2.

, 13.12.2014

Beta cell capacity

Modifiers

TIME

( FPG)


ADA 2012
1C

:

/

CVD /





1C
A1C

1/7/2015

<7%.

,
,
7-7.9%
,
<6.5%.

Diabetes Care 2012;suppl.1: s11-s63


,


HbA1C

2,
-

2013

. J. Abrahanson et al Endocrine Practise 2013;19:327-337

 2:

GLP-1

DPP-IV

Hyperglycemia

SU

(, ), ()
, , ,

TZD

, , ,

(, )

(, , )

SGLT-2

1. Inzucchi SE. JAMA. 2002;287:360372. 2. Dormandy JA, et al. Lancet. 2005;366:12791289. 3. Buse JB, et al. Diabetes Care. 2004;27:26282635. 4. DeFronzo
RA, et al. Diabetes Care. 2005;28:10921100. 5. Kendall DM, et al. Diabetes Care. 2005;28:10831091. 6. Kolterman OG, et al. Am J Health-Syst Pharm.
2005;62:173181.

 ;


.

.

: , ,

: .

1/7/2015

11

SU

TZD

DPP-4

SGLT-2

GLP-1 A

SU
+
TZD
DPP-4
SGLT-2
GLP-1 A

TZD
+
SU
DPP-4
SGLT-2
GLP-1 A

DPP-4
+
TZD
SU
SGLT-2

SGLT-2
+
TZD
DPP-4
SU
GLP-1 A

GLP-1 A
+
TZD
SGLT-2
SU

+
TZD
DPP-4
SGLT-2
GLP-1 A


3 : 1998-2006-2012

Exp Clin Endocrinol Diabetes. 2009 Oct;117(9):505-10, BMC Endocr Disord. 2014 Mar 5;14(1):23

 DPP-4:
,

GLP-1 (736)

DPP-4

DPP4

GLP-1 (936)

2

-

Drucker DJ. Exp Opin Invest Drugs. 2003;12:87100; Ahrn B. Curr Diab Rep. 2003;3:365372.

 , , DPP-4

Deakon C.F.Diabetes, Obesity & Metabolism, 2011; 13: 7-18

 DPP-4
DPP-4

Deakon C.F.Diabetes, Obesity & Metabolism, 2011; 13: 7-18

Colightly LK et al. Comparative Clinical Pharmacokinetics of Dipeptidyl Peptidase Inhibitors. Clin

Pharmacokinet 2012; 51(8): 501-514

, 52 ,

.
,
.
: 2 , 40
.
,
3 12

35kg/m2, 125mg%
150-200 mg%, 1C 7.4%
1/7/2015

18

 HbA1c
vs placebo
HbA1c (%) (SE)

(n = 333)
Placebo (n = 163)

0.69%

12

18

24

,
HbA1c , 0.46% 6 , 0.70% 24 ( ,
p < 0.0001)
HbA1c: 8.0% ; 8.0% placebo;
FAS LOCF.
Del Prato S, et al. Diabetes Obes Metab. 2011;13: 258267.

 FPG
FPG (mg/dL) (SE)

(n = 318)
Placebo (n = 149)

23.3
mg/dL

12

18

24

FPG
24 23.3 mg/dL (p < 0.0001)
FPG: 163.86 mg/dL ; 165.72 mg/dL placebo;
FAS, LOCF.

Del Prato S, et al. ADA 2010, Abstract 695-P; Del Prato S, et al. Diabetes Obes Metab. 2011;13: 258267.

Barnett AH. et al. Diabetes, Obesity and Metabolism, 2012; 14: 1145-1154

2
62 , ., :31.3, check-up
. : SGOT/SGPT=3X .
HbA1c: 8.2% , LDL: 123mg/dl, TG: 176mg/dl, HDL: 36mg/dl

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

1/7/2015

7.

1 + 2 +

8.

SGLT-2

22

 HbA1c

HbA1c (%), (SE)

5 mg + > 1500 mg (n = 523)

Placebo (n = 175) + > 1500 mg (n=177)

-0.64%

12

18

24

HbA1c
24 (p < 0.0001)
HbA1c: 8.09% ; 8.02% ;
FAS LOCF.

Taskinen MR, et al. Diabetes Obes Metab. 2011;13:6574.

1 (SE) HbA1c (%), FAS (LOCF)

8.0
7.5

0.35

7.0
6.5
6.0

()
2

[97.5% CI]

+ (n = 764) 7.69 0.03

0.16

0.20 [0.09, 0.30]

+ (n = 755)

0.36

HbA1c, %

7.69 0.03

Lancet. 2012;380:475483


(1/2)
1
SE
Kg - FAS (LOCF)

2.0
1.5

4.8x

+1.4

1.0
0.5

0
-0.5

12

28

52

78

104

-1.0

-1.3

-1.5
-2.7
-2.0

(p < 0.0001)

775

776

(% )

280 (36)

58 (7)

3
(%
)

12 (4)

1 (2)

(p < 0.0001)

1. ; 2. 70 mg/dL; 3.
, .
: Gallwitz B, et al. Lancet. 2012;380:475483.

DPP-4
( )
.

DPP-4 ( )
,

AACE October 2009

3
59 , , :29.5.1, 6 :
850mg: 1X2 3mg: 1X1, HbA1c=6.9%.
2-4

;
1.
2. SU
3. SU
4. SU
5. SU
6.
7.

1/7/2015

SU

SGLT-2
27

(70.6%)
(34.5%)

(70.5% 68.8% ).
DPP-4(
) 10,6%

41%.

G. Rombopoulos, et.al. Hormones 2013;12(4):550-558.

G. Rombopoulos et.al. Presented in American Endocrine Society Congress (ENDO) 2013 San Francisco

Diabetologia 2010 Sep, 53:2079 Engl J Med 2010 Oct, 363:1410

 vs

Gallwitz B, et al. Lancet. 2012;380:475483.

4
62 , , :28.7, 5 :
, , , -. HbA1c=7.6%

1/7/2015

31

 HbA1c
+ SU
HbA1c (%), (SE)

5 mg + MET + SU (n = 778)
Placebo + MET + SU (n = 262)

0.6%

12

18

24

, HbA1c
0.6% 24 (p < 0.0001)
HbA1c: 8.1% ; 8.1% placebo; FAS LOCF; To
HbA1c.

Owens DR, et al. Diabet Med. 2011;28:13521361.

 HbA1c 102
1

HbA1c (%)

HbA1c 24
102 (p-value < 0,0001)
-

Placebo

0,0

0,8% HbA1C
102

-1,0
0

n=

12

18

24

30

1531 14901463 14401429 1400

42

54

1302

1183

66
1090

78

90

102

1007

948

903

()
- 24 4 78
. 4 : (n=296);
(n=457); + SU (n=544) (n=234).
1. Pre-specified analysis of treatment in oral mono-, dual and triple combination therapy (full analysis set, observed cases).
2. Coefficient of durability (COD) is defined as HbA1c at week 102 visit subtracted by HbA1c at week 24 visit
Source: data on file.

5
60 2

(glargine ) 34
500x2 (-)
HbA1c=7,3%
( )

( )
,
=140/85 mm Hg
BMI=28 kg/m2 (=83 kg, =1.70 m)

 placebo

(SE) HbA1c ; , FAS (OC)

12

18

24

32

40

52

76

64

-0.65

Placebo, n 617
Linagliptin, n 618

606
611

565
593

537
568

493
527

440
496

370
426

301
386

163
233

76
122

Yki-Jrvinen H, et al. Diabetes Care. 2013;36:38753881.

 HbA1c 24

1 (SE) HbA1c (%), 24 FAS (LOCF)

Placebo
n=

HbA1c, %

617
8.29 0.03

618
8.31 0.03

p < 0.0001

FAS,; LOCF, HbA1c 24, .

1. , HbA1c, ,
2. .
: Yki-Jrvinen H, et al. Diabetes Care. 2013;36:38753881. .

% 24 (TS)

, n

630

631

% 52 (TS)

630

631

Yki-Jrvinen H, et al. Diabetes Care. 2013;36:38753881.

 HbA1c
2
HbA1c 2
(%) 24

HbA1c (%)
24

0,5

> 1 5

> 5

p <0,0001

p <0,0001

p <0,0001

0,03
0
-0,01

-0,17
-0,5

-0,49
-0,59 -0,62

-0,66

-0,67 -0,66

-1
n=
HbA1c (%)

120

261

227

570

381

1045

8,2

8,1

8,0

8,1

8,2

8,2

Pre-specified sub-group analysis on pooled data 4 -III randomized

placebo-controlled trials: , , + SU,

p-values for between group difference (versus placebo)
Source: data on file

Placebo

( placebo)

placebo ( SU
- )

placebo. ;

placebo
()

FDA/EMA.

Karagiannis et al., Ther Adv Drug Saf 2014:138

1.
2.
3.

4.
5.

Linagliptin: HbA1c
75
Change from baseline HbA1c by age, placebo-corrected
Adjusted mean (SE) change in HbA1c at 24 weeks of treatment (%)
75 years

<75 years

n
p value

42

90

36
<0.0001

1. Full-analysis set.
Source: Barnett AH, et al. Lancet. 2013;382:14131423

70
<0.0001

Background metformin
sulphonylurea
insulin therapy

Screening
Enrolled: 377
T2DM patients
aged 70 years
with insufficient
glycaemic control
(HbA1c 7.0%)

Placebo
run-in period
(2 weeks)

Assessment
of eligibility
Excluded: 136

Randomization (n=241)

> 70 , SU

Placebo (n = 79)

Treatment duration:
24 weeks

Linagliptin 5 mg
QD (n = 162)

Barnett AH, et al. Lancet. 2013;382:14131423.

Adjusted mean HbA1c change from baseline1 (%)

- 0.64%

Week

12

18

24

Barnett AH, et al. Lancet. 2013;382:14131423.






eGFR

Barnett AH, et al. Lancet. 2013;382:14131423.

 (n=265)
e-GFR<30ml/min

et al. 49th EASD Congress, submitted for publication

Sita Vilda Saxa - Lina

Sita

Vilda

Saxa

Lina

87%

85%

75%

<5%
85%

eGFR: 50-90

100mg

100mg (2)

5mg

5mg

eGFR: 30-50

50mg

50mg

2.5mg

5mg

eGFR: < 30

25mg

50mg

2.5mg

5mg

25mg

50mg

5mg

,
133
eGFR<30ml/min ( )
5mg vs. placebo (
)

: 1
HbA1c: 8.2%
Mc Gill et al., Diabetes Care 36:237244, 2013


Hba1c
eGFR

- 0.71%

Mc Gill et al., Diabetes Care 36:237244, 2013

n = 2,472

:
30 <UACR 3,000 mg/g Cr
eGFR 30 mL/min / 1.73 m2
n = 564

-/ARB*
n = 217

Placebo
n = 55

(n = 1,908)
UACR 30 mg/g Cr
UACR >3,000 mg/g Cr
eGFR <30
UACR

(n = 347)
-/ARB
-/ARB

n = 162

:
UACR
24
Diabetes Care. 2013 Nov;36(11):3460-8



UACR
12 24
* (95% CI)

-46%

-47%

12
(p = 0.0750)

+3%

-25%

-28%

-2%

24
(p = 0.0357)

UACR(%)

Diabetes Care. 2013 Nov;36(11):3460-8

Sita Vilda Saxa - Lina

SPC

Sita

Vilda

Saxa

Lina

> 3


(1 )

/ > 2-3 ULN
Br J Clin Pharmacol. 2012 Jul;74(1):75-85.

: 5mg QD,

:
~30%,
~95%

( DPP-4)

1: ~ 95%

&

1 At steady state

~10%
()

~90%

~ 5%

Source: US SmPc

relative
in exposure
increase
Fold
to

hepatic function
normal

( Child-Pugh [A-C])
Child-Pugh Grade
1.5

A Well-compensated disease

5-6

B Significant functional compromise

7-9

C Decompensated disease

10-15

0.5

(Grade A)

(Grade B)

(Grade C)

( Child-Pugh)
n=8

n=7

n=9

n=8

Source: Graefe-Mody et al. 4th International Congress on Prediabetes and the Metabolic Syndrome, Madrid, Spain, April 6-9, 2011


- 8 3
(n=3319)

Cardiovasc Diabetol. 2012 Jan 10;11:3


- 8 3
(n=3319)

Cardiovasc Diabetol. 2012 Jan 10;11:3



CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride
in Patients With Type 2 Diabetes
(
)
: (4 MACE)
6000
8
2018
CARMELINA: Cardiovascular and Renal Microvascular Outcome Study With
Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk
placebo ( )
: (3/4 MACE)
:
8300
4
2018
http://clinicaltrials.gov


DPP-4, ,

2


( MARLINA)
,
.
.

 -



2.
( )
+
+
+ +

 DPP-4

D-4

HGO =
Unger RH. Metabolism 1974;23:581593