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2.

, 28.1.12
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ADA 2012
1C


:

/

CVD
/






1C
1C A1C

1/31/2012


<7%.

,
,
7-7.9%
,

<6.5%.
Diabetes Care 2012;suppl.1: s11s11-s63

;


.

.


: ,
,


: .

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( HbA1c 9%
).


: .
( , ) : .
:
: , SU .


.
, .

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http://www.ede.gr

2011

1/31/2012

NICE

HbA1C 6.5%*

HbA1C 6.5%*

SU

DPP-4 inhibitor

SU



SU


(
)

TZD ()
SU



SU
DPP-4 inhibitors

* Or individually agreed target. Monitor patient following initiation of a new therapy and continue only if beneficial metabolic response occurs (refer to guideline for
suggested metabolic responses). Discuss potential risks and benefits of treatments with patients so informed decision can be made.
When selecting a TZD take into account up-to-date advice from the relevant regulatory bodies, cost, safety and prescribing issues. Do not commence or continue a
TZD in people who have heart failure, or who are at higher risk of fracture.

1/31/2012

1/31/2012

1/31/2012

http://www.ede.gr


,
.
sitagliptin

(79%)
. (
: 350 ml/min).

.

Drucker et al. Nature Reviews Drug Discovery 6, 109110 (February 2007) | doi:10.1038/nrd2245

1/31/2012

DPP-4 GLP-1

Meal
Intestinal
GLP-1
release
Active
GLP-1



DPP-4



.

.

DPP-4=dipeptidyl
peptidase-4; GLP-1=glucagon-like peptide-1
1/31/2012

DPP-4
inhibitor

Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR.
Adapted from Deacon CF, et al. Diabetes. 1995; 44: 11261131.

GLP-1 (7-36)NH2
GIP (1-42)
10

2,

:



Updated on Tuesday, December 08, 2009


1/31/2012

11

1050 HbA1c 6.5%9%.


(100 mg 1x1) (1000 mg x 2).
24 .

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12

-0,43%

-0,57%


HbA1c>8%

-1,13% (n=74)

-1,24% ( n=73)



HbA1c<7%

34 %

39%

1,7%

3,3%

11,6%

20,7%

HbA1c

Sitagliptin non-inferior to metformin. Non-inferiority was to be declared if the upper boundary of the 95%
confidence interval (CI) for the between-group difference in this endpoint was <0.40%.
HbA1c 7.2% . -0.43% (n = 455) -0.57% (n = 439).
(95% CI) 0.14% (0.06, 0.21), -.

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13

HbA1c

HbA1c
HbA1c <7%
7-8%
>8%

Pablo Aschner et al. Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2
diabetes. Diabetes, Obesity and Metabolism, "Accepted Article"; doi: 0.1111/j.14631326.2009.01187.x

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14

,
.


,
.
PPAR (.. ),
PPAR
PPAR
.
Updated on Tuesday, December 08, 2009
1/31/2012

15

vs
(52 Weeks)
8.4

Glipizide (n=411)

8.2

Sitagliptin 100 mg qd (n=382)

8.0
Mean Change in HbA1c

7.8
7.6

Mean change from baseline (for both groups)*: - 0.67%

7.4
7.2
7.0
6.8
6.6
6.4
6.2

Diabetes, Obesity and Metabolism, 9, 2007, 194205

6.0
0

12

24

38

52

Time (weeks)

1/31/2012

*per-protocol analysis; -0.51% and -0.56% for sitagliptin and glipizide in LOCF analysis
16

Sitagliptin :

a + metformin (n=416)
Sitagliptinb + metformin (n=389)

Body Weight (kg SE)

2
1
between groups = 2.5 kg

P<0.001

-1

% of Patients With One Episode

Least squares mean change over timec

Hypoglycemiac
32%
P<0.001

5%

-2

Week 52

-3

12

24

38

52

Weeks
aSpecifically glipizide; bSitagliptin (100

mg/day) with metformin (1500 mg/day); cAll-patients-as-treated population


Least squares mean between-group difference at week 52 (95% CI): change in body weight = 2.5 kg [3.1, 2.0]
(P<0.001);
Least squares mean change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: 1.5 kg (P<0.001)
with metformin vs sulfonylurea with metformin study.
Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194205.

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17

Two Years extension Data


HbA1c
:

HbA1C
FPG

Adapted from T. Secket al. Int J Clin Pract, April 2010, 64, 5,
562576.

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18

1/31/2012

19

vs :
HbA1c
Per-Protocol Population
Sitagliptin 100 mg + metformin (n=443)

Patients at HbA1c Goal, %

70

Glimepiridea + metformin (n=436)

59,6

60
50
40

(95% CI)
7.5% (13.8, 1.1)

52,4
(95% CI)
6.7% (12.3, 1.1)

27,5

30
21,2
20
10
0

<6.5%
CI=confidence interval.
aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per
1/31/2012
day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160168.

<7.0%
20

vs :

Patients With 1
Hypoglycemic Episode, %

APaT Population
(95% CI)
15.0% (19.3, 10.9)
(P<0.001)

25

22
Sitagliptin 100 mg
+ metformin (n=516)
Glimepiridea
+ metformin (n=518)

20
15
10

5
0

APaT=all patients as treated; CI=confidence interval.


aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per
day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160168.

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21

019

JANUVIA
HbA1c
8.2

Placebo +
100 mg
+

% HbA1c

8.0

N=174

7.8
7.6

- 0.70%


Placebo

p< 0.001

7.4
N=163

7.2
7.0
0
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12

18

24

22
J Rosenstock et al. Clinical Therapeutics 2006, 28(10)

Sitagliptin
Pioglitazone

2.0
1.5
1.0
0.5
0.0
Placebo + pioglitazone (n=174)

-0.5

Sita 100 mg qd + pioglitazone (n=163)

-1.0

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12
Weeks

18

24

23
Charbonnel et al. Diabetes Care 2006; Rosenstock J et al. Clin Ther 2006.



29 controlled (19662007)

::

GLP-1
(risk ratio 2,9 3,2 ).
O DPP- 4
(risk ratio 1,2 1,5
. ) (risk ratio 1,4) .

R. Amori, A. Pittas et al. JAMA 2007; 298: 194


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24

Liraglutide vs Sitagliptin
450 Fu=26 .
- HbA1C
::
Liragl.. 1,2 mg: 1,24%, 1,8 mg: 1,5%
Liragl
Sitagl. 100mg : 0,9%
- (): Liragl
Liragl:: 5%
Sitagl: 5%
- : Liragl: 21%
Sitagl: 5%
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25
LANCET 2010



2,
:


.
Updated
1/31/2012on Tuesday, December 08, 2009

26

Placebo+
Placebo++
+
++

K. Hermansen et al Diabetes, Obesity and Metabolism, 9, 2007, 733745

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27

-
2,
:


PPAR (.. ),
PPAR
PPAR
.


PPAR , PPAR


.
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28


( ),

.

Updated on Tuesday, December 08, 2009


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29

:
HbA1c
.
FAS Population at 24 Weeks (LOCF)a

Receiving
Premixed
Insulin

HbA1c LS Mean Change


From Baseline, % (SE)

Mean baseline HbA1c, %


0.0

8.59
n=80

Receiving Long- or Intermediateacting


Insulin

8.50
n=80

8.69

n=225
n=232

0.2

0.04
0.02
Sitagliptin

0.4

Placebo

0.6

0.8

P-value for treatment by subgroup


interaction = 0.949

0.58

1.0 of rescue therapy.P<0.001


data after initiation
FAS=full analysis set; LOCF=last observation carried forward; LS=least squares;
SE=standard error.
1/31/2012
T. Vilsbll
et al. Diabetes, Obesity and Metabolism 12: 167177, 2010.
aExcluding

8.76

0.61

P<0.001

30

:

HbA1c 1
FAS Population at 24 Weeks (LOCF)a

15
13

P<0.0012

Sitagliptin 100 mg qd (n=305)

Patients at HbA1c Goal, %

Placebo (n=312)

10

5
5

0
HbA1c Goal <7.0%

aExcluding data

after initiation of rescue therapy.


FAS=full analysis set; LOCF=last observation carried forward; qd=once daily.
1. Vilsbll T et al. Diabetes Obes Metab. 2010;12(2):167177.

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31

:

( 2-h PPG FPG)
Mean baseline
PPG, mmol/L

16.2

Mean baseline
FPG, mmol/L

16.2

0,0

0,3

n=257

0
n=240

P<0.001
Sitagliptin 100 mg qd

2
aExcluding data

1,7

Placebo

LS Mean Change From


Baseline FPG, mg/dL

LS Mean Change From


Baseline 2-h PPG, mmol/L

9.8

10.0

n=310

n=313

0,5
0,2

1,0

1,5

1,0

2,0
P<0.001

after initiation of rescue therapy.


FAS=full analysis set; FPG=fasting plasma glucose; LOCF=last observation carried forward; LS=least squares; PPG=postprandial glucose; qd=once daily.
Vilsbll T et al. Diabetes Obes Metab. 2010;12(2):167177.

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32

Sitagliptin
- Sitagliptin

- Cross over 20
sitagliptin placebo (
)

- sitagliptin FPG
12mg%
12
mg% HbA1C 0,27%

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ADA

70th

s.s. 2010

33


50 ml/min
2 .
30-50 ml/min
2 ( 50mg,
50 mg ( ), 2.5 mg (
) , 5mg ( ).
50/850 50/1000
.
<30 ml/min

: 25mg (
) (
).
For patients with mild renal insufficiency in which the creatinine clearance (CrCl) is 50 ml/min, approximately corresponding to
serum creatinine levels of 1.7 mg/dl in men and 1.5 mg/dl in women, no dosage adjustment for sitagliptin is required. For
patients with moderate renal insufficiency (CrCl 30 to <50 ml/min, approximately corresponding to serum creatinine levels of >1.7
to 3.0 mg/dl in men and >1.5 to 2.5 mg/dl in women), the dose of sitagliptin is 50 mg once daily. For patients with severe renal
insufficiency (CrCl <30 ml/min, approximately corresponding to serum creatinine levels of >3.0 mg/dl in men and >2.5 mg/dl in
1/31/2012
women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg
once daily.

34

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35

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36

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37

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38


HbA1C




placebo


-
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39


;
(
).

( DPP-IV)

.

.

( )

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40

1/31/2012

41

, 52 ,


: 2 , 40
.
,
3 12
35kg/m2, 125mg%
150-200 mg%, 1C 7.8%
1/31/2012

42

2
52 , ., :31.3, check-up
. : SGOT/SGPT=2X .
HbA1c: 8.4%

;
1. , ,
2
2. 1 +
3. 1 + 2 +
4. 1 + 2 +
5. 1 + 2 +
6. 1 + 2 +
7. 1 + 2 +

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43

3
59 , , :30.1, 6 :
850mg: 1X2 3mg: 1X1, HbA1c=6.9%.
2-4

;
1.
2. SU
3. SU
4. SU
5. SU
6. SU

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44

4
62 , , :29.7, 5 :
, ,
, -. HbA1c=7.5%.


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45

5
52 , , :31.3, ,
.
, SGOT/SGPT=3X HbA1c: 8.6%, LDL: 123mg/dl, TG: 176mg/dl, HDL:
36mg/dl

;
1. , ,
2

1/31/2012

2.

1 +

3.

1 + 2 +

4.

1 + 2 +

5.

1 + 2 +

6.

1 + 2 +

7.

1 + 2 +

8.

1 + 2 +

9. 1 + 2 +

46

Exenatide LAR vs sitagliptin


pioglitazone: DURATION 2
- 514 exenatide LAR (172 .)
sitagliptin (172 .) piolgitazone (172 .). Fu= 26 .
55 , 1C:
1C: 8,3%, : 7
( )
-

1C: Exen. LAR:


LAR: 1,5%
Sitagliptin: 0,9%
Pioglitazone: 1,2%
: Exen. LAR 16% vs 22% 2

: Ex. Lar 20% vs 5%, : LAR 8% vs 2%,


2%, : LAR
13% vs 7%
, , .
()

1/31/2012

ADA 70TH s.s. 2010


Lancet June 2010

47

VILDAGLIPTIN vs SITAGLIPTIN

1/31/2012
Marfella R et al, J Diabetes Complications. 2010 March - April;24(2):79-83.

48
48


DPP4
Dipeptidyl peptidase 9 (DPP-9)
Dipeptidyl peptidase 8 (DPP-8)
Fibroblast activation protein a (FAP) (serpase)

DPP-4 Gene
Family

Dipeptidyl peptidase 4 (DPP-4)

Dipeptidyl peptidase 6 (DPP-6)


Prolyl endopeptidase (PEP)
Other
Proline
Specific Peptidases
1/31/2012

Quiescent cell prolyl peptidase


(DPP7, DPP-11)/DPP-11
Aminopeptidase P (APP)
Prolidase

49

DPP-4 CD-26
.

DPP-8 DPP-9,
. ( ,
, ).
DPP-8 up-regulated - DPP-9
, .
.

DPP-IV Fibroplast Fibroblast


activation protein R (FAP-R, ).
. (

J.1/31/2012
Med.
Chem. 2004,
47, 4135-4141

).

50


Enzyme

IC50 (nM)

DPP-4
DPP-8
DPP-9
DPP-2/DPP-7
FAP
PEP
APP

18
48.000
>100.000
>100.000
>100.000
>100.000
>100.000

C.F. Deacon, J.J. Holst / The International Journal of Biochemistry & Cell Biology 38 (2006) 831844

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51


DPP--4;
DPP
NAI, .
:
GIP, PACAP.
RANTES, eotaxin, IP-10, SDF-1R,
substance P, -casomorphin, NPY, and
PYY.

J. Med. Chem. 2004, 47, 4135-4141


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