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Agonistas del Receptor de GLP-1 en el tratamiento de la diabetes mellitus tipo 2
Manel Puig DomingoServei d´Endocrinologia
Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona
Conflictos de interés
• Comités de asesoramiento internacional: Lilly, Novartis
• Comités de asesoramiento nacional: Lilly, Novartis, Novo-Nordisk, Sanofi-Aventis
• Conferencias: Lilly, Novo-Nordisk
Opciones Terapéuticas en la Diabetes Tipo 2 hasta el 2012
19821982--55 19951995 2001200119221922 19501950’’ss 19961996 2003 2003
SulfonilureasSulfonilureasSulfonilureasInsulina HumanaInsulina HumanaInsulina Humana
MetforminaMetforminaMetforminaLisproLisproLispro
GlinidasGlinidasGlinidasGlarginaGlarginaGlargina
??
Insulina animalInsulina animalInsulina animal
GlitazonasGlitazonasGlitazonas
AspartAspartAspart
Inhibidores de DPPInhibidores de DPP--44Agonistas Agonistas del R de GLPdel R de GLP--11
DetemirDetemir
2006
La DM2 es una enfermedad progresiva: UKPDS 6-Year Data
Time from randomization (Years)0 1 2 3 4 5 6
HbA
1C (M
edia
n %
)
0
6
7
8
9
6.2% HbA1c upper limit of normal
ConventionalChlorpropamideGlibenclamideInsulinMetformin
Time from Randomisation (Years)
HbA
1c(M
edia
n %
)
Los tratamientos clásicos no modifican la historia natural de
la DM2Los tratamientos clásicos producen hipoglicemias,
ganancia ponderal, y actualmente se discute su
seguridad, y esto también es válido para la insulina
(y tampoco la terapia insulínica)
UKPDS. Lancet. 1998;352:854-865.
La función de la célula β disminuye a lo largo del tiempo en pacientes con Diabetes Tipo 2
Tiempo desde el Diagnóstico (años)
Func
ión
de la
Cél
ula β
(%)
Holman RR. Diabetes Res Clin Pract. 1998;40(suppl 1):S21-S25.; UKPDS. Diabetes. 1995;44:1249-1258.
-12 -10 -8 -6 -4 -2 0 2 4 6
Es posible que la función de la célula βya haya disminuido
en un 50% en el momento del diagnóstico
La función de la célula β disminuye
progresivamente con el tiempo
aproximadamente un 6% por año
100
80
60
40
20
0
La función de la célula β disminuye a lo largo del tiempo en pacientes con Diabetes Tipo 2
100
Tiempo desde el Diagnóstico (años)
Func
ión
de la
Cél
ula β
(%)
Holman RR. Diabetes Res Clin Pract. 1998;40(suppl 1):S21-S25.; UKPDS. Diabetes. 1995;44:1249-1258.
-12 -10 -8 -6 -4 -2 0 2 4 6
Es posible que la función de la célula βya haya disminuido
en un 50% en el momento del diagnóstico
La función de la célula β disminuye
progresivamente con el tiempo
aproximadamente un 6% por año
80
60
40
20
0
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
ND IFG T2DM ND T2DM
β-C
ell v
olum
e (%
)
Obese Lean
-50%-50%
-63%-63% -41%-41%
βcell mass in T2 DM
ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitusButler AE et al. Diabetes. 2003;52:102-110.
The ideal antidiabetic drug• Longer durability of glucose control/efficacy • Agents that delay/prevent loss of β-cell function • Agents that increase β-cell mass and function • Therapies that provide superior control of
postprandial glucose • Agents that do not cause increased weight gain,
and/or increase cardiovascular risk in any manner
• Agents that improve metabolic syndrome risk factors
• Agents that directly affect the progression of diabetic complications
Acciones clásicas y nuevas de la molécula de supervivencia GLP-1
Tejido Adiposo
Cerebro Estómago
Absorción de glucosa y almacenamiento
Sensibilidad a la Insulina
Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157.
HígadoPáncreas
Músculo
Secreción de Insulina
Secreción de Glucagón
Biosíntesis de Insulina
Proliferación de la célula Beta
Apoptosis de la célula Beta
Vaciamiento Gástrico
ApetitoNeuroprotección
Cardioprotección
Función Cardiaca
Producción de Glucosa
Corazón
GLP-1
Intestino
{
Structure of native GLP-1 and two GLP-1 R agonists
11
Agonistas del Receptor GLP-1 de acción prolongada
Exenatide LAR: Microsphere Delivery Exenatide LAR: Microsphere Delivery System for Continuous Therapeutic Levels System for Continuous Therapeutic Levels
♦ Exenatide is incorporated into PLG microspheres1
• PLG is a medical biodegradable polymer (degraded to CO2 and water)2
• Via hydration, exenatide at or near the surface dissolves and diffuses away (initial release)3
• PLG degrades, creating pores for exenatide diffusion and release from microspheres (sustained release)4
• Allows gradual drug delivery at a controlled rate2
PLG indicates poly(D,L-lactide-co-glycolide).1. Malone J et al. Expert Opin Investig Drugs. 2009;18:359-367. 2. Tracy MA et al. Biomaterials. 1999;20:1057-1062. 3. Langer R, Folkman J. Nature. 1976;263:797-800. 4. Bawa R. et al. J. Controlled Release. 1985:1:259-267.
Plasma Exenatide LAR reachesPlasma Exenatide LAR reaches SteadySteady--State State Concentrations Within 6Concentrations Within 6--7 Weeks 7 Weeks
0
50
100
150
200
250
300
350
400
450
500
3 6 9 12 15 18 21 24 27
Treatment Period Follow-up Period
0.8 mg exenatide QW2.0 mg exenatide QW
10 µg exenatide BID(single dose)
12 hours
0 1
Time (weeks)
Plas
ma
Exen
atid
e (p
g/m
L)
• Data are mean ± SD
Fineman M et al. Clin Pharmacokinet. 2010;50(1):65-74.
HbA1c Changes Over 52 Weeks of Exenatide LAR treatment
Exe LAR, n = 120; BL = 8.3%
Time (Weeks)
LS M
ean
Cha
nge
(SE)
in H
bA1c
(%)
-2.0%-2.0%
*
**
* * * * *
40 5244 48363330262218141060-2.5
-2.0
-1.5
-1.0
-0.5
0.0Controlled Extension (All Exe LAR)
Exenatide BID EQW, n = 121; BL = 8.2%
• *p<.05Buse et al. Diabetes Care 2010;33(6):1255-61.
<7.0% ≤6.5% ≤6.0%0
25
50
75
100EQW, 2-Year Completers (N = 216)EQW, Intent-to-Treat (N = 295)
60%55%
39% 36%
17% 16%
Target HbA1c
% A
chie
ving
Tar
get
Exenatide LAR: Subjects Achieving HbA1c Target Goals After 2 YearsTarget Goals After 2 Years
• EQW: exenatide once a week (Exenatide LAR)
Taylor, et al. BMC Endocr Disord. 2011;11(1):9 [Epub].
Changes in HbA1c vs. ComparatorsLS
Mea
n C
hang
e (S
E) In
HbA
1c(%
)
-1.9*
-1.5*-1.5*-1.5
-1.2
-0.9
-1.3
DURATION-11 DURATION-23 DURATION-34
0
-0.5
-1.0
-1.5
-2.0
Baseline (%) 8.3 8.38.6 8.5 8.58.3 8.3
-1.6*
-0.9
DURATION-52
8.5 8.4
Exenatide BID
Insulin Glargine
Sitagliptin
Exe LAR
Pioglitazone
N = 233 223160 166 165148 147 129 123
• *p<.05 vs. comparator, intent-to-treat population
1. Drucker et al. Lancet 2008;372(9645):1240-50.2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):2010-81.
3. Bergenstal et al. Lancet 2010;376(9739):431-9.4. Diamant et al. Lancet 2010;375(9733):2234-43.
Proportion of Subjects Achieving HbA1cTarget of ≤7% (or <7%) vs. Comparators
• DURATION-1: evaluable population; DURATION-5, -2, and -3: intent-to-treat population; DURATION-5 and -3: target of <7%
1. Drucker et al. Lancet 2008;372(9645):1240-50.2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):2010-81. 3. Bergenstal et al. Lancet 2010;376(9739):431-9.
4. Data on file, Amylin Pharmaceuticals, Inc. 5. Diamant et al. Lancet 2010;375(9733):2234-43.
Prop
ortio
n (%
)
DURATION-11
0
80
50
40
10
70
60
30
20
77
61
p<.05
DURATION-23,4
36
49
p<.05
62
p<.05DURATION-35
60
48
p = .01
100
90
DURATION-52
58
30
p<.0001
Exenatide BID
Insulin Glargine
Sitagliptin
Exe LAR
Pioglitazone
N = 129 130 129 123 160 166 165 233 223
Postprandial Glucose Changes: Exenatide LAR vs Exenatide twice a day
Exenatide LAR 2 mg, n = 27 Exenatide 10 mg BID, n = 24
Mea
n G
luco
se (m
mol
/L) 15.0
10.0
5.0
12.5
7.5
• p =.0124, Exenatide LAR vs. exenatide twice a day
Drucker et al. Lancet 2008;372(9645):1240-50.
Time (Hours)
-1 0 1 2 53 4 -1 0 1 2 3 4 5M
ean
Glu
cose
(mm
ol/L
) 15.0
10.0
5.0
Time (Hours)
12.5
7.5
Baseline (Dotted line, circle)Week 14 (Solid line, square)
Changes in Fasting Glucose vs. Comparators
LS M
ean
Cha
nge
(SE)
in F
G (m
mol
/L)
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
0
-2.3*
-1.4
-1.9*
-0.7
-1.8‡
-0.9
-1.5
-2.1§
-2.8
Exenatide BID
Insulin Glargine
Sitagliptin
EQW
Pioglitazone
Baseline (mmol/L)DURATION-11 DURATION-52,3 DURATION-23, 4 DURATION-35
9.9 9.2 9.6 9.3 9.2 9.2 9.1 9.9 9.7N = 148 147 228 220160 166 165129 123
• *p<.001 vs. exenatide BID, ‡p=.004 vs. sitagliptin, §p=.001 vs. insulin glargine• Intent-to-treat population
1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.3. Data on file, Amylin Pharmaceuticals, Inc.
4. Bergenstal et al. Lancet 2010;376(9739):431-9. 5. Diamant et al. Lancet 2010;375(9733):2234-43.
Changes in Body Weight vs. Comparators
4
-5
Exenatide BID
Insulin Glargine
Sitagliptin
Exe LAR
Pioglitazone
-3.6-3.7
0
-2
-3
-4
-1
2
3
1
-2.6†-2.3*
-0.8
1.4
-2.3
-1.4
2.8
LS M
ean
Cha
nge
(SE)
in
Bod
y W
eigh
t (kg
)DURATION-11
102 102Baseline (kg)DURATION-52
97 94DURATION-23 DURATION-34
91 9189 87 88N = 148 147 233 223160166 165129 123
• *p<.001 vs. sitagliptin and p<.0001 vs. pioglitazone †p<.05 vs. insulin glargine, intent-to-treat population
3. Bergenstal et al. Lancet 2010;376(9739):431-9. 4. Diamant et al. Lancet 2010;375(9733):2234-43.
1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.
Changes in HbA1c and Body Weight: Exenatide LAR vs insulin glargine
Wei
ght C
hang
e fr
om B
asel
ine
(kg)
HbA1c (%) Change from Baseline
16
12
8
4
0
-4
-8
-12
-16-6 -4 -2 0 2 4 6
79.4%31.4%
0.0%4.5%
4.4%1.4%
16.2%62.7%
Insulin Glargine (N = 223)Exenatide LAR (N = 233)
• Intent-to-treat population
Diamant et al. Lancet 2010;375(9733):2234-43.
Changes in Systolic Blood Pressure vs. Comparators
LS m
ean
chan
ge (S
E) in
SB
P (m
mH
g)
-14
-12
-10
-8
-6
-4
-2
0
2
DURATION-11 DURATION-52 DURATION-23,5 DURATION-34
Baseline (mmHg) 128 130 130 128 126 126 127 135 133
EQWExenatide BIDSitagliptinPioglitazoneInsulin Glargine
-4.7-3.4 -2.9
-1.2
-3.6
+0.2
-1.6-3.0
-1.0
N = 129 123148 147 233 223160 166 165
*
ITT Patients
• *p =.010 vs. sitagliptin, intent-to-treat (ITT) population4. Diamant et al. Lancet 2010;375(9733):2234-43.5. Data on file, Amylin Pharmaceuticals, Inc.
1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.3. Bergenstal et al. Lancet 2010;376(9739):431-9.
Changes in Diastolic Blood Pressure vs. Comparators
LS m
ean
chan
ge (S
E) in
DB
P (m
mH
g)
-8
-6
-4
-2
0
2
78 80 78 77 80 79 80 81 80
-1.7 -1.7
+0.2
-0.1
-1.4 -0.4
-2.5
-1.0 -1.0
129 123148 147 233 223160 166 165Baseline (mmHg)
N =
DURATION-11 DURATION-52 DURATION-23,5 DURATION-34
EQWExenatide BIDSitagliptinPioglitazoneInsulin Glargine
ITT Patients
• No statistically significant between-group differences in diastolic blood pressure reduction were observed.• Intent-to-treat (ITT) population• EQW: exenatide once a week (LAR), BID: twice a day1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.3. Bergenstal et al. Lancet 2010;376(9739):431-9.
4. Diamant et al. Lancet 2010;375(9733):2234-43.5. Data on file, Amylin Pharmaceuticals, Inc.
Changes in LDL-C: Exenatide LAR vs Comparators
LS M
ean
Cha
nge
(SE)
in L
DL-
C (m
mol
/L)
0
-0.05
-0.10
-0.15
-0.20
-0.25
0.05
0.10
0.15
-0.13*
0.03
0.07
-0.17†
0.050.05
-0.03
0.04
-0.05
Exenatide BID
Insulin Glargine
Sitagliptin
Exe LAR
Pioglitazone
Baseline (mmol/L)
DURATION-11,5 DURATION-52 DURATION-23,5 DURATION-34
2.4 2.6 2.7 3.1 2.7 2.7 2.9 2.7 2.7N = 148 147 233 223160 166 165129 123
• *p=.02 vs. exenatide BID, †p<.01 vs. exenatide BID, intent-to-treat population
1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.3. Bergenstal et al. Lancet 2010;376(9739):431-9.
4. Diamant et al. Lancet 2010;375(9733):2234-43.5. Data on file, Amylin Pharmaceuticals, Inc.
Changes in HDL-C: Exenatide LAR vs Comparators
-0.05
-0.10
0
0.05
0.10
0.15
0.20
LS M
ean
Cha
nge
(SE)
in H
DL-
C (m
mol
/L)
-0.03-0.02
0.00
0.03 0.05*0.05
0.16
0.00 0.01
Baseline (mmol/L)DURATION-11,5 DURATION-52 DURATION-23,5 DURATION-34
1.1 1.2 1.1 1.2 1.1 1.1 1.1 1.2 1.2N = 148 147 233 223160 166 165129 123
• *p<.001 EQW vs. pioglitazone, intent-to-treat population
Exenatide BID
Insulin Glargine
Sitagliptin
Exenatide LAR
Pioglitazone
1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.3. Bergenstal et al. Lancet 2010;376(9739):431-9.
4. Diamant et al. Lancet 2010;375(9733):2234-43.5. Data on file, Amylin Pharmaceuticals, Inc.
Changes in Triglycerides: Exenatide LAR vs. Comparators
• *p=.006 EQW vs. pioglitazone, intent-to-treat population
Geo
met
ric L
S M
ean
(SE)
Rat
io
Endp
oint
to B
asel
ine
0
0.5
1.5
1.00.85 0.89
0.940.99 0.95* 0.960.84
0.95 0.89
1. Drucker et al. Lancet 2008;372(9645):1240-50.2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.3. Bergenstal et al. Lancet 2010;376(9739):431-9.
4. Diamant et al. Lancet 2010;375 (9733):2234-43.5. Data on file, Amylin Pharmaceuticals, Inc.
Exenatide BID
Insulin Glargine
Sitagliptin
Exenatide LAR
Pioglitazone
Baseline (mmol/L) DURATION-11,5 DURATION-52,5 DURATION-23,5 DURATION-34,5
1.78 1.87 1.78 1.99 1.70 1.64 1.96 1.85 1.82N = 148 147 233 223160 166 165129 123
Fasting Lipid Profile Changes After 2 Years of Exenatide LAR treatment
Total Cholesterol LDL-C HDL-C TriglyceridesBaseline (mmol/L) 4.5 2.4 1.2 1.8
0.01
-15%*
-0.12*
-0.22*Cha
nge
from
Bas
elin
e (m
mol
/L)
Cha
nge
from
Bas
elin
e (%
)0
-0.05
-0.15
-0.25
-0.10
-0.20
-5
-10
-20
-15
0
Exenatide LAR(N = 148)
• *p<.05 vs. baseline, completer sample
Kim et al. 69th ADA 2009.
Changes in Cardiovascular Risk Biomarkers under exenatide LAR
-7
-4
-16*
p<.0001
p = .014
LS M
ean
Cha
nge
(SE)
fr
om B
asel
ine
(%)
-1
-23*
33*
50403020100
-10-20-30
-5
-10
-15
-20
-25
0
BNP ACR
-24*
-14*
-33*
-10
-20
-30
-30
0
hs-CRP
Sitagliptin (N = 166)Exenatide LAR (N = 160)
Pioglitazone (N = 165)
• *p<.05 vs. baseline, intent-to-treat population• BNP: B-type natriuretic peptide, ACR: albumin-to-creatine ratio, hs-CRP: high-sensitivity C-reactive proteinBergenstal et al. Lancet 2010;376(9739):431-9.
Exenatide LAR: Adverse Events ≥5%
ExeLAR1-5
N=670n (%)
ExeBID1,2,5
N=268n (%)
SITA3,5
N=166n (%)
PIO3,5
N=165n (%)
Insulin Glargine4,5
N=223n (%)
Nausea 126 (18.8) 93 (34.7) 16 (9.6) 8 (4.8) 4 (1.8)
Diarrhea 83 (12.4) 24 (9.0) 16 (9.6) 12 (7.3) 8 (3.6)
Headache 55 (8.2) 17 (6.3) 15 (9.0) 7 (4.2) 20 (9.0)
Nasopharyngitis 51 (7.6) 9 (3.4) 4 (2.4) 5 (3.0) 40 (17.9)
Vomiting 51 (7.6) 38 (14.2) 4 (2.4) 5 (3.0) 3 (1.3)
Injection site pruritus 43 (6.4) 3 (1.1) - - 1 (0.4)
• Intent-to-treat population, SITA: sitagliptin, PIO: pioglitazone1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10. 3. Bergenstal et al. Lancet 2010;376(9739):431-9.
4. Diamant et al. Lancet 2010;375(9733):2234-43.5. Data on file, Amylin Pharmaceuticals, Inc.
Incidence of Hypoglycemia by SU use
0
20
40
60
80
100
• *p<.05 Exenatide LAR vs. insulin glargine, intent-to-treat population1. Drucker et al. Lancet 2008;372(9645):1240-50. 2. Blevins et al. J Clin Endocrinol Metab 2011;96(5):1301-10.3. Data on file, Amylin Pharmaceuticals, Inc.
4. Bergenstal et al. Lancet 2010;376(9739):431-9. 5. Diamant et al. Lancet 2010;375(9733):2234-43.
Concomitant SU
DURATION 11
DURATION 52.3
DURATION 35
No SU
Inci
denc
e (%
) of M
inor
Hyp
ogly
cem
ia
DURATION 11
DURATION 52,3
DURATION 35
DURATION 24
Exenatide BID
Insulin Glargine
Sitagliptin
Exenatide LAR
Pioglitazone
0
20
40
60
80
100
0 1.1 1.3
15.4
3.0
19.114.5
3.012.5 11.8
20.3
42.4
0 0
n = 93 93 89
0.6
89 160 166 165 164 157 55 52 40 34 69 66
*
*
Exenatide LAR:Changes in Heart Rate M
ean
Cha
nge
in H
eart
Rat
e fr
om
Bas
elin
e (b
pm)
0
2
4
6
8
10
4.51*
DURATION-11 DURATION-52 DURATION-21 DURATION-33
4.12*
2.51*
4.03*
• *p<.05 vs. baseline• bpm: beats per minute1. Data on file, Amylin Pharmaceuticals, Inc.2. Blevins et al. J Clin Endocrin Metab 2011;96(5):1301-103. Diamant et al. Lancet 2010;375(9733):2234-43.
Are GLP-1 R agonists the ideal antidiabetic drugs ?
• Longer durability of glucose control/efficacy • Agents that delay/prevent loss of β-cell function • Agents that increase β-cell mass and function • Therapies that provide superior control of postprandial
glucose • Agents that do not cause increased weight gain, and/or
increase cardiovascular risk in any manner • Agents that improve metabolic syndrome risk factors • Agents that directly affect the progression of diabetic
complications
??
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