13/12/14

&

GLP-1

2
3

Toft-Neilsen M-B et al. J Clin Endocrinol Metab 2001;86: 3717-3723

Cummings DE et al. Diabetes 2001;50: 1714-1719

GLP-1
L-

GLP-1

/ -
-

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

,

3 :

1.

1
2.

-1
3.



2

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

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

PPG

GLP-1

GLP-1

GLP-1

( )

PPG

GLP-1

Drucker DJ. J Clin Invest. 2007, 117:24-32.

Samson M et al.,. Diabetes Metab Res Rev. 2009, 25:502-514.

pmol / kg min

2500

Controls

3000

2000

T2D

GLP-1

1500

1000

2 (T2D)

500

0
0

Adapted from Kjems LL, et al. Diabetes. 2003;52:380-386.

GLP-1

GLP-1

GLP-1

0,5 pmol/kg/min

1,0 pmol/kg/min

2,0 pmol/kg/min

,
2
20

-10

-40

-70

NS

<0,05)

-100

Adapted from: Knop FK, et al. Diabetologia. 2007;50:797-805.

8
8 2

-AUC

,

GLP-1

GLP-1

61%
GLP-1

AUC 0-210 min

ng/mlmin

Adapted from: Gutniak M, et al. N Engl J Med. 1992;326:1316-1322.

500

400

GLP-1*
300

mL

Placebo
<0,0001

200

100

0
0

60

120

180

240

* 1,5 nmol / kg
Nauck MA et al.,. Diabetologia. 1996, 39:1546-1553.

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

Counts retained (%)

100

Placebo

80
60
40
P = 0.46

20
0

Stomach retention (%)

60

120

180

(min)
Vella et al. Diabetes 2007; 56(5): 1475
Steven et al. Aliment Pharmacol Ther 2012; 36: 379

240

P = 0.16

60
40
20
0

Placebo

10
0
80

0 30 60 90 12 15 18 21 24
0 0 0 0 0

(min)

 GLP-1
DPP-4
GLP-1

DPP-4

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

* ()

GLP-1
GLP-1,
PPG 2.

 (Exenatide)
(Exenatide-LAR) GLP-1

Cumulative acetaminophen AUC (g*min/mL)

Exenatide once weekly

2500

Exenatide twice daily

n = 26

2000

n = 26

2000

Baseline

1500

Baseline

1500

Week 14

1000
500
0

2500

1000

Week 14

500

50

100

150

200

Time (min)

Drucker DJ, et al. Lancet 2008;372:124050.

250

300

50

100

150
Time (min)

200

250

300

:

-His-Gly-Glu-Gly-Thr-Phe-Thr-SerAsp-Leu-Ser-Lys-Gln-Met-Glu-Glu-GluAla-Val-Arg-Leu-Phe-Ile-Glu-Trp-LeuLys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-AlaPro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-LysNH2

50% GLP-1

1,5 4,5

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

14

4-
GLP-1
GLP-1,

1,5 4,5

GLP-1
GLP-1*
IC50
**

GLP-1
,

1.
2.
3.

Werner U , et al. ReguI Pept. 2010, 164(2-3):58-64.

Barnett AH , et al. Core Evid. 2011, 6:67-79.
Christensen M , et al. Drugs. 2009, 12(8):503-513.

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

GLP-1

5,48 1,3 nM

1,43 0,2 nM

~4
GLP-1

DR6012:

20 g

5 g

2, 13-, ,

542 2,

20 g

30 g

5 g

10 g

20 g

30 g

-0,1

LS A1C (%)

10 g

HbA1c 7,5%

-0,2

-0,18

-0,3
-0,4
-0,5
-0,6

-0,47
p = 0,0056

-0,50

-0,65

p = 0,0033

-0,7

p<0,0001

-0,69

-0,8

-0,75
p<0.0001

p<0,0001

-0,9

-0,76

-0,78

p<0,0001

-1

-0,87

p<0,0001

p<0,0001

HbA1c ( )
:

Ratner R et al. Diabet Med 2010, 27:10241032

(%)

5-30 g

HbA1C <7%

90

67,9

70

52,0

60
50

77,4

68,6

80

p<0,0001

p<0,0001

p = 0,0133

61,5
p<0, 0006

51,0

47,3

p<0,0001

64,8

p<0,0001

p = 0,0217

p = 0,0460

40

31,8

30
20
10
0
5 g

10 g

20 g

30 g

5 g

10 g

20 g

30 g

16

DR6012:

20
mg

LS (kg)

5 g

10 g

20 g

n= 51

-0,5

30 g

n= 53

5 g

n= 52

10 g

20 g

30 g

n= 54

-1
-1,5
-2
-2,5

-2,0

-2,1

p = 0,9299

p = 0,6920

-2,39

-3

-1,94
-2,61

p = 0,2962

-3,5

p<0,1058

-3,01

-2,21

p = 0,0099

-4

p = 0,5010

40

25

18,5

20
15

5 g

5,8 5,5

10 g

20 g

5,7

30 g

5 g

7,1

9,3
3,7

0,9

10 g

20 g

30 g

(%)

(%)

30

25,5

22,2

25
20
15
10

14,3

11,5
7,5

7,3

4,6

5
5 g

10 g

20 g

30 g

5 g

10 g

20 g

30 g

35

3,6

33,3

30

p<0,0001

p<0,0001

10

35,2

35

-3,89

-3,47

-4,5

(%)

35
30

25,9

25
20
15
10

5,5

7,7

9,1

11,1
7,4

5,7

7,3

7,1

5
0

5 g

10 g

20 g

30 g

5 g

10 g

20 g

30 g

Ratner R et al. Diabet Med 2010, 27:10241032

17

DR6012:

HbA1c 7%

90
*
77%

% HbA1C
<7.0% 13

80

*
68%

70

52%

60

50

*
69%

47%

*
65%

**
62%

51%

40

32%

30
20
10
0

n= 26

n= 26

n= 36

n= 35

n= 26

n= 35

n= 32

n= 41

n= 34

5 g

10 g

20 g

30 g

5 g

10 g

20 g

30 g

Ratner R et al. Diabet Med 2010, 27:10241032

*p<0,0001, **p<0.005, p<0.05

18

**
* ( CIMT)
*
*
* stress
*
*
*
*
DECODE study group. Arch Intern Med 2001;161(3):397-405. Cavalot et al. JCEM 2006;91(3):813-9. Hanefeld et al. Diabetologia 1996;39(12):1577-83. Esposito et al. JCEM 2008;93(4):134550. Scognamiglio et al. Circulation 2005;112(2):179-84. Bibra et al. Horm Met Res 2009;41(2):109-15. Monnier et al. JAMA 2006;295(14):1681-7. Ceriello et al. Horm Met Res 1998;30(3):146-9.
Neri et al. Eur J Nutr 2010; epub 7 Mar. Shiraiwa et al. Diabetes Care 2005;28(11):2806-7. Gapstur et al. JAMA 2000;283(19):2552-8. Clement. Curr Diab Rep 2009;9(5):355-9.

GLP-1


GLP-1

GLP-1

GLP-1

IR

LAR

25

12

FPG

PPG

(02
bpm)

( 25 bpm)

15 kgr

25 kgr

2050%, (
)

2040%
( ~48 )

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

GLP-1 GLP-1

GLP-1

PPG

GLP-1

(mg/dL)

( <0,0001)

GLP-1

()

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

Lixisenatide (n = 75)

C-peptide

p < 0.0001

Data shown are changes from baseline in each parameter at 28 days

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

Glucagon

AUC0:30-4:30 (hpg/mL)

AUC0:30-4:30 (hng/mL)

AUC0:30-4:30 (hIU/mL)

Insulin

p < 0.0001

Liraglutide (n = 68)

p = 0.032

post hoc Kapitza et al,

Lyxumia PPG 24
3 (, , )

Lyxumia
AUC PPG


.

AUC PPG
24 ( 3 )
25

*
Lorenz M, et al. Regul Pept 2013; 185C: 1-8

t1/2 ( (mins)

1
()

28
()

28
(placebo)

P=0.0031

20gr xPlacebo
1
=


, , 55 :
Glargine 28 IUs
DPP-4 (1000/50) 1x2
4mg, .

:
: 128mg/dL
HbA1c : 8,2%
: 32 mg/dL
: 0,8 mg/dL
BMI: 30 kg/m2

: 145/100 mmHg

128

132
148

130

126

138

210

126

220

132

196

230

130
140

210

132

132
140

138

220


6mg

basal-bolus

GLP-1


, , 65 :
30/70 (2 )
2000mg

:
HbA1c : 8,4%
,


8kgr

(Basal-plus basal-bolus)

GLP-1

DPP-4

M GetGoaL Duo1: -, , 2
,
Lantus () + (TZDs)
+

n= 898

7 HbA1c 10%

15
10

Lantus () +
( TZDs)

TZDs
SUs*
*

n=446

N223

20

- 7 HbA1c 9%
+
-
7 -SMBG > 140 mg / dl

Lantus () + (TZDs)
+

N223
Lantus

Lantus -

Scr
- 80 100 mg/dl ( )

2-
screening

- 24

run in 12

* Lantus
Riddle MC , et al. Diabetes Care. 2013 Sep;36(9):2497-503

31

31

GetGoaL Duo1: HbA1c (%)

( screening)
Lantus + Met (TZDs)

Lantus + Met (TZDs) +

8.6

(n = 221)

8.4

(n = 215)

HbA1c +/- SE

8.2
8.0
7.8
7.6%
7.6

7.56%
7.3

7.4
7.2
7.0

7.0

6.8
6.6
scr. -12

-8

-4 -1 Bas.

16

24 24LOCF

mITT population, LOCF = Last observation carried

forward
Bas. = Baseline. Scr. = Screen.
Riddle MC , et al. Diabetes Care. 2013 Sep;36(9):2497-503

32

GetGal Duo1:
- HbA1c 24

**

56,3%

60%

= 121

50%

40%

(N=215)
(N=221)

38,5%

32,1%
= 85

30%
= 69
20%

10%

0%

16,3%
= 36

* p-value
<0,0001

HbA1c 6.5%

** p-value
: 0,0001

HbA1C <7%

mITT population
Riddle MC , et al. Diabetes Care. 2013 Sep;36(9):2497-503

33

GetGal Duo1:

(N=194)
(=204)

PPG 2

2 (mmol/L)

24
0,5

(mmol / L)

(mmol / L)
24

0,08

-0,5

-0,5

(mmol / L)

(mmol / L)

-1
-1,5
-2
-2,5
-3
-3,5

-3,09

-1,5
-2
-2,5
-3
-3,5

p<,0001

-0,33

-1

-3,42

-4

: -3,16 mmol/L
(95%: -3,95 -2,38)

: -3,09 mmol/L
(95%: -3,84 -2,33)

Baseline defined as time of randomization

Riddle MC , et al. Diabetes Care. 2013 Sep;36(9):2497-503

34

GetGal Duo1:

(N=217)

p = 0,0012

(kg)

1,4

(=220)

1,16

1,2
1
0,8
0,6
0,4
0,2

0,28
= 87,5

= 86,8

24: -0,89 kg (95%: -1,42 -0,35)

Riddle MC , et al. Diabetes Care. 2013 Sep;36(9):2497-503

mITT population. Baseline defined as time of randomization

36

*

RAI 2,
:

* Raccah D, et al. 2014

Denis Raccah, et. al. Journal of Diabetes and Its Complications. 2014 Jan-Feb;28(1):40-4.

, 2.
PPP
:
OPAL1
1-2-3 2
ELEONOR3
:
GetGoal-Duo 14
GetGoal-L5

T2DM: type 2 diabetes mellitus; HbA1c: glycated hemoglobin; RAI: rapid-acting insulin; RCT: randomised
controlled trial; 1.Lankish MR, et al Diabetes Obes Metab 2008; 10:1178-1185; 2.Davidson MB et al,
Endocr Pract 2011; 17:395-403. 3.Del Prato S, et al. Diabetes Technol Ther 2012; 14:175-182. 4.Riddle
MC, et al. Diabetes Care 2013;36:2497-2503. 5.Riddle M, et al. Diabetes Care 2013;36:2489-2496.

Raccah D, et al. J Diabetes Complications 2014; 28:404.

*
Study

Design

Enrolled
population

Treatment

Basal+LIXI

GetGoal-Duo 1 (Riddle 24-week, randomised, DB, Glargine (titrated) QD + MET TZD + Patients insufficiently
et al., 2013)

PBO-controlled

N=446

Outcomes
Efficacy,

lixisenatide QD vs glargine QD +

controlled with MET SU safety

MET TZD + PBO

TZD

GetGoal-L (Riddle et

24-week, randomised, DB, Basal insulin QD MET +

al., 2013)

PBO-controlled

Patients insufficiently

Efficacy,

lixisenatide QD vs basal insulin

controlled with basal

safety

N=496

MET + PBO*

insulin MET

OPAL (Lankisch et al., 24-week, randomised,

Glargine + OAD + glulisine at

Patients insufficiently

Efficacy,

2008)

breakfast vs glargine + OAD +

controlled with >3

safety

glulisine at main meal

months of glargine +

open-label

N=393

Basal+RAI

OAD
ELEONOR (Del Prato

24-week, randomised,

Glargine (titrated) + glulisine QD +

Patients with >3 months

et al., 2012)

open-label

MET with a SMBG programme vs

of OADs at maximal dose safety, QoL

N=290

Efficacy,

glargine + glulisine QD + MET with a

Telecare programme

1-2-3 (Davidson et al., 24-week, randomised,

OADs + glargine (titrated) + glulisine Patients on 2 or 3 OADs

Efficacy,

2011)

QD vs OADs + glargine + glulisine

safety, QoL

N=343

open-label

at stable dose

BID vs OADs + glargine + glulisine

TID

*For subjects with HbA1c 7.5% at screening, basal insulin was reduced by 20% at randomisation. Glulisine administered at breakfast or
with mail meal. Mean daily dose at the end of Treatment was 11.6U; Glulisine administered with main meal with greatest glycaemic
impact (GI). Mean daily dose at the end of treatment was 9.5U; Glulisine administered QD before main meal with the greatest GI, BID
before the two meals with the greatest GI, or TID before each meal of the day, with a mean daily dose at the end of treatment of 28U,
51U, 70U for glulisine QD, BID, and TID, respectively.N numbers are the intent-to-treat population.LIXI: lixisenatide; DB: double-blind;
PBO: placebo; QD: once daily; MET: metformin; TZD: thiazolidinedione; SU: sulphonylurea; OAD: oral antidiabetic drug; SMBG: selfmonitored blood glucose; QoL: quality of life; BID: twice daily; TID: three-times daily.

Raccah D, et al. J Diabetes Complications 2014; 28:404.

HbA1c <7%,

Raccah D, et al. J Diabetes Complications 2014; 28:404.

PPG

GLP-1

, ,

PPG
Hirsch IB et al. Diabetes Obesity and Metabolism 2014; 16: 206-214

 GLP-1

FPG

* glargine

PPG

** 10 g

GLP-1**

FPG

PPG

A1C. A1C 1,74%

1,04% ( -0,69%, P <0,001)

JB Buse et al.,. Ann Intern ed. 2011, 154:103-112

GLP-1

FPG > PPG

HbA1C

PPG > FPG

QoL