Actualités Dans Le Diabète de Type2: Les Inhibiteurs de La DPP-4

Actualits
dans le diabte de type2:

Les inhibiteurs de la DPP-4
Pr Ag Fatma MNIF BOUSSARSAR
Service dEndocrinologie-Diabtologie SFAX
Sfax 17 Mai 2014
CHU Hdi CHAKER SFAX
UR04SP31
Obsit-Sd Mtabolique
The Diabetes Epidemic: Global Projections,
20102030
IDF. Diabetes Atlas 5
th
Ed. 2011
TUNISIA
8.5%, 2010

Growing to
11%, 2030

Impact de la Thrapie Intensive du Diabte:
Rsum des Etudes Cliniques Majeures
Study Microvasc CVD Mortality
UKPDS
+ +
+
+
+
+
DCCT / EDIC*
+ +
+
+
+ +
ACCORD
+
+
q
ADVANCE
+
+ +
VADT
+
+ +
Long Term Follow-up
Initial Trial
* in T1DM

Kendall DM, Bergenstal RM. International Diabetes Center 2009

UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854.
Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977.
Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545.
Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum:
Moritz T. N Engl J Med 2009;361:1024)
Pour rduire
les complications
Diminuer
le taux dHbA1c
Sans augmenter
les hypoglycmies
Pour amliorer la
qualit de vie
Objectifs glycmiques
FPG
<130 mg/dL
(7.2 mmol/L)
HbA
1c
< 7.0%
PPG
<180 mg/dL
(10.0 mmol/L)
FPG
<6.0 mmol/L
(110 mg/dL)
HbA
1c
< 6.5%
PPG
<8.0 mmol/L
(145 mg/dL)
FPG
<130 mg/dL
(7.2 mmol/L)
HbA
1c
< 7.0%
PPG
<180 mg/dL
(10.0 mmol/L)
IDF
2
ADA
1
Consensus
tunisien
1. Diabetes Care 2012;32 (Suppl 1):S1-S97
2. IDF Clinical Guidelines Task Force. International Diabetes Federation 2005.
Objectifs glycmiques
a
HbA1c 6.5%.
Liebl A, et al. Diabetologia. 2002; 45: S23S28.
In the CODE study of a European cohort of over 7000 patients with
T2DM, ONLY 31% of patients had adequate glycaemic control
P
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(
%
)

Approximately 70% of patients with T2DM do not reach
HbA1c goals
a
100%
HbA
1c
<7%
HbA
1c
7%
Middle East
+ Egypt
North Africa Tunisia
%

o
f

p
a
t
i
e
n
t
s

29.0
71.0
31.5
68.5
24.1
75,9
IDM PS, data on file
En Tunisie 24% des patients DT2 ont une HbA1c <7%
des patients DT2 sont mal quilibrs
Tunisie
Nbre dHbA1c/ an
2.5 1.1

HbA1c (moyenne)
9.4 2.1

>9 %

< 7% (ADA)

< 6 %(IDF)
36 %

15.2 %

7.8%

Diabcare Tunisie 2008 (5 Centres Hospitaliers)
Pre-
Diabetes
Type 2 diabetes
Years from
diagnosis
0
5 -10
-5
10 15
Pre-diabetes
Onset Diagnosis
Insulin secretion
Insulin resistance
Post-Meal glucose
Fasting glucose

-Cell function
Progressive -Cell Failure
Evolution naturelle du DT2
T2DM Antihyperglycemic Therapy: General Recommendations

Diabetes Care, Diabetologia. 19 April 2012
[Epub ahead of print]
Diabetes Care, Diabetologia.
19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM

Options thrapeutiques
Anti diabtiques Oraux et Injectables non
insuline:

- Metformine
- Sulfonylures
- Thiazolidinediones
- Inhibiteurs de la DPP-4
- Agonistes des rcepteurs GLP-1

- Meglitinides
- Inhibiteurs a-glucosidase
- Sequestrants acides biliaires
- Agonists Dopamine-2
- Amyline mimetiques
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Incrtines
18/05/2014
Grle
Vidange gastrique
acclre Deficit dInsulinoscretion
prcoce
Glucose
Scretion excessive de
Glucagon
Captation insuffisante par le muscle
Libration excessive dAG
Production excessive
de Glucose
Diabte type 2
De la physiopathologie dcoule les principaux
modes daction des A.D.O
18/05/2014
Diabetes Obes Metab 1999
Grle
Deficit dInsulinoscretion
Glucose
glucagon
Sulphonylures
Glinides
Inhibiteurs de la-
glucosidase
GLP1
Inhibiteurs DDPIV
18/05/2014
Diabetes Obes Metab 1999
Grle
Deficit dInsulinoscretion
Glucose
glucagon
Nouveaux mdicaments du diabte de type 2
Les Incretines
Analogues du Glucagon Like Peptide 1 (GLP-1)
Inhibiteurs DDPIV
LES INCRETINES
Analogues deGLP1
Inhibiteurs DDPIV
Inhibiteurs de la DPP4+ Metformine; autres combinaisons
Inhibiteurs de la DPP4: Indications
Incrtines / Inhibiteurs de la Di-Peptidyl Peptidase - 4 :
Mode daction
Sommaire
Inhibiteurs de la DPP4:Profil de tolrance
Inhibiteurs de la DPP4 et Ramadan
Inhibiteurs de la DPP4+ Metformine; autres combinaisons
Mode daction
Sommaire
Mode daction

Intestine Secretion
Insulin

Dfinition de leffet incrtine
In cret in
Intestin

Scrtion
dhormones
incrtines

Cellules K GIP
Cellules L GLP-1
Le pancras est
un organe cible
des incrtines
Effet incrtine :
Amplification de
linsulino-scrtion
Cellule
Cellule a
Incrtines
7 Insuline
N Glycmie
N Glucagon
N Glycmie
Glycmie constante
1 g/l
Alimentation 7 GLP-1 (x 6 8) libration dinsuline
Leffet incrtine
- 26 -
Mise en vidence de leffet incrtine chez le sujet
non diabtique

0
10
10
15
20
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5
60 120 180
Temps (min)
0
40
60
80
n
s
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I
I
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(
m
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/
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)

20
5
10 60 120 180 5
*
*
* *
*
*
*
Effet incrtine
Glucose per os
Perfusion isoglycmique de
glucose IV
Temps (min)
Adapt de Nauck M et al. Diabetologia. 1986;29:4652.
* p0.05
70% de la scrtion dinsuline en rponse un repas est
lie leffet incrtine
Effet incrtine = Insulinoscrtion en rponse au glucose oral significativement
suprieure celle obtenue en rponse au glucose administr par voie IV
- 27 -
g
l
y
c
m
i
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(
m
m
o
l
/
L
)

Sujets contrls Diabtiques de Type 2
Altration de leffet incrtine chez les sujets
diabtiques de type 2

Adapt de Nauck M et al. Diabetologia. 1986;29:4652.
0
10
10
15
20
5
60 120 180
Temps (min)
0
40
60
80
I
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s
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I
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m
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/
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20
0
10
15
20
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5
Temps (min)
0
40
60
80
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s
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(
m
U
/
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)

20
5 10 60 120 180 5
10 60 120 180 5 10 60 120 180 5
*
*
* *
*
*
*
*
*
*
Effet
incrtine normal
Effet
incrtine diminu
Glucose per os
Isoglycmie par glucose IV
* p0.05
-60 0 60 120 180 240
20.0
18.3
16.6
15.0
13.3
6.1
4.4
140
130
120
110
100
90
120
90
60
30
0
Glucose
(mmol/l)
Insulin
(mU/l)
Glucagon
(ng/l)
Meal
Time (min)
Type 2 diabetes
Normal subjects
Delayed/depressed
insulin response
Mller et al. N Engl J Med. 1970
Nonsuppressed
glucagon
Normal subects n=11; Type 2 diabetes n=12
L'insuline et le glucagon en rponse aux repas chez des
sujets normaux et de diabte de type 2
Diabte de type 2

Diminution de leffet
incrtine

Associe une rduction
de la scrtion de GLP-1
pendant les repas
et une altration
de lactivit du GIP

Activit du GLP-1 intacte
Stimule Scrtion de linsuline Stimule
- Scrtion du glucagon Inhibe
-
-
Prise alimentaire
Vidange gastrique
Rduite
Ralentie
- Synthse de linsuline Stimule
Favorise Prolifration cellulaire Favorise
Normale Scrtion Rduite
Altre Activit Prserve
Actions physiologiques
Diabte de type 2
GIP GLP1
Glycmie constante
1 g/l

Altration de leffet incrtine chez les sujets
diabtiques de type 2

Le rle de la dipeptidyl peptidase-IV (DPP-IV)

Adapt de Deacon CF, et al. Diabetes. 1995;44:1126-1131.
GIP et GLP-1 :
demi-vie courte
(1 2 minutes
pour le GLP-1)

De laction
de la DPP-IV
+
Leur limination
rnale

Inactivation du GLP-1 par la DPP-4
Repas
Synthse
intestinale
de GLP-1
GLP-1 actif
GLP-1
T = 1 2 min
GLP-1 inactif
(> 80 % du pool)
Dgradation
protolytique
(DPP-4)
GLP-1
Extrmit N-terminale
Extrmit C-terminale
Amide
.
Adapt de Deacon CF, et al. Diabetes. 1995;44:1126-1131.

Inhibiteurs de la DPP-4 : Mode daction

GLP-1
actif
GLP-1
Inactif
(>80% du pool)
GLP1 T
1/2
= 1 2 min

DPP-4
Inhibiteur DPP-4
7 GLP-1 endogne :
Restaure la sensibilit
au signal glucose
Insuline
Glucagon
Contrle glycmique
Scrtions
intestinales
Comparaison de la Rponse des cellules au glucose en cas
dHyper- versus Hypoglycmie avec et sans traitement par
inhibiteurs de la DPP4 (la Vildagliptine)
AUC=area under the curve; N=25 (completers population). *P=0.019; **P=0.039.
Ahrn B, et al. Poster 560-P. Presented at: 68th Scientific Sessions of the American Diabetes Association;
June 6-10, 2008; San Francisco, CA;
Thornberry NA, et al. Best Pract Res Clin Endocrinol Metab. 2009; 23: 479486.
La Vildagliptine amliore la masse des cellules
du pancras du rat
Duttaroy et al. Diabetes 2005;54(Suppl. 1): A141. Abstract 572P and poster presented at ADA
Vildagliptin
60 mg/kg
21 days
Vehicle
Insulin
Replication
-
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M
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(
m
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Vehicle Vilda
p<0.05
Vehicle
B
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U
-
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120
100
80
60
40
20
0
Vilda
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p<0.05
Apoptosis -cell mass
Day 7 Day 21
p<0.001
Vilda=vildagliptin
2.5
2.0
1.5
1.0
0.5
0
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0
Vehicle Vilda
Pharmacokinetic Properties of DPP-4
Inhibitors
Sitagliptin
1
(Januvia)
Vildagliptin
2
(Galvus)
Saxagliptin
3

(Onglyza)
Alogliptin
5

(Takeda)
Absorption t
max
14 h 1.7 h
2 h (4 h for active
metabolite)
12 h
Bioavailability ~87% 85% >75 %
4
N/A

Half-life (t
1/2
) at
clinically relevant
dose
12.4 h ~23 h
2.5 h (parent)
3.1 h (metabolite)
12.421.4 h
(25800 mg)
Distribution 38% protein bound 9.3% protein bound Low protein binding N/A
Metabolism ~16% metabolized
69% metabolized
mainly renal
(inactive metabolite)
Hepatic
(active metabolite)
CYP3A4/5
<8% metabolized
Elimination
Renal 87%
(79% unchanged)
Renal 85%
(23% unchanged)
Renal 75%
(24% as parent; 36% as
active metabolite)
Renal
(60%71%
unchanged)

DPP-4=dipeptidyl peptidase-4.
1. JANUVIA EU-SPC 2010. 2. Galvus EU-SPC 2010. 3. Onglyza EU-SPC 2010. 4. European Public Assessment Report for Onglyza.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001039/WC500044319.pdf. Accessed October
14, 2010.
5. Christopher R et al. Clin Ther. 2008;30(3):513527.
IDPP4+ Metformine chez le patient insuffisamment
contrl par la Metformine seule; autres combinaisons
Inhibiteurs de la DPP4 : indications
Mode daction
Sommaire
Facilit dutilisation
Pas deffets secondaires
Pas dhypoglycmies
T2DM Anti-hyperglycemic Therapy: General Recommendations
Adapted Recommendations: When Goal is to Avoid Weight Gain
Adapted Recommendations: When Goal is to Avoid Hypoglycemia

Si Metformine maltolre ou contreindique

42
Sitagliptin Consistently and Significantly Lowers A1C
With Once-Daily Dosing in Monotherapy
*Between group difference in LS means.
Raz I et al; PN023; Aschner P et al. PN021; Nonaka K et al; A201. Abstracts presented at: 66
th
Scientific Sessions of the American
Diabetes Association; June 9-13, 2006; Washington, DC.
Change vs
placebo*
Placebo (n=74)
Sitagliptin 100 mg (n=168)
Time (wk)
18-Week study
0 6 12 18
A
1
C

(
%
)

7.2
7.6
8.0
8.4
-0.6%
(P<.001)
Placebo (n=244)
24-Week study
Time (wk)
0 5 10 15 20 25
-0.79%
(P<.001)
A
1
C

(
%
)

7.2
7.6
8.0
8.4
Placebo (n=75)
Time (wk)
Japanese study
-1.05%
(P<.001)
A
1
C

(
%
)

7.2
7.6
8.0
8.4
6.8
0 4 8 12
IDPP4 + Metformine chez le patient insuffisamment
Mode daction
Sommaire
Inhibiteurs de la DPP4: Profil de tolrance
Initial Combination Therapy with Sitagliptin and
Metformin: Effective and Durable Glycemic Control
Over 1 Year in Patients With T2DM
23
41
25
35
44
57
48
63
67
77
0
10
20
30
40
50
60
70
80
90
Week 54 Completers APT
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Proportion of patients
achieving an A1C target of <7%
Sitagliptin 100 mg qd (n=106/58)
Metformin 500 mg bid (n=117/77)
Metformin 1000 mg bid (n=134/101)
Sitagliptin 50 mg + metformin 500 mg bid (n=147/106)
Sitagliptin 50 mg + metformin 1000 mg bid (n=153/124)
Proportion of patients achieving an A1C target
of <7% at Week 24 remaining at <7% at Week 54
P
r
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p
o
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t
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%
)

70
59
79
80
85
0
10
20
30
40
50
60
70
80
90
Sitagliptin 100 mg qd (n=33)
Metformin 500 mg bid (n=34)
Metformin 1000 mg bid (n=63)
Sitagliptin 50 mg + metformin 500 mg bid (n=65)
Sitagliptin 50 mg + metformin 1000 mg bid (n=96)
Initial Combination Therapy with Sitagliptin and
Metformin: Change From Baseline in A1C at Week 54
by Baseline A1C Subgroups*
10%
(mean 10.4%)

9% and <10%
(mean 9.4%)

8% and <9%
(mean 8.4%)

<8%
(mean 7.6%)

H
b
A
1
C

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f
r
o
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b
a
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a
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W
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k

5
4

(
%
)

-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
Sitagliptin 100 mg (28/43/19/16)
Metformin 500 mg bid (32/39/30/16)
Metformin 1000 mg bid (40/53/33/8)
Sitagliptin 50 mg + metformin 500 mg bid (39/49/38/21)
Sitagliptin 50 mg + metformin 1000 mg bid (33/60/43/17)
Incidence of Hypoglycemia With Sitagliptin With
Metformin Was Similar to Placebo With
Metformin
24-Week Add-on Therapy to Metformin Study
All-patients-as-treated population
a
Sitagliptin 100 mg/day;
b
Metformin 1500 mg/day

Adapted from Charbonnel B et al. Diabetes Care. 2006;29:26382643.
Patients with at least one episode of hypoglycemia over 24 weeks
P
a
t
i
e
n
t
s

(
%
)

Placebo + metformin
b
(n=237)
Sitagliptin
a
+ metformin
b
(n=464)
2.1%
1.3%
0.0
1.0
2.0
3.0
4.0
5.0
Sitagliptin With Metformin Provided Weight
Loss Similar to Placebo With Metformin at Week
24
24-Week Add-on Therapy to Metformin Study
a
Excluding data after initiation of glycemic rescue therapy;
b
least squares means;
c
Sitagliptin 100 mg/day;
d
Metformin 1500 mg/day

Adapted from Charbonnel B et al. Diabetes Care. 2006;29:26382643.
0.6
P=0.017
vs baseline
0.7
P<0.001
vs baseline
Placebo + metformin
d
(n=169)
Sitagliptin
c
+ metformin
d
(n=399)
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
C
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i
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o
d
y

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h
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a

f
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a
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(
k
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b

Initial Fixed-Dose Combination Therapy With Sitagliptin
+ Metformin vs Metformin Monotherapy: Study Design
Day 1
Randomization
Week 44
Screening
period
Phase A Phase B
Screening
1 week
18 weeks
a
Metformin was initiated at 500 mg bid and titrated up to 1000 mg bid over 4 weeks. Patients who were unable to tolerate the
maximum dose of sitagliptin/metformin FDC or metformin were allowed to be down-titrated to a minimum dose of
sitagliptin/metformin FDC 50/500 mg bid or metformin 500 mg bid.
bid=twice daily; FDC=fixed-dose combination; OHA=oral antihyperglycemic agent; qd=once daily; R=randomization; T2DM=type 2
diabetes mellitus.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 59, 2009.
2. Data on file, MSD.
R
26 weeks
Week 18
T2DM, aged
1878 yrs,
Off OHA
4 months,
HbA
1c
7.5%
Sitagliptin 50 mg bid + metformin 1000 bid
a
(n=626)
Metformin 1000 mg bid
a
(n=624)
Initial Fixed-Dose Combination Therapy With Sitagliptin
+ Metformin vs Metformin Monotherapy: HbA
1c
Results
Over 18 Weeks
H
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c

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E
)

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B
a
s
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i
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,

%

Week

Sitagliptin/metformin FDC (n=560)
Mean baseline HbA
1c
=9.9%
Metformin (n=566)
Mean baseline HbA
1c
=9.8%
LS means
difference
0.6; P<0.001
7
8
9
10
0 6 12 18
FAS=full analysis set; FDC=fixed-dose combination; LS=least-squares; SE=standard error.
FAS Population
Initial Fixed-Dose Combination Therapy With Sitagliptin +
Metformin vs Metformin Monotherapy: Change from Baseline in
HbA
1c
by Baseline HbA
1c

at Week 18
FAS=full analysis set; FDC=fixed-dose combination.
H
b
A
1
c

L
S

M
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a
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C
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f
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B
a
s
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l
i
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,

%

Baseline HbA
1c
,% <8 8 and <9 9 and <10 10 and <11 11
FAS (Week 18)
P=0.009
P<0.001
P<0.001
Mean HbA
1c,
% 7.6 8.4 9.5 9.4 10.4 12.2
n=
1.1
1.6
2.0
2.9
3.6
2.7
2.1
1.7
1.1
0.8
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
Sitagliptin/metformin FDC
Metformin
99 95 99 111 87 101 124 109 150 148
P=0.158
P=0.111
Sitagliptin Add-on to Metformin Improved 24-Hour
Glucose Profile in Patients With Type 2 Diabetes
Post Prandial
Fasting/Pre-Prandial

Vildagliptine + metformine: bien tolre

AE=adverse event.
Only data using the marketed regimen of vildagliptin are shown.
Bosi E, et al. Diabetes Care. 2007; 30: 890895.
Vildagliptin
50 mg twice daily
+ metformin
(n=183), n (%)
Placebo
+ metformin
(n=181), n (%)
Any AE 119 (65.0) 115 (63.5)
Any gastrointestinal AE 27 (14.8) 33 (18.2)
Upper respiratory tract infection 14 (7.7) 16 (8.8)
Dizziness 11 (6.0) 7 (3.9)
Nasopharyngitis 11 (6.0) 13 (7.2)
Influenza 10 (5.5) 11 (6.1)
Diarrhoea 8 (4.4) 10 (5.5)
Nausea 8 (4.4) 9 (5.0)
Pain in extremity 8 (4.4) 6 (3.3)
Headache 7 (3.8) 6 (3.3)

Vildagliptine vs SU associe la metformine:
design de ltude et objectifs

Objective: demonstrate long-term efficacy and safety of vildagliptin vs glimepiride
as add-on to metformin
Target population: patients with T2DM inadequately controlled on stable metformin monotherapy
(metformin minimum dose 1500 mg/day; HbA1c 6.58.5%)
Design: double-blind, randomised, multicentre, active-comparator, 104-week study
n=1556: Glimepiride up to 6 mg once daily + metformin
n=1562: Vildagliptin 50 mg twice daily + metformin
4 weeks
Metformin
*Randomised population.
HbA1c=haemoglobin A1c; SU=sulfonylurea; T2DM=type 2 diabetes mellitus.
Matthews DR, et al. Diabetes Obes Metab. 2010; 12: 780789.
3118*
104 weeks
39
600
500
400
300
200
100
0
NI=non-inferiority
Ferrannini et al. Diabetes Obes Metab 2009;11:15766
Data on file, Novartis Pharmaceuticals
Vildagliptin 50 mg twice daily + metformin
Glimepiride up to 6 mg once daily + metformin
Duration: 52 weeks
Add-on to metformin: vildagliptin vs glimepiride
Time (weeks)
M
e
a
n

H
b
A
1
c

(
%
)

NI: 97.5%
CI (0.02, 0.16)
0.4%
0.5%
I
n
c
i
d
e
n
c
e

(
%
)

1389 1383 n=
N
o
.

o
f

e
v
e
n
t
s

1389 1383 n=
N
o
.

o
f

e
v
e
n
t
s

1389 1383 n=
Time (weeks)
B
o
d
y

w
e
i
g
h
t

(
k
g
)

1.8 kg
difference
Vildagliptine: aussi efficace que glimepiride
associs la metformine 52 semaine
sans prise de poids et avec moins dhypoglycmies
7.5
7.3
7.1
6.9
6.7
6.5
8 4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
20
15
10
5
0
1.7
18.2 554
12
10
8
6
4
2
0
0
10
91.0
90.5
90.0
89.5
89.0
88.5
88.0
87.5
8 4 0 4 8 12 16 20 24 28 32 36 40 44 48 52
Severe events
(grade 2 and
suspected grade 2)
Number of
hypoglycemic
events
Patients with
1 hypos (%)
Add-on treatment to metformin
(~1.9 g mean daily)
55 Author | 00 Month Year
Set area descriptor | Sub
level 1
level 1
level 1
level 1
level 1
level 1
level 1
Addition of Sitagliptin to Insulin Therapy:
Study Design
Single-blind
placebo run-in
period
Continue on a stable dose of
insulin with or without metformin
Begin single-blind run-in period
Randomization Week 24
24-Week Stable Insulin Dose Period
QD=daily.
T. Vilsbll et al. Diabetes, Obesity and Metabolism 12: 167177, 2010.
Patients with type 2 diabetes
Age >21 years
Receiving insulin (including
glargine, detemir, ultralente, NPH,
lente, or premixed insulin) alone
or with metformin 1500 mg/day
Not receiving premeal short-
acting insulin
HbA
1c
7.5% and 11%
Placebo (n=319)
Sitagliptin 100 mg QD (n=322)
R
Screening
visit
Week 2
0 6 12 18 24
0.1
Addition of Sitagliptin to Insulin Therapy:
HbA
1c
Change From Baseline Over Time
a
Baseline mean HbA
1c
: 8.72% for sitagliptin, 8.64% for placebo
FAS=full analysis set; LOCF=last observation carried forward; LS=least squares; SE=standard error.
T. Vilsbll et al. Diabetes, Obesity and Metabolism 12: 167177, 2010.
FAS Population (LOCF)
Placebo
a

Sitagliptin
a

Difference = 0.56%
(P<0.001)
H
b
A
1
c

L
S

M
e
a
n

C
h
a
n
g
e

F
r
o
m

B
a
s
e
l
i
n
e
,

%

(
S
E
)

Weeks
0.0
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.8
0.03%
0.59%
(n=305)
(n=312)
contrl par la Metformine seule et autres combinaisons
Mode daction
Sommaire
Inhibiteurs de la DPP4 : Profil de tolrance

Inhibiteurs de la DPP4: profil de tolrance tendu

Les inhibiteurs de la DPP4 ont dmontr un bon profil de
scurit et de tolrance
>11,500 patients en 38 tudes de Phase II et III * travers
tout le monde(mis part le Japan) traits par vildagliptine ou
bien par lassociation fixe vildagliptine + metformine

>1.2 million patient-trait par an dexposition la vildagliptine
ou bien lassociation fixe vildagliptine + metformine

(post-
marketing exposure)
*Treatment duration ranked from 12 to >104 weeks.
a
As of March 2010 ;
b
As of January 2011;

Data on file. Novartis Pharma AG, Basel, Switzerland. 2010.
Scurit et Efficacit chez linsuffisant
rnal 52 semaines
52 week AE renal study
Moderate RI
Results:
50 mg qd Placebo
122 76
94 64
# of Patients
Severe RI
Safety profile similar to placebo
Clinically significant decrease in HbA1c
Diabetes Obesity and Metabolism 2012 epub ahead of print

IDPP4: Contre indications- Prcautions demploi
Pas dutilisation dans les cas suivants :
Grossesse et lallaitement
Insuffisance cardiaque de classe III ou IV (classification
NYHA)
Insuffisance hpatique et/ou si lvation des
transaminases > 3 x LSN* avant traitement pour la
Vildagliptine
Chez le patient diabtique de type 1 ou pour le traitement
de lacidoctose diabtique.
Contre-indiqu :
en cas dhypersensibilit la substance active ou
lun des excipients

Utilisation avec prudence :
Chez le patient sous hmodialyse prsentant une
insuffisance terminale.
Chez le patient prsentant une insuffisance cardiaque de
classe I et II.

38 Ph2/Ph3 of >8,000 patients
and studies with 301 patients 75
year between 12-104 weeks.

Only DPP4 inhibitor without
cautionary label for patients > 75
years in EU.EU.
Diabetes Obesity and Metabolism 13: 55-64, 2011

Vildagliptine :inhibiteur de la DPP 4 indiqu chez
le DT2 75 ans .Sans restrictions demploi en Europe

Vildagliptine + metformine: une rduction de
1.1% dHbA1c chez les DT2 75 ans
sans hypoglycmie ni prise de poids
Overall AEs, drug-related AEs and SAEs were all reported with a lower frequency in elderly patients receiving vildagliptin (133.9, 14.5 and 8.8 events per
100 SYE, respectively) than in elderly patients receiving comparators (200.6, 21.8 and 16.5 events per 100 SYE, respectively), and the incidence of
discontinuations due to AEs was similar in the 2 treatment groups (7.2 vs 7.5 events per 100 SYE, respectively). The incidences of AEs, drug-related AEs,
SAEs and discontinuations due to AEs were overall comparable between younger and older patients. The most notable difference was a higher incidence
of SAEs in the comparator group in patients 75 years vs <75 years.
1
Efficacy pool: all randomised, double-blind, controlled, parallel-group studies with
duration 24 weeks and with patients 75 years. Only includes studies with the approved dose of 50 mg twice daily.
2
Safety pool: a pool of 38 Phase II
and III studies (monotherapy and add-on therapy). *P <0.05 vs baseline (within group). AE=adverse event; BL=baseline; HbA1c=haemoglobin A1c;
SAE=serious adverse events; SYE=subject-year exposure. Schweizer A, et al. Diabetes Obes Metab. 2011; 13: 5564.
Pooled analysis (24 weeks) of 3 add-on therapy studies, patients 75 years
n =
BL (%) =
25
8.5
HbA1c
1
n =
BL (kg) =
25
82.8
Body weight
1
n 31
Any events,
n (%)
0 (0.0%)
Severe
events,
n (%)
0 (0.0%)
Hypoglycaemia
2
-1,1
-1,2
-1,0
-0,8
-0,6
-0,4
-0,2
0,0
C
h
a
n
g
e

i
n

H
b
A
1
c

(
%
)

f
r
o
m

b
a
s
e
l
i
n
e

-0,2
-0,5
-0,4
-0,3
-0,2
-0,1
0,0
C
h
a
n
g
e

i
n

w
e
i
g
h
t

(
k
g
)

f
r
o
m

b
a
s
e
l
i
n
e

*
Inhibiteurs DPP4
*Bnfices et risques cardiovasculaires au long
cours non encore tudis
*Plusieurs tudes :
TECOS : sitagliptine
CAROLINA : linagliptine
SAVOR /: saxagliptine
EXAMINE : alogliptine
Curr cardio rep (2013) 15, 327 -3-9
Etude SAVOR /: saxagliptine
n engl j med 369;14 nejm. october 3, 2013
*16492 diabtiques haut risque cardiovasculaire
*TTT par saxagliptine / placebo
*Suivi 2,1ans
n engl j med 369;14 nejm.org october 3, 2013
*5380 diabtiques
ayant eu un IDM ou
SCA dans les derniers
15-90jours

*TTT par alogliptine /
placebo

*Suivi 40 mois (18
mois en moyenne )
Etude EXAMINE /: Alogliptine
Etude EXAMINE /: Alogliptine
n engl j med 369;14 nejm.org october 3, 2013
Mortalit toutes causes Mortalit cardio vsx
GRAIG CURRIE EASD sep 2013
Comparaison sur la mortalit de lassociation
Met + Sulf / Met +DPP4-i
Inhibiteurs de la DPP4 : Profil de tolrance
Mode daction
Sommaire
Inhibiteurs de la DPP-IV et Ramadan
Inhibiteurs de la DPP4: indications
Ramadan
J-45

Effets de la Vildagliptine chez le DT2 qui jene

VECTOR: pas dhypoglycmies sous
Vildagliptine
Mean between-group difference in patients
who experienced at least one HE was 41.7% (P=0.0002)

*Mean between-group difference (vildagliptin cohort minus SU cohort) in the number of
HEs: 0.9 (95% CI 1.5, 0.4) (P=0.0013)
Mean between-group difference (vildagliptin cohort minus SU cohort) in the number of
severe (grade 2) HEs: 0.0 (95% CI 0.1, 0.0) (P=0.4289) Hassanein M, et al. Curr Med Res Opin. 2011; 27: 1367-1374
HEs*
Experienced 1 event
Mean (SD)
Range
95% CI
Total
Severe (grade 2) HEs

Experience 1 event
Mean (SD)
Range
95% CI
Total

0
0.0 (0.0)
0
(0, 0)
0

0
0.0 (0.0)
0
(0, 0)
0

15
0.9 (1.3)
0-4
(0.5, 1.4)
34

1
0.0 (0.2)
0-1
(0.0, 0.1)
1
Vildagliptin cohort
n=23
SU cohort
n=36
VECTOR: HbA1c and Observance
Vildagliptin significantly lowered
HbA1c (7.7% to 7.2%) vs SU
(7.2% vs 7.3%) post-Ramadan. Between-
group difference 0.5% (P=0.0262)
Hassanein M, et al. Curr Med Res Opin. 2011; 27: 1367-1374
+0,1% -0,4%
-0,5%
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