:

. .
--

, . .
.


2DM

(NGT)

GT

T2DM

GT = , NGT = , T2DM = 2


Langerhans
4

:

(-),
(-),
(-)
(
).

-
80% ,
-
15%.
3

 -

Undifferentiated cells
Duct-derived progenitor
Nestin-positive intra-islet progenitor

Neogenesis
(birth)

Differentiated cells
-Cell
-Cell

GLP--1
GLP

Duct cell

Apoptosis
(death)

Lumen

Pancreatic
duct

Activin A
Betacellulin
Hepatocyte growth factor
GLP--1
GLP

Kemp et al. Rev Endocr Metab Disord. 2003

3040 days

 - 2
3,5

b -Cell volume (%)

3,0
-50%

2,5
2,0

-63%

1,5
1,0
0,5
0,0
ND

IFG

Obese

T2DM

ND

Lean

ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus

Butler et al. Diabetes. 2003

T2DM

-
-

.
- ,
,
, .

,

, .

 -
2

Dunning BE et al. Diabetologia. 2005;48:1700

2005;48:1700--1713.

 /
Meal

20.0
18.3
Glucose
(mmol/l)

16.6
15.0

Type 2 diabetes

13.3

Normal subjects

6.1
4.4
120
Insulin
(mU/l)

90

Delayed/depressed
insulin response

60
30
0
140

Nonsuppressed
glucagon

130
Glucagon
(ng/l)

120
110
100
90

-60
Mller et al. N Engl J Med. 1970

60

120 180 240 Time (min)

Normal subects n=11; Type 2 diabetes n=12

 Incretin Effect

(pmol/L)

IV

(mg/dL)

200
50 g
150

100

50

400

300

200

100

0
30

N=6

30

60 90 120 150 180 210

()

IV =
Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492498.

30

30

60 90 120 150 180 210

()

IV
9

+
HGO
*

-Cells
Pancreas
b -Cells

SU
GLINIDES

TZD
MET

*HGO=
Adapted from Ohneda A, et al. J Clin Endocrinol Metab. 1978;46:504510; and
Gomis R, et al. Diabetes Res Clin Pract. 1989;6:191198.

10


, GLP
GLP--1 (
(
-1) GIP,
( )

,

,


2
Creutzfeldt Wl. Diabetologia. 1979;16:7585.

11

 GLP
GLP-1

*
*

*Observed in animal models

Adapted from Holst JJ. Diabetes Metab Res Rev. 2002;18:430
2002;18:430--441.

12

 GLP
GLP-1
G- 3

3




-

1. Dunning BE et al.
al. Diabetologica. 2005;48:1700
2005;48:1700--13.
2. Degn KB, et al.
al. Diabetes. 2004; 54:239754:2397-2403.

3 Gromada J and Rorsman P Horm Metab Res 2004; 36:82236:822-9.

13

 GLP
GLP-1

GLPGLP-1 :
,

14

 GLP
GLP--1 ,

GLP-1

( )

( )

Kieffer, Habener. Endocr Rev 1999;20:876913. Flint et al. J Clin Invest 1998;101:51520. Wettergren et al. Dig Dis Sci
1993;38:66573. During et al. Nat Med 2003;9:11739. Perry et al. J Pharmacol Exp Ther 2002;302:8818. Perry et al. J.
Neurosci Res 2003;72:60312.Bose et al. Diabetes 2005;54:14651. Kavianipour et al. Peptides 2003;24:56978. Thrainsdottir
et al. Diab Vasc Dis Res 2004;1:403. Nikolaidis, et al. Circulation 2004;109:9625. Nystrom et al. Am J Physiol Endocrinol
Metab 2004;287:E120915. Nystrom et al. Regul Pept 2005;125:1737.

 Exendin-4

Gila
monster
Exendin-4

meal-related peptide

Plasma Exendin-4 Concentration (pg/mL)

Exendin-4 in the Gila Monster

400000

300000

200000

100000

0
0

Time After Meal (h)

Data from Young AA. Insulin Resistance and Insulin Resistance Syndrome
2002, 235-262

12

 GLPGLP-1
DPP--4
DPP
DPP--4
DPP

H
7

9
G
37

S
R

D
G

V
K

S
V

L W A

E
I

G
F

Q
E

A
A
K

T = 1
12

17
*

 DPP

DPP-4
GLP
GLP-1

GLPGLP
-1

GLP-1 t = 1 2 min

GLPGLP
-1
DPPDPP
-4

DPPDPP
-4
GLP-1 = Glucagon-Like Peptide-1; DPP-4= Dipeptidyl Peptidase-4
Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.
Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

GLP-1

(>80%)
18

 DPPDPP-4

D-4


HGO =
Unger RH. Metabolism 1974;23:581593

19

Incretin mimetics and DPPDPP-4 inhibitors:

major differences
Properties/effect

Incretin mimetics

DPP-4 inhibitors

Mechanism of stimulation of insulin

secretion exclusively through GLP-1 effect

Yes

Unknown

Restitution of insulin secretion (2 phases)

Yes (exenatide)

Yes

Hypoglycaemia

No

No

Maintained counter-regulation by
glucagon in hypoglycaemia

Yes

Not tested

Inhibition of gastric emptying

Yes

Marginal

Effect on body weight

Weight loss

Weight neutral

Side effects

Nausea

None observed

Administration

Subcutaneous

Oral

Gallwitz. Eur Endocr Dis. 2006

DPP--IV Inhibitors
DPP
Sitagliptin (Januvia)
Vildagliptin (Galvus)
Saxagliptin (Onglyza)
Alogliptin
Linagliptin

Glucose
Glucose--dependent stimulation of insulin secretion
Reduction of gastric emptying
Reduction of inappropriate glucagon secretion
Beta
Beta--cell proliferation / regeneration
Adapted from: Nauck MA et al. (2009). Diabetes Care 32(S2):S223

Vilda
Vil
dagli
glip
ptin
Gli: WHO suffix for antidiabetic agents
Da, p: Dipeptidyl AminoPeptidase
Tin: Enzyme inhibitor
Vil: a gift from Novartis Research

Tyr547
Phe357
Tyr666

Arg358

S2
S1

Ser209

Glu206

Ser630

Glu205

Trp629

Arg125
His740
His126

Nils Ostermann
Novartis XX-ray lab,
Basel, Switzerland

Phe357
Tyr547

Tyr631

Arg358

LAF237
Vildagliptin
Galvus

S2
S1

Ser209

Ser630

Glu206
Glu205

His740
His126

Arg125
Asn710

22

Vildagliptin::
Vildagliptin

, DPP
DPP--4
> 80%,

::

/ P450 CYP

::
85% ,
, 15%


23
Data on file, Novartis Pharmaceuticals

Vildagliptin:
Vildagliptin:
,

:: 24
HbA1c
(%)

0.2

HbA1c
BL ~ 8,
8,4%

HbA1c
placebo

0.01
0.0
-0.2
-0.4
-0.6
-0.8
-1.0

-0.5
*

-0.5
-0.7
**

*
-0.8

**

BL = , PBO = , Vilda = vildagliptin.

ITT.
*P = 0,01, **P <0,001 PBO.
Pi-Sunyer X, et. al. Diabetes Res Clin Pract. 2007.

-0.7
** -0.9
**
Vilda 50 mg qd (n=84)
Vilda 50 mg bid (n=79)
Vilda 100 mg qd (n=89) 24
PBO (n=88)

Effect of vildagliptin on the dayday-time

plasma glucagon profile

Glucagon 125
(ng/l)
100

Day 0

75

Day 28

50
0700

1700

1100
Time (h)

Mari et al. J Clin Endocrinol Metab. 2005

2100

Vildagliptin: -
( )
)

Vildagliptin
60 mg/kg
21

P < 0.001

100
80
60
40
20
0

Vilda

2.5
2.0
1.5

P < 0.05

1.0
0.5
0.0

Vilda

7
Vilda=vildagliptin
Duttaroy A, et al. Diabetes. 2005
2005;; 54 (suppl 1): A141. Abstract 572572-P.

-
- (mg)

120

Apotag- (%)

BrdU- (%)

P < 0.05

0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00

Vilda

21
26

 -
.

Scherbaum W et al. Diabetes Obes Metab 2008; 10:1114

 24 vildagliptin

HbA1c

HbA1c >9%

~8
~8,,7%
N

459

238

166

88

HbA1c
(%)

0.0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2

-1.1
-1.3

-1.4

-1.8

-1.6
-1.8

-2.0

Schweizer A, et al. Diabetes Care. 30 (2), February 2007.

.

-1.9

Vildagliptin 50 mg
8 mg
28

 Vildagliptin

45 mg QD

HbA1c (%)

HbA1c
0.0

-0.3

-0.2
-0.4
-0.6

-0.8
-0.8
-1.0

-1.0
*

-1.2

HbA1c= 8,7%
Vilda 50 mg QD + Pio (n=124)
Vilda 50 mg BID + Pio (n=136)
. + Pio 45 mg QD (n=138)
29

* P0
0,,001 45 mg + .
.
Garber et al, Diabetes obesity and metabolism, 2006

 :
:

TG

TC

LDL--C
LDL

HDL--C
HDL

14

(%)

12
10
8
6

**

4
2
0
-2
-4

-6
-8
*P=0,01, ** P0,003 Vildagliptin .
Schweizer A, et al. Diabetes Care. 30 (2), February 2007.

**

**

Vildagliptin 100 mg/

mg/ (n=449)
8 mg/
mg/ (n=231)

30

 :
:

(kg)

Vildagliptin 50 mg BID
8 mg QD

1.6
1

-0.3
-1

* P<0,001 vildagliptin.
Schweizer A, et al. Diabetes Care. 30 (2), February 2007.

31

U.S. Population with Diagnosed Diabetes,

1995--2008
1995

Too fat
Too thin




.
SUs, , Ds,
2 kg 1% HbA1C

Buse J et al. Clin Ther. 2007;29:139-153.

 vildagliptin

1500 mg
Vilda 50 mg QD + Met
Vilda 50 mg BID + Met
Placebo + Met

8.6
11.0

8.4

8.0
7.8
7.6

*
7.4

FPG (mmol/L)

HbA1c (%)

8.2
10.0

9.0

*
7.2

8.
0

-4

12

16

20

( )

* P<0,001 .
Bosi E, et al. Diabetes Care February 2007

24

-8

-4

12

16

20

( )

34

24

 Vildagliptin
Vildagliptin
GLP
GLP--1 24

DPP
DPP--4 1-4

30

vildagliptin
GLP-1

GLP
GLP--1

GLP
GLP--1
DPP
DPP--45-7

GLP-1
(pmol/L)

25
20
15
10
5
0
Vildagliptin

(n=5)

Vildagliptin

(n=12)

*P <0,05
DPP-4= -4, GLP-1= -1
1Ahrn B, et al. J Clin Endocrinol Metab 2004; 89: 2078-2084; 2Balas B, et al. J Clin Endocrinol Metab 2007; 92: 1249-1255;
3Matikainen N, et al. Diabetologia 2006; 49: 2049-2057; 4Rosenstock J, et al. Diabetes Care 2008; 31: 30-35;
5Yasuda N, et al. Biochem Biophys Ref Commun 2002; 298: 779-784; 6Hinke S, et al. Biochem Biophys Ref Commun 2002; 291: 1302-1308;
7Migoya E, et al. Presented at EASD 2007; abstract 0111; 8Dunning B, et al. Presented at EASD 2006; abstract 0174.

35


HbA1c

Glim 4 mg

9.0

Vilda 50 mg qd (n=132)
Vilda 50 mg bid (n=132)
PBO (n= 144)

HbA1c (%)

8.8
8.6
8.4
HbA1c (2305)

8.2
8.0
7.8
7.6
-4

12

16

20

24

( )
Vilda = vildagliptin, PBO= , Glim =
ITT
Data on file, Novartis Pharmaceuticals, LAF237A2305

36

Vildagliptin:
Vildagliptin:
52
(~1.9 g )

HbA1c (%)

Vildagliptin 50 mg bid + metformin

Glimepiride up to 6 mg qd + metformin

0.4
% NI:

97.5%
CI
(0.02,0.16)

0.5
%

()
Ferrannini E et al, Diabetes Obes Metab. 2009 Feb;11(2):157Feb;11(2):157-6637

Vildagliptin::
Vildagliptin

(kg)

(~1.9 g )

1.8 kg

()
Vildagliptin 50 mg bid + metformin
Glimepiride up to 6 mg qd + metformin
38

Ferrannini E et al, Diabetes Obes Metab. 2009 Feb;11(2):157Feb;11(2):157-66

Vildagliptin vs Glimepiride:

>1
(%)

(grade 2
grade 2)

1389/ 1383

1389/ 1383

1389/ 1383

(%)

n=

Vildagliptin 50 mg bid + metformin

Glimepiride up to 6 mg qd + metformin
39
Ferrannini E et al, Diabetes Obes Metab. 2009 Feb;11(2):157Feb;11(2):157-66

 Vildagliptin 2

+
Vildagliptin 50 mg QD +

HbA1c (%)

9.0

Vildagliptin 50 mg BID +
( + )
. +

Vildagliptin +

8.5

8.0

7.5
-4

12

16

20

24

28

32

36

40

44

48

52

()
40
Fonseca V, et al. Diabetologia published on line March 27, 2007

 Vildagliptin
, 24

.
Vildagliptin +
. +

50

200

45

40

185
160

10
8

30

20

10

33

120
6
80

113

40

6
4
2

0
0

, 2 :
: vildagliptin ,
,
(P<0
<0,,01).
41
Fonseca V, et al. Diabetologia, published on line March 27, 2007.
2007.

Metformin+ sitagliptin 100 1x1 n=20

vs.

Metformin + vildagliptin 50 1x2 n=18

24

(MAGE)
.
,
GLP--1, ,
GLP
42

R. Marfella et al. / Journal of Diabetes and Its Complications 2009

43

R. Marfella et al. / Journal of Diabetes and Its Complications 2009

44

R. Marfella et al. / Journal of Diabetes and Its Complications 2009


1.
24
2. GLP
GLP--1

3.

45

 GLP
GLP--1

()

GLP-1

(
)
:

p38 MAP

GLUT-1
-

PAI-1 TNF

Gutzwiller J-P et al. Endocrinol Metab 2004;89:305561;Zhao T et al. J Pharmacol Exp Ther 2006;317:110613;
Furchgott RF and Zwadaki JV. Nature 1980;288:3736; Golpon HA et al. Regul Pept 2001;102:816;
Liu HB et al. ADA 2006; Gutzwiller J-P et al. Digestion 2006;73:14250.; Bose AK et al. Diabetes 2005;54:14651


Odds Ratio

Vildagliptin

n / N (%)

Vilda 50 mg qda 356 / 1502 (23.07)

All
comparators
n / N (%)
432 / 1662 (26.0)

Peto odds ratio

(95% CI)

0.88 (0.75
(0.751.04)

Vilda 50 mg bida 2099 / 6116 (34.3) 1697 / 4872 (34.8) 1.04 (0.96
(0.961.13)

0.1

1
Vildagliptin

10
Vildagliptin

bid=twice daily; CI=confidence interval; qd

qd=once
=once daily; vilda
vilda=
=vildagliptin
vildagliptin..
avs comparators (all nonnon-vildagliptin treatment groups). AllAll-study safety (excluding openopen-label) population.
Ligueros--Saylan M, et al. Diabetes Obes Metab
Ligueros
Metab.. 2010; 12: 495
495509.


Odds Ratio
Vildagliptin
n / N (%)

All comparators
n / N (%)

Peto odds ratio

(95% CI)

Vilda 50 mg qda 2 / 1502 (0.13)

4 / 1662 (0.24)

0.76 (0.15
(0.153.89)

Vilda 50 mg bida 7 / 6116 (0.11)

9 / 4872 (0.18)

0.70 (0.26
(0.261.88)

0.01

0.1

Vildagliptin

AEs=adverse events; bid=twice daily; CI=confidence interval; qd

qd=once
=once daily; vilda
vilda=
=vildagliptin
vildagliptin..
avs comparators (all nonnon-vildagliptin treatment groups). AllAll-study safety (excluding openopen-label) population.
Ligueros--Saylan M, et al. Diabetes Obes Metab
Ligueros
Metab.. 2010; 12: 495
495509.

10

100

Vildagliptin

Clinical experience with vildagliptin in the management

of type 2 diabetes in a patient population 75 years:
years:
a pooled analysis from a database of clinical trials

77 .
HbA1c
75 -0,9%
8,3% (p <0,0001) -1,1%
8,5% (p = 0,0004).
0,0004).

A. Schweizer et al, Diabetes, Obesity and Metabolism 13: 55

5564, 2011.


2
75

0,9 kg (p = 0,0277) -0,2 kg (NS),

,
AE, ()

A. Schweizer et al, Diabetes, Obesity and Metabolism 13: 55

5564, 2011.

Vildagliptin:: low risk for hypoglycaemia in very elderly

Vildagliptin
(75 years)

BL=

8.3

8.5

Change in HbA1c (%)

from baseline

-0.3

Monotherapy (n=62)
Add--on therapy (n=25)
Add

-0.8
-0.9
-1.3

-1.1
**

-1.8

Hypoglycaemic events

Monotherapy

Add--on therapy
Add

Any events

0.0

0.0

Severe events

0.0

0.0

*P <0.001; **P
**P =0.0004

Schweizer A, et al. Diabetes Obes Metab 2011; 13: 55

5564

Vildagliptin:: low risk for hypoglycaemia during Ramadan1

Vildagliptin
A study on 12,243 Muslims showed 7.5-fold increased risk of severe
hypoglycaemia during Ramadan2
BL=

7.6

7.2

Change in HbA1c (%) from

baseline

0.1
0.0

-0.2
Vildagliptin 50 mg twice daily (n=23)
Sulfonylurea (n=36)

-0.4

Hypoglycemic events

Vildagliptin

Sulfonylurea

Any events

34 (in 15 pts)

Severe events

1Hassanein

M, et al. Curr Med Res Opin 2011; 27: 1367

13671374;
M, et al. Diabetes Care 2010; 33: 1895
18951902

2Al
Al--Arouj

Age-related Decline in Renal Function in Patients with

Type 2 diabetes


(
1c 6,57,0%, (CrCl<10ml/min) <7,5%,
<7,5-8,0%)
-

(, , , ,
, )

 1c

1c

1c

>2.5 mg/dl
<11 mg/dl

1.



/ .
2. ,
(CrCl<50ml/min),
60%.
3. ,
.

Vildagliptin Provided Robust Reduction in HbA1c in T2DM

Patients with Moderate or Severe Renal Impairment
Moderate RI
Mean Change from Baseline to
End Point

Severe RI

Between-treatment Difference
vs Placebo

Mean Change from Baseline to Between-treatment Difference

End Point
vs Placebo

128

N=

122

95

BL=

7.86

7.79

BL=

7.69

7.65

Vildagliptin 50 mg qd

Adjusted Mean Change from Baseline in

HbA1c (%)

157

Adjusted Mean Change from Baseline in

HbA1c (%)

N=

Placebo

*P <0.0001 vs placebo. Full analysis set. BL=baseline; HbA1c=haemoglobin A1c; RI=renal impairment; T2DM=type 2 diabetes mellitus.

Lukashevich V et al. Diabetes Obes Metab 2011; 13: 947

( 50 ml/min).
(ESRD)
Galvus 50 mg .

(ESRD) .


(2)

1
.

(alanine aminotransferase (ALT) aspartate
aminotransferase (AST) > 3x )


16 2011 positive opinion
EMEA 2nd line monotherapy
60 .

75
,


::
DPP
DPP--4

12 Phase IIb / III

3,415 sitagliptin vs.
2,724 patients placebo
34.5% vs. 32.9% (NS)

From: WilliamsWilliams-Herman, D et al. (2008). BMC End Dis 8(14)

LIFESTYLE MODIFICATION

A1C 7.6-9.0%

A1C 6.5-7.5%
Monotherapy
MET

GLP1

DPP4

Dual Therapy
TZD

GLP1 or
DPP4 or
TZD

AGI
MET

GLP-1 or DPP4

Glinide or SU
TZD

GLP-1 or DPP4

GLP1
or
DPP4

+
AGI

MET

Triple Therapy
MET +
GLP1 or
DPP4

TZD
+

GLP1
or
DPP4

GLP1
or
DPP4

+SU

TZD
GLP1
or
DPP4

Triple Therapy

Colesevelam
MET

Triple Therapy

MET

TZD

Drug nave,
No symptoms

SU or
Glinides

Dual Therapy
MET

A1C >9%

+TZD

+TZD

+SU

Symptoms or
under treatment

TZD

Glinides
or SU

Adapted from AACE

December 2009 update
with permission

Insulin + other agents

 GLP-1
?
-
,

THE END!!!!