GLP-1

.
'

&
. . .

Release of GLP-1 Is Impaired in Patients

With T2DM

GLP-1 (pmol/L)

20

15

Breakfast

NGT
IGT
T2DM

*
*

10
*
5

0
0

60

120

180

Time (min)
*P < .05 vs T2DM
Adapted from Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:3717-3723.

240

 GLP-1
L-

GLP-1 :
&
GLP-1
5-10
L- GLP-1
,

GLP-1
, GLP-1
, DPP-4,

t : GLP-1 = 2min, GLP-1 = 5min



,


3 :
1)

1
2)

PPG

3)

1. DeFronz RA. Med Clin N Am. 2004, 88:787-835.

2. Horowitz M et al., Diabetic Medicine. 2002, 19:177-194.

2

| 4

Inappropriate Insulin and Glucagon Responses

to Glucose in Patients With T2DM
Insuli
n

100

50

0
60

60

120 180 240

Glucagon (pg/mL)

NGT
T2DM

150

Insulin (U/mL)

Glucagon
NGT
T2DM

160
140
120
100
80
60

Time (min)
Muller WA, et al. N Engl J Med. 1970;283:109-115.

60

120 180 240

 GLP-1
( - )

500

400

300

mL

GLP-1*
Placebo
<0,0001

200

100

0
0

60

120

180

240

* 1,5 nmol / kg

Nauck MA et al.,. Diabetologia. 1996, 39:1546-1553.

10

 GLP-1

(
)
-


(
)
-*

 GLP-1
GLP-1

GLP-1
L-

GLP-1

Drucker DJ. Cell Metab. 2006;3:153-165

GLP-1 Improves -Cell Mass in Zucker Diabetic

Fatty Rats
(n=16)

-Cell Mass

-Cell Proliferation

-Cell Apoptosis

30

2.5

16

P <0.05

-Cell Mass (mg)

12

2.0
% Apoptotic -Cells

% Proliferating -Cells

P <0.01

1.5

1.0

0.5

0
Control

GLP-1
Treated*

P <0.001

10

0
Control

*GLP-1 infused at 30 pmol/kg/min over 2 days

Adapted from Farilla L, et al. Endocrinology. 2002;143:43974408.
14

20

GLP-1
Treated*

Control

GLP-1
Treated*

15

-: 22 -2

Insulin secretion
rate
(pgkg1min1)

2
0
1

Placebo

5
Placebo
/ :
1 0 min
0

IV glucose

5
0

100

110

120

130

140

150

160

(min)

Insulin (UmL1)

100

8
0
6
0
4
0

Placebo / :
0 min

2
0
0

200

110

*Derived by an AUC-based method (both graphs) (min)

100 IV glucose 200

300

Barnett AH. Core Evid 2011;6:67-79;

Christensen M, et al. Expert Opin Investig Drugs 2011;20:549-557


GLP-1

GLP-1

GLP-1
DPP-IV

(Januvia)
(Galvus)

(Onglyza)

(Trajenta)

(Byetta)
(Victoza)
(Lyxumia)

GLP-1 RAs :

Table adapted from Werner U, et al. Regulatory Peptides 2010;1 644:5 864; and Meier JJ. Nat. Rev.
Endocrinol 2012; 8: 72842.

17

 GLP-1
DPP-4

GLP-1

DPP4

GLP-1

24-

2-4

++

HbA1c

0,5-1,5%

0,5-0,9%

++

+ ++

0-12% (
)

0-4% ()

26-28% ()

0-1% ()

Ahren Bo., Curr Diab Reports. 2007, 7:340-347.
Cobble, M., Diabetology & Metabolic Syndrome, 2012,
4: 8, 1-10

| 18


GLP-1

Meier JJ. Nat Rev Endocrinol 2012; 8: 728-42

21



pM nM

28

liraglutide OD
T 13 h

50

100

24

80

40

60

30

40

20

20

10

4.0

4.5

5.0
5.5
6.0
Time after first dose (days)

6.5

20
16
12
8

7.0

Modelling of plasma concentration of active drug vs. maximal concentration at steady state achieved following clinically relevant
doses OD or BD. Based on published exenatide data and modelled liraglutide data.
Jonker et al. Diabetes 56(Suppl. 1):A160

Absolute concentration

Normalised concentration (%)

exenatide BD
T 2.4 h

 ,
()
GLP-1

9
GLP-1
8,5

,
4

GLP1

GLP-1

()

Nauck MA, et al. Diabetes. 2011;60:1561-1565.

|

23

GLP-1


GLP-1
GLP-1

GLP-1

PPG

(mg/dL)

( <0,0001)

GLP-1

()

: Kapitza C, et al., Diabetes, Obesity and Metabolism 2013

| 24

 2
GLP-1
, FPG
PPG

GLP-1

GLP-1

FPG

PG

FPG

PG

: Fineman MS, et al. Diabetes Obes Metab. 2012.

[published online ahead of print Jan 10 2012]. doi: 10.1111/j.1463-1326.2012.01560.x


GLP-1

FPG

PPG

* glargine
** 10 g

GLP1**

FPG

PPG

A1C. A1C
1,74%
1,04% (
-0,69%,
P <0,001)
JB Buse et al.,. Ann Intern
ed.
2011,

| 26

154: 10


GLP-1, 44

-His-Gly-Glu-Gly-Thr-Phe-ThrSer-Asp-Leu-Ser-Lys-Gln-MetGlu-Glu-Glu-Ala-Val-Arg-LeuPhe-Ile-Glu-Trp-Leu-Lys-AsnGly-Gly-Pro-Ser-Ser-Gly-Ala-ProPro-Ser-Lys-Lys-Lys-Lys-LysLys-NH2

50%

GLP-1

1,5 4,5

: C215H34761O65S
Werner U et al. Regulatory eptides. 164, (2010) 58 : 4858,6 ( )
64.

| 27

27

4-
GLP-1
GLP-1,

1,5 4,5

GLP-1

,
1. Werner U , et al. ReguI Pept. 2010, 164(2-3):58-64.
2.
Barnett AH , et al. Core
Evid. 2011, 6:67-79.

3.
4.
5.

Christensen M , et al. Drugs. 2009, 12(8):503-513.

Sanfi Internal Specific Non-clinical Pharmacology Report
MVT0010.
Sanfi Internal Specific Non-clinical Pharmacology Report
MVT0011.

* 125I-GLP-1 (736)
GLP-1 R,
CHO-K1 in
vitro
** (7-36)

GLP-1
GLP1*
IC50
GLP1

**

5,48 1,3 nM
1,43 0,2 nM

~4
GLP-1
| 28

 HbA1C
FPG,
PPG
%
6,0

7,0%8,0

9,
0%

1C
1C

130

180

FPG

PPG

mg / dL

Standards of medical care in diabetes

2012.
Diabetes Care. 2012;35(suppl
1):S11-S63.

mg / dL

206 mg / dL
~ 1/3

PPG

~ 1/3

~ 1/3
*

138 mg /
dL

Cervera et al.,. Am J Physiol Endcrinol Metab. 2008, 294:

E846-E852.

 2013

| 38

ADA 2015

ADA/EASD 2012

6.0%

7.0%

8.0%...
-

, ,
,

, ,
,

40

45

50

55

60

65

70

75

80

10

15

20
-

GETGAL

>5.000

50 | 900 | >5.000

(1)

OAD

(OADs)

GetGal-S
SU
MET

GetGoal-

MET

GetGoal-ono

GetGoal-


MET

GetGal-F1

GetGoal-Mono

MET
GetGoal-

MET

GetGoal--

MET SU

GetGal-L


MET
GetGoal-L-


SU
GetGoal-Du1


MET

 A1C :
,
A1C
(%)

GG-1

GG-S2

n=244
n=164

0
-0,2

-0,38

-0,87

-1,0

<0,0001

3.

n=544
n=274

-0,10

-0,2

-0,4

A1C
-0,6

-0,8
(%)

GG-P3

n=320

-0,2

-0,4

-0,4

-0,6

-0,6

-0,8

-0,8

-1,0

-0,85

<0,0001

n=159

-1,0

0,34

0,90
P
<0,0001

1.
Ahren B , et al. O-0591.IDF World Diabetes Congress, 4-8 2011, , UAE.
2.
Ratner RE , et al. 785. EASD 47 , 12-16 . 2011: , .
Pinget M , et al. 1010-P. ADA 72 , 8-12 2012. , PA.

| 45

 :
,

(kg)

GG-1

GG-S2

GG-P3

n=248
n=168

(kg)

n=554

n=315

n=278

n=157

-0,5

-0,5

-0,5

-1,0

-1,0

-1,5

-1,5

-2,0
-2,5
-3,0

-2,01

1,64

P=0,2
3

-2,0

-0,93

-1,0

-0,21

+0,2
1

P=0,1
9

-1,5

-1,76

-2,0

P=0<0,000
1

1. Ahren B , et al. O-0591.IDF World Diabetes Congress, 4-8 2011, , .

2. Ratner RE et al. 785. EASD 47 , 12-16 . 2011: , .
3. Pinget M , et al. 1010-P. ADA 72 , 8-12 2012. , .

| 46

 :
,

* (%)
1
GG-
GG-S2
GG-P3

n=255
n=170

20%

(%)

10%

10%

0%

n=285

20%
15%

2,4%

15,3%

12,3
%

5%

0,6%

n=574

15%

5%

n=323

15%
10%
5%

0%

n=161

20%

3,4%

1,2%

0%

* GG-M GG-S
GG-P
1. Ahren B , et al. O-0591.IDF World Diabetes Congress, 4-8 2011, , UAE.
2. Ratner RE , et al. 785. EASD 47 , 12-16 . 2011: , .
3. Pinget M , et al. 1010-P. ADA 72 , 8-12 2012. , PA.

| 47

 A1C :


A1C 24

GG-L

n=304

GG-L

n=131

n=158

BL=8,4%

A1C
(%)

BL=8,4%

1.

3.

GG-Du1

n=142

n=221

+0,1
1
BL=8,0%
BL=8,1%

P=0,00
02

glargine +
TZD

n=215

BL=7,6%

0,38
-0,74

BL =
A1C

BL=7,6%

-0,40

-0,77

<0,000
1

-0,71

<0,000
1

Riddle M , et al. 983-P. ADA 72 , 8-12 2012. , PA.

2. Seino Y , et al. Diabetes bes Metab. 2012, 14(10):910-917.
Rosenstock J , et al. 62-OR. ADA 72 , 8-12 2012. , PA. Diabetes. 2012, 61(suppl
| 1):17.
48


A1C<7,0% :

A1C<7,0%

24
GG-L
GG-L
GG-Du1
1

P=0,00
01

60%

56,3%

50%
P<0,00
01

40%

20%

1.
2.
3.

=
36

38,5%
=8
5

=
69

28,3%

0%

35,6%

P<0,00
01

30%

10%

Glargine +

TZD

12,0%
5,2%

n=304
n=158

n=146
n=154

n=215
n=221

Riddle M , et al. 983-P. DA 72 , 8-12 2012. , PA.

Seino Y , et al. Diabetes bes Metab. 2012, 14(10):910-917.
Rosenstock J , et al. 62-OR. ADA 72 , 8-12 2012. , PA. Diabetes. 2012, 61(suppl
1):17.

| 49

2


24 (mmol/L)

GG-L

n=235
n=123

1,72

-2

(mmol/L)

GG-L

GG-Du1

glargine +

TZD

n=131
0

-2

n=142

0,14

-8

p<,0001

0,08

0
-0,5

-1,5
-2,0

-6

5,54

n=204
0,5

-1,0

-4

-4

-6

n=194

-2,5
-8

-10

-3,0

7,96
p<,0001

-3,5

-3,09
p<,0001

1.

3.

Riddle M , et al. 983-P. ADA 72 , 8-12 2012. , PA.

2. Seino Y , et al. Diabetes bes Metab. 2012, 14(10):910-917.
Rosenstock J , et al. 62-OR. ADA 72 , 8-12 2012. , PA. Diabetes. 2012, 61(suppl 1):17.

| 50

(kg)
GG-L

GG-L

n=311
n=157
n=161

(kg)

0,5

n=150

GG-Du1

glargine +

TZD

n=214
n=220

1,1
6

P=0,00
12
P=0,09

<0,000
1
1.
2.
3.

Riddle M , et al. 983-P. ADA 72 , 8-12 2012.

, PA.
Seino Y , et al. Diabetes bes Metab. 2012, 14(10):910-917.
Rosenstock J , et al. 62-OR. ADA 72 , 8-12 2012. , PA. Diabetes.
2012, 61(suppl 1):17.

| 51

GG-L

GG-L

GG-Du1

n=167

n=328

n=157

n=154

n=223

n=223

(TEAE)

114
(68,3%)

241
(73,5%)

110
(70,1%)

137
(89,0%)

152
(68,2%)

178 (79,8%)

7 (4,2%)

12 (3,7%)

9 (5,7%)

10 (6,5%)

10 (4,5%)

17 (7,6%)

1 (0,3%)*

1 (0,6%)

2 (0,9%)

8 (4,8%)

25 (7,6%)

5 (3,2%)

14 (9,1%)

8 (3,6%)

19 (8,5%)

9 (4,0%)

,
n (%)

TEAE


()

1.
2.
3.

34
(20,4%)

132
(40,2%)

23
(14,6%)

94 (61,0%)

36
(16,1%)

89 (39,9%)

9 (5,4%)

24 (7,3%)

4 (2,5%)

10 (6,5%)

7 (3,1%)

15 (6,7%)

14 (8,4%)

86
(26,2%)

7 (4,5%)

61 (39,6%)

11 (4,9%)

61 (27,4%)

1 (0,6%)

27 (8,2%)

3 (1,9%)

28 (18,2%)

3 (1,3%)

21 (9,4%)

Aronson R, , et al. 983-P. ADA 72 2012. , PA.

Seino Y , et al. Diabetes bes Metab. 2012, 14(10):910-917.
Rosenstock J , et al. 62-OR. ADA 72 , 8-12 2012. , PA. Diabetes. 2012, 61(suppl 1):17.

| 52

Prandial insulin vs GLP-1

agonist added to basal insulin
Setting: USA
,
Design:
: n=5577
GLP-1 : n= 1143
: 60
: 6 1
Postgraduate Med,
2014
126: 49-60

Prandial insulin vs GLP-1

agonist added to basal insulin

Postgraduate Med, 2014

126: 49-60

Prandial insulin vs GLP-1

agonist added to basal insulin

Postgraduate Med, 2014

126: 49-60

Prandial insulin vs GLP-1

agonist added to basal insulin

Postgraduate Med,
2014


GLP-1
OADs

:

Postgraduate Med,
2014

 Lyxumia
A
GLP-1,
,

/ ,

| 58




10g
14

20g
15
,

.
,

.



4-3-2

GLP-1

GLP-1

GLP-1


-2



HbA1c
,


GLP-1


Oral Glucose
IV Glucose

2.0

11

C-peptide (nmol/L)

Glucose (mmol/L)

5.5

1.5

*
*

*
*

1.0

Incretin Effect
*

0.5
0.0

01 02

60
120
Time (min)

180

01 02

60
120
Time (min)

Mean SE; N = 6; *P .05; 01-02 = glucose infusion time.

Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin
Endocrinol Metab. 1986;63:492-498. Copyright 1986, The Endocrine Society.

180


60 2 9-
HbA1c 8,2%
: 1000 mg X2
4 mg X1, salospir 100 mg
BMI 32,4 g/m2

: 110-120-98-105-130
: 160-230

0,9 mg/dl, eGFR=95

ml/min/1,73m2
LDL 95 mg/dl

| 67

-


2 mg
o Lixisenatide 20 g X1
:
: 85-120 mg/dl
< 130 mg/dl

HbA1c 6,7%
: 2 Kg 3


76 2 12-
29,2 Kg/m2
5 mg X1,
150 mgx1, 10 mg,
salospir 100 mg X1, 20 mg
EF 45%
eGFR 28 ml/min/1,73m2
HbA1c 8,4%
:
: 130-150 mg/dl
: 170-240 mg/dl

-
glargine 10
, 18


: 85-120 mg/dl
: <160 mg/dl

3 : HbA1c 7%
: +1 Kg


70 , ,

2 15-
31 Kg/m2
HbA1c 8,2 %
850 mg X 2, Exforge 10/160
X1, 20 mg, salospir 100 mg

: 120-150 mg/dl
: 170-230 mg/dl
A 145-155/80 mmHg
1,1 mg/dl, eGFR 75 ml/min/1,73m2

Lixisenatide 20 g X1
:
: 90-130 mg/dl
: <150 mg/dl

130-140/75 mmHg
3 HbA1c 6,8%
: 2 Kg 3