 h)
Nocturnas (00:00-05:59 h)
EDITION 1
BB
EDITION 2
Cambio IB
EDITION 3
Inicio IB
Incidencia de hipoglucemias confirmadas (≤70 mg/dl) o severas en DMT2
Nocturna -21% Nocturna -23%
Nocturna -11% (ns)
24h -7% 24h -10%
U300 U100 U300 U100
Tasa por paciente y año 2.10 3.06 15.22 17.73
RR (95% CI) vs U100 0.69 (0.57 to 0.84) 0.86 (0.77 to 0.97)
P value 0.0002 0.0116
-14% -31%
Hipoglucemia a cualquier hora (24 h)
0
10
U300 U100
8
4
2
4 8 12 16 20 24 28
6
Time, weeks
0
Maintenance Maintenance
Hipoglucemia nocturna (00:00–05:59 h)
0
3
U300 U100
2
1
4 8 12 16 20 24 28
Time, weeks
0
*eventos confirmados: basado en niveles de glucosa plasmática ≤3.9 mmol/L (≤70 mg/dL)
Ritzel R et al. New insulin glargine 300 U/mL: Glycemic control and hypoglycemia in a meta-analysis of Phase 3ª EDITION clinical trials in people with T2DM. Poster presentation on EASD 2014. Abstract 963 Available at http://www.easdvirtualmeeting.org/resources/18908 Accessed November 2014
Tiempo, semanas Tiempo, semanas
Hip
ogl
uce
mia
no
ctu
rna
Hip
ogl
uce
mia
cu
alq
uie
r h
Análisis agrupado EDITION 1, 2 y 3 en DMT2
Menos hipoglucemias confirmadas y/o severas con U300 vs Lantus® por la noche y durante todo el día (24 h)
0%
10%
20%
30%
40%
50%
60%
70%
0 to 2 2 to 4 4 to 6 6 to 8 8 to 10 10 to 12 12 to 14 14 to 16 16 to 18 18 to 20 20 to 22 22 to 24
Clock time, hours
% p
arti
cip
ante
s ≥
1 h
ipo
glu
cem
ia c
on
firm
ada
(≤7
0 m
g/d
L [3
.9 m
mo
l/L]
) o s
ever
a
Ritzel R et al. New insulin glargine 300 U/mL: Glycemic control and hypoglycemia in a meta-analysis of Phase 3ª EDITION clinical trials in people with T2DM. Poster presentation on EASD 2014. Abstract 963 Available at http://www.easdvirtualmeeting.org/resources/18908 Accessed November 2014
→Menos pacientes ≥ 1 hipoglucemia sintomática con Gla-300 vs Gla-100: 49,6% vs 56,4%; RR 0,88 [95% CI: 0,82 a 0,94] durante los 6 meses de estudio
→Hipoglucemia severa baja en ambos grupos (≥ 1 evento): 2,3% con Gla-300 vs 2,6% con Gla-100; 0,11 eventos/participante /año en ambos grupos.
Hipoglucemias nocturnas
Tiempo (horas)
Lantus
U300
Lantus®
Análisis agrupado EDITION 1, 2 y 3 en DMT2
Hipoglucemia confirmada y/o severa durante las 24 horas
EDITION 4
Datos en archivo, saf_hypo_ph2_3, pág. 219, 273; Home PD et al. Presentación en póster en la reunión de la ADA 2014; abstract 80-LB; datos en archivo, JP1-efc12449_15_3_1_ae_data, pág. 7, 9; Matsuhisa M et al. Presentación en póster en la reunión de la EASD 2014; abstract 975
Gla-100 Gla-300
47
El estudio no se diseñó ni tuvo la capacidad para demostrar la diferencia en el riesgo de hipoglucemias entre Gla-300 y Gla-100 como
criterio de valoración preespecificado
0
20
40
60
80
100
BL to M6 BL to W8 W9 to M6 BL to M6 BL to W8 W9 to M6
RR 1,00 (0,95 a 1,04)
RR 0,98 (0,92 a 1,04)
RR 0,98 (0,91 a 1,06)
Part
icip
ante
s c
on ≥
1 h
ipoglu
cem
ias c
onfirm
adas (≤70 m
g/d
l [3,9
mm
ol/l]) y/o
hip
oglu
cem
ias s
evera
s (
%)
En cualquier momento (24 h) Nocturnas (00:00-05:59 h)
RR 0,98 (0,88 a 1,09)
RR 0,82 (0,70 a 0,96)
RR 1,06 (0,92 a 1,23)
Riesgo relativo (IC del 95 %)
Incidencia de hipoglucemias confirmadas (≤70 mg/dl) o severas en DMT1
Lunt H et al. 967-P. American Diabetes Association’s 75th Scientific Sessions; Boston, MA; June 5 - 9, 2015
T2D: PEGLISPRO vs Glargine IMAGINE 4. DM2: insulina basal + prandial
Nocturna -45% Total +10%
Lunt H et al. 967-P. American Diabetes Association’s 75th Scientific Sessions; Boston, MA; June 5 - 9, 2015
T1D: PEGLISPRO vs Glargine IMAGINE 3. DM1: insulina basal + prandial
Nocturna -47% Total +11%
T1D: PEGLISPRO vs Glargine IMAGINE 5. DM2: insulina basal + ADOs (tto previo con insulina basal)
Nocturna -60% Total -23%
Trescoli C et al. 971-P. European Association for the Study of Diabetes 51st Annual Meeting; Stockholm, Sweden; September 14-18, 2015
New Basal Insulin Formulations
• Introducción
• Mecanismo de acción, duración, variabilidad
• Estudios pivotales – Control glucémico
• HbA1c • Glucemia basal
– Hipoglucemias – Peso – Dosis de insulina
• Seguridad
– Cardiovascular – No cardiovascular
Degludec: Weight neutral vs Glargine
Efectos adversos:
en general, ambos tratamientos fueron bien tolerados y presntaron tasas similiares de efectos adversos
W: semanas; M:meses
Cam
bio
de
pe
so (
me
dio
), k
g
Ritzel R et al. New insulin glargine 300 U/mL: Glycemic control and hypoglycemia in a meta-analysis of Phase 3ª EDITION clinical trials in people with T2DM. Poster presentation on EASD 2014. Abstract 963 Available at http://www.easdvirtualmeeting.org/resources/18908 Accessed November 2014
Diferencia media MC entre grupos (6º mes) -0,28 (IC 95% -0,55 a -0,01) kg
P=0,039
W: semanas; M: meses
Análisis agrupado EDITION 1, 2 y 3 en DMT2
Diferencia pequeña, pero significativa, en el aumento de peso con U300 vs Lantus
PEGLISPRO Peso
Lunt H et al. 967-P. American Diabetes Association’s 75th Scientific Sessions; Boston, MA; June 5 - 9, 2015 Trescoli C et al. 971-P. American Diabetes Association’s 75th Scientific Sessions; Boston, MA; June 5 - 9, 2015 Chang AM et al. 972-P. European Association for the Study of Diabetes 51st Annual Meeting; Stockholm, Sweden; September 14-18, 2015
DM1: basal y bolos DM2: basal y bolos
DM2: basal
New Basal Insulin Formulations
• Introducción
• Mecanismo de acción, duración, variabilidad
• Estudios pivotales – Control glucémico
• HbA1c • Glucemia basal
– Hipoglucemias – Peso – Dosis de insulina
• Seguridad
– Cardiovascular – No cardiovascular
0,5 1 2
BEGIN BB T1 LONG2 (52)
Trial ID (wks)
BEGIN FLEX T1†1 (26)
BEGIN BB T2 LONG3 (52)
BEGIN ONCE LONG4 (52)
BEGIN LOW VOLUME5 (26)
BEGIN ONCE ASIA6 (26)
BEGIN FLEX T21 (26)
Rate ratio [95% CI]
0.89 [0.84;0.93]
0.87 [0.81;0.94]
1.03 [0.97;1.10]
0.97 [0.89;1.05]
0.89 [0.82;0.98]
0.80 [0.71;0.90]
0.90 [0.82;0.99]
†The ratios reported in Mathieu et al. 2013 (Table 2) deviate from those above as the publication analyses all IDeg patients (i.e. both the forced flex and standard arms) References: 1. Data on file, DOF-MA-IDeg-24APR2013-001, Novo Nordisk A/S; 2. Heller et al. Lancet 2012;379:1489–97; 3. Garber et al. Lancet 2012;379:1498–507; 4. Zinman et al. Diabetes Care 2012;35:2464–71 (+ supplementary online data); 5. Gough et al. Diabetes Care 2013;36:2536–42; 6. Onishi et al. J Diabetes Investig 2013;4:605–12 (+ supplementary online information)
For T1D patients, the total daily dose of IDeg was significantly 12% lower than IGlar (p<0.0001)1
For insulin-naïve T2D patients, the total daily dose was 10% lower with IDeg than IGlar (p=0.0004)1
DEGLUDEC Total daily dose overview by trial
Datos en archivo, E19_Insulin dose_Absolute and Relative differences_M12_2014-09-03.doc, pág. 6, 12, 14, 22, 38, 44 1Ficha técnica en EE. UU., 27 feb 2015
Dosis de insulina basal en el mes 6 (U/kg)
Estudios de DMT2 Estudios de
DMT1
EDITION 1
BB
EDITION 2 Cambio IB
EDITION 3 Inicio IB
EDITION 4
Gla-300 0,98 0,93 0,62 0,47
Gla-100 0,88 0,85 0,53 0,40
Diferencia relativa Gla-300 vs Gla-
100, % +11,55 +10,44 +16,58 +17,51
57
T2
T1
Glargina U 300 Dosis de insulina basal en el mes 6
58
PEGLISPRO Dosis de insulina
Lunt H et al. 967-P. American Diabetes Association’s 75th Scientific Sessions; Boston, MA; June 5 - 9, 2015 Trescoli C et al. 971-P. American Diabetes Association’s 75th Scientific Sessions; Boston, MA; June 5 - 9, 2015
DM2: tto previo con insulina basal DM1: basal y bolos
New Basal Insulin Formulations
• Introducción
• Mecanismo de acción, duración, variabilidad
• Estudios pivotales – Control glucémico
• HbA1c • Glucemia basal
– Hipoglucemias – Peso – Dosis de insulina
• Seguridad
– Cardiovascular – No cardiovascular
DEGLUDEC Seguridad cardiovascular
61
Year
Year
Primary Co-Primary
Year
A: Co-primary Outcome 1 B: Co-primary Outcome 2
C: Mortality
Pro
po
rtio
n w
ith E
ven
ts
Pro
po
rtio
n w
ith E
ven
ts
Pro
po
rtio
n w
ith E
ven
ts
La mortalidad es un criterio de
valoración secundario del estudio
Pro
porc
ión c
on los e
pis
odio
s
Pro
porc
ión c
on los e
pis
odio
s
Pro
porc
ión c
on los e
pis
odio
s
A: Covariable principal 1
C: Mortalidad
B: Covariable principal 2
Año
Año
Año
Nº en riesgo
Nº en riesgo
Nº en riesgo
The ORIGIN trial Investigators. Basal insulin and Cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012 Jul 26;367(4):319-28
GLARGINA U-300 Seguridad cardiovascular (ORIGIN)
PEGLISPRO Seguridad cardiovascular
Lunt H et al. 967-P. American Diabetes Association’s 75th Scientific Sessions; Boston, MA; June 5 - 9, 2015 Trescoli C et al. 971-P. American Diabetes Association’s 75th Scientific Sessions; Boston, MA; June 5 - 9, 2015
DM1 DM2
Mark L. Hartman1 et al. Liver Enzyme and Liver Fat Content (LFC) Results from Basal Insulin Peglispro (BIL) Clinical Trials in Type 1 (T1D) and Type 2 Diabetes (T2D). 973-P. American Diabetes Association’s 75th Scientific Sessions; Boston, MA; June 5 - 9, 2015
PEGLISPRO Seguridad no cardiovascular
Lunt H et al. 967-P. American Diabetes Association’s 75th Scientific Sessions; Boston, MA; June 5 - 9, 2015
PEGLISPRO Seguridad no cardiovascular
Cost-effectiveness of insulin degludec compared with insulin glargine for patients with type 2 diabetes treated with basal insulin – from the UK health care cost perspective
Diabetes, Obesity and Metabolism 16: 366–375, 2014
New Basal Insulin Formulations PRECIO
RESUMEN Nuevas insulinas basales vs Glargina U-100
Mejor que G-100
Igual que G-100
Peor que G-100
COMPARATIVA FRENTE A GLARGINA U-100
DURACIÓN > 24 H
VARIABILIDAD HbA1c GB HIPO
TOTAL HIPO
NOCTURNA PESO
DOSIS INSULINA
SEGURIDAD CV
SEGURIDAD NO CV
PRECIO
DEGLUDEC
GLARGINA U-300
PEGLISPRO
¿?
¿? ¿?
Characteristics of New Basal Insulin Analogs
Benefits over Glargine
•Longer duration of action
•Less variability
•Less weight gain
•Less (nocturnal) hypoglycemia
•Better glycaemic control?
Simon ACR. Diabetes Technol Ther. 2011;13(suppl 1):S103-108. Grunberger G. Diab Obes Metab. 2013;15(suppl 1):1-5.
Room for Improvement
•More consistent 24+ hour coverage
•Flat time-action profile
•Less day-to-day variability
•Less weight gain
•Less hypoglycemia
•More suppression of hepatic glucose production
MUCHAS GRACIAS
IDegLir
a C
ore
Scie
nce:
V.
2.0
. ,
23/J
un/2
015
Flexible vs Fixed dosing in T2D: study design BEGIN FLEX T2D
Inclusion criteria
• Type 2 diabetes ≥6 months
• Previously treated with OADs and/or basal insulin
• HbA1c:
OADs only 7–11% Basal insulin ± OADs 7–10%
• BMI ≤40 kg/m2
• Age ≥18 years
Patients with type 2 diabetes
(n=687)
0 26 weeks
Open label
IGlar OD ± OADs (n=230) (metformin/SU/pioglitazone)
IDeg Fixed OD ± OADs (n=228) (metformin/SU/pioglitazone)
IDeg Flexible OD ± OADs (n=229) (metformin/SU/pioglitazone)
Meneghini et al. Diabetes Care 2013;36:858–64
IDegLir
a C
ore
Scie
nce:
V.
2.0
. ,
23/J
un/2
015
Flexible vs Fixed dosing in T2D: results BEGIN FLEX T2D
Meneghini et al. Diabetes Care 2013;36:858–64
IDeg Flexible OD IDeg Fixed OD IGlar OD
0
90
144
114
180
162
126
72
FPG
(mg/d
L)
0
45
60
50
75
70
55
40
HbA
1c (m
mol/m
ol)
65
35
3,0
4,0
5,0
6,0
7,0
8,0
9,0
10,0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
FPG
(m
mol/
L)
5,0
5,5
6,0
6,5
7,0
7,5
8,0
8,5
9,0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
HbA
1c (
%)
HbA1c FPG
0.0
IDeg Flexible vs IGlar Treatment difference:
non-inferior
0.0
IDeg Flexible vs IGlar Treatment difference: –0.42 mmol/L, p=0.04
ns
Time (weeks)
23% lower rate with IDeg Flexible than with IGlar
(ns)
Time (weeks)
IDeg Flexible vs IDeg Fixed Treatment difference:
ns
Confirmed hypoglycaemia Nocturnal confirmed hypoglycaemia
Time (weeks) Time (weeks)
IDeg Flexible vs IDeg Fixed Treatment difference:
–0.05 mmol/L (ns)
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1,6
1,8
2,0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Confirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per
patient)
18% higher rate with IDeg Flexible than with IDeg Fixed (ns)
0,0
0,1
0,2
0,3
0,4
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Noctu
rnal confirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per
patient)
Jeandidier N et al. Poster presentation at EASD 2014; Abstract 961 Available at: http://www.easdvirtualmeeting.org/resources/18792 Accessed September 2014
-0,6
-0,4
-0,2
0
0,2
0,4 Flexible Fixed
LS mean change (SE) in HbA1C from Month 6–9, %
EDITION 1 EDITION 2
Hipoglucemias similares
0
10
20
30
40
50
60
70
Confirmed or severe at any time (≤70 mg/dL [3.9 mmol/L])
Confirmed or severe nocturnal (≤70 mg/dL [3.9
mmol/L])
0
10
20
30
40
50
60
70
Confirmed or severe at any time (≤70 mg/dL [3.9 mmol/L])
Confirmed or severe nocturnal (≤70 mg/dL [3.9 mmol/L])
Dosificación flexible vs fija: EDITION 1 & 2 sub-estudios
Control glucémico similar con intervalos fijos de administración (24 h) vs intervalos flexibles (24 ± 3 h)
Average 24-h glucose profiles during the last 2 weeks of each treatment period (CGM population; pooled data period A + B)
Bergenstal RM et al. Poster presentation at EASD 2014; Abstract 949 Available at: http://www.easdvirtualmeeting.org/resources/18574 Accessed
September 2014
11
10
9
8
7
0 2 4 6 8 10 12 14 16 18 20 22 24
Morning injection
U300 Lantus®
11
10
9
8
7
0 2 4 6 8 10 12 14 16 18 20 22 24
Evening injection
11
10
9
8
7
0 2 4 6 8 10 12 14 16 18 20 22 24
Combined: Morning and evening
Time, h
11
10
9
8
7
0 2 4 6 8 10 12 14 16 18 20 22 24
U300
Morning Evening
11
10
9
8
7
0 2 4 6 8 10 12 14 16 18 20 22 24
Lantus®
Time, h
Morning Evening
Los perfiles de glucemia media parecen más constantes con U300 comparados con U100,
independientemente del momento de inyección (mañana o tarde)
Inyección por la mañana
Inyección por la tarde
Combinado: Mañana y tarde
Per
file
s d
e gl
uco
sa ,
med
ia (
EE),
mm
ol/
L
Estudio PDY12777: monitorización continua glucosa DM1
Perfil de glucosa más constante con U300 vs U100