2

.

,


:
: 20102010-2030


2

( )

Lancet 2011;378:1822011;378:182-197

( )

( )

Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslins Diabetes Mellitus.
Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145
2005:145168.

 .
.

2 4


3

8/10

4

50%
..
1 Fong

(
) 5

DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99

1):S99S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94
1):S94S98.
3 Kannel WB, et al.
al. Am Heart J 1990; 120:672
120:672676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.
5Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78
1):S78S79.

DCCT

Kumamoto

UKPDS

9 7.2%

9 7%

8 7%

Retinopathy

63%

69%

17-21%

Nephropathy

54%

70%

24-33%

Neuropathy

60%

Improved

Cardiovascular
disease

41%

16%*

HbA1C

*p=0.052

DCCT/EDIC study: 11-year follow up (total 17 years), showed 57%

reduction in CVD risk.
UKPDS: 10 year follow up (total 20 years), showed significant reduction in
CVD risk
DCCT Research Group. N Engl J Med 1993;329:977
UKPDS 33: Lancet 1998; 352, 837837-853
DCCT--EDIC study:NEJM 2006;353:2643
DCCT
Holman etal:NEJM2008;359
.

HbA1c
< 7%
:
Glu <130mg/dl
Glu ( 2 ) < 180
mg/dl

,


HbA1c <6,5%


,
,



HbA1c :7-7,5 %



(mg/dl)

(mg/dl)

HbA1c %

70-130 mg/dl

< 180 mg/dl

<7%

( Glu > 180 mg/dl )

< 180 mg/dl

<7%

< 8% ,

5

American Diabetes Association

American Geriatric Society

>
10
1C

1C

< 6,0

< 6,5

< 6,5

< 9,0%

+
6,5 7,0

< 7,0

+
7,0 8,0

>9,0

Diabetes Metab Res Rev 2010;26:239

IGT

(Uncontrolled)

126
(mg/dl)

100

()

20

10

10

20

30

Adapted from Bergenstal RM, et al. Diabetes mellitus, carbohydrate metabolism and lipid disorders. In Endocrinology. 4th ed. 2001.





.




.

( )
( - TZDS )






GLUT 4

(
)

 Chol TGL

( Cl cr <30 ml/min )
K




12

Metformin::
Metformin

Profile

Profile

(UKPDS)

(
)

( 50%)
( 4%
o

o)

o
(cl..<3
(cl.
.<30)
0)
o
o

De Fronzo, Ann Int Med 2000, Inzucchi JAMA 2002

Gastrointestinal side effects

HbA1c

(%)

HbA1c (%)

0
-0.5
-1
-1.5
-2
-2.5

10
8
6
4
2
0

500

1000

1500

2000

2500

(mg)

500

1000

1500

2000

2500

(mg)

Garber AJ, et al. Am J Med 1997; 103:491497.

 ( )
PPAR ,

.
GLUT 4, GLUT2

LPL TGL
PEPCK
TNFa
.


: TGL, HDL,
sdLDL

( SGOT, SGPT )

3 mmHg
CRP

( -
)

( )


(
> 2,5
).

( Cl cr < 10 ml/min )

 TZD
TZD,, ,

2
-

-1

CRP

LDL

LDL
LDL

..



( , )
GLP 1
( , )
DPP4 ( ,
, ,
)

(mg)

2.5 - 20

40- 320

1-6

80

12

12

11

18 -24 (>24)

18 -24

24

6%

<1%

1-2%

50%
50%

. 80%
10-20%

. 60%
40%

1 -2 %

<2%

1 -8%

20%

15%

15%

HbA1C

HbA1C

HbA1C

>98%

>98%

>98%

(mg)
/ 24
()

..

* : .. <60mg/dl
<60mg/dl


1.
2.
3.
4.

1


(,
, )
5.
6. stress
7.
8.
9.
10.
11.

..

Meglitinides


: (Novonorm 0.5mg, 1mg, 2mg)
(Starlix 60mg, 120mg, 180mg)

60 mg%

HbA1C

0.7-2 mg%

(
)

() (1-2 Kg
)

..

(Tmax) (h)

0.82 (1)

(t 1/2) (h)

<1.5

4-6

3-4

80%

0.5-16

90-180

2-4

2-4

(mg/ 24)
( /
24)

..

 HbA1c (%)

0.2
0

0.00

0.4

0.05

0.08

0.2
0.23
0.40

0.6

0.51

0.8
0.82

1.0

Metformin 1 g bid

1.2

Nateglinide 60 mg ac + metformin 1 g bid

1.4

Nateglinide 120 mg ac + metformin 1 g bid

0.77

1.38

HbA1c <8%

HbA1c
89.5%

HbA1c >9.5%

Marre M et al. Diabetes 2000;49(Suppl 1):1517PO (Study B354)

IR

PPG

FPG
HbA1c
UKPDS

HOORN study
DECODE study


(cardiovascular risk)

(-
))

GIP

GLP--1
GLP

(-
))

GLP-1=glucagon
GLP1=glucagon--like peptide
peptide--1; GIP=glucoseGIP=glucose-dependent insulinotropic polypeptide.
Brubaker PL et al. Endocrinology 2004;145:2653
2004;145:2653
2659; Zander M et al. Lancet 2002;359:824
2002;359:824
930; Ahren B. Curr Diab Rep 2003;3:365
2003;3:365

372; Buse JB et al. In Williams Textbook of Endocrinology.

Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427
2003:14271483; Drucker DJ. Diabetes
Care 2003;26:2929
2003;26:2929
2940.

37

GLP1
( 5 g, 10g ), 2 /
( 0,6- 1,2- 1,8 g ) ,
1 /

 3:
E HbA1c 30



2,5

(Kg)

2,0

+
1,5
1,0

(30 )

+
(30 )

(30 )

n=336

n=377

n=733

n=733

0
-0,3

-0,24
-0,6

-1,0

-0,9

-1,5
-2,0

-3,5

-0,9
-1,6

-1,6

-1,6

P <0,05
placebo

2,5
-3,0

(30 )

0,5

-0,5

-1,6

-1,75

P <0,01
placebo

-2,8
P 0,001
placebo

placebo

5 g
g

10 g

Diabetes Care 2005 28(5):109228(5):1092-1100, Diabetes Care 2004 27(11):262827(11):2628-2635, Diabetes Care 2005 28(5):108328(5):1083-1091,
Ann Intern Med 2007 146(7):477146(7):477-485

(3 )
HDL-
-10,8 mg/dl
*

10
0

-44,4 mg/dl

-10
-20
-30

*
.

-10,8 mg/dl

*
LDL-
-10,8 mg/dl

*
o
..
-3,5 mmHg

..
-3,3 mmHg

-40
-50

Curr Med Res Opin 2008 24 (1):275(1):275-286

 LEAD

 DPP4

ab Glucobay 50 mg, 100mg

.

.

GLP-1 DPP4

():

Glycaemic, lipid and blood pressure control in 1998 and 2006

in Greek diab. Population
[Data are shown as mean value (SD)].

1998

On target

2006

On target

HbA1c (%)

8.1 (2.0)

36.1%

7.0 (1.2)

56.1%

< 0.001

SBP (mmHg)

139.3 (17.9)

22.5%

134.9 (18.7)

35.5%

< 0.001

DBP (mmHg)

80.9 (8.7)

23.0%

77.6 (9.8)

48.2%

< 0.001

HDL-C (mmol/l)

1.2 (0.3)

50.5%

1.3 (0.4)

52.3%

0.002

LDL-C (mmol/l)

3.9 (1.1)

10.4%

2.9 (0.9)

40.2 %

< 0.001

TGL (mmol/l)

2.0 (1.3)

53.6%

1.7 (0.9)

59.9%

< 0.001

Liatis et al, Exp Clin Endocrinol Diabetes 2009



,




.

 2011:

, 1 3

, 3 6


Statement ADA & EASD 2006,2008

+ Metformin

-
*

+ +/-

Diabetes Care 2006; 29 :1963 -72

Consesus Statement ADA & EASD 2008. Diab. Care 2008; 31: 1-3

Guidelines
NICE 2009
1 : Metformin +
A1C> 6,5%
2 : - Sulfonylurea
- DPP-4 TZDs (
Sulfonylurea
)
A1C 7,5%
3 : Sulfonylurea + Metformin
- DPP-4 TZDs
GLP-1
- (NPH
)
( HbA1c 9.0%)
BMJ 2009;338:1668


Consensus Statement ADA EASD 200
2009
9
1: ( )
:
Lifestyle
+
Metformin

Lifestyle

Lifestyle + Metformin
+
Basal Insulin

+
Metformin
+
Intensive
Insulin

Lifestyle + Metformin
+
Sulfonylurea

2: ( )
Lifestyle + Metformin
+ Pioglitazone

/.

Lifestyle + Metformin
+

GLP--1
GLP


/

Lifestyle +
Metformin
+
Pioglitazone
+
Sulfonylurea*
Lifestyle +
Metformin
+
Basal insulin

Nathan et al, Diabetologia, on line 2008, DOI. 10.1007/s0012510.1007/s00125-008

008--1157
1157--y

HbA1c%

Lifestyle.

1-2

Metformin

1,0-2,0

/ ,

Insulin

1.5-3.5

,
.

1-4 , ,
, ,

Sulfonylurea

1,0-2.0

, , (
glibeniclamide chlorpropamide)

Thiazolidinedione

0,5-1,4%

. Profile (pioglitaz.)
. (pioglitaz.)

, CHF, ,
, ,
(rosiglitaz.)

GLP-1

0,5-1,0

2 , / ,
,

0,5-0,8

/ . 3 / ,

Glinide

0.5-1.5

, 3 /, ,

DPP-IV

0,5-0,8

Tier 1:

Step 1:

Step 2:

Tier 2:

D. M. Nathan et al, Diabetologia DOI 10.1007/s0012510.1007/s00125-008

008--1157
1157--y

 :
International Diabetes Center (IDC)
(IDC)--2009


1, 2 3

Diabetes, Obesity and Metabolism 2011;13:992011;13:99-117


2011
&

HbA1c

1,0-2,0

DPP
DPP--4

1,0-2,0

0,5-0,8

1,0-2,0

0,5-1,5

0,5-1,4

0,5-0,8

,

(GFR<30ml/min)
,
,
(>>
MR).

( >
)
,

GLP
GLP--1
0,5-1,0

&


2
2
A 2011
A1c > 8.5%
( )

A1C < 8.5%

+ 1

A1C > 9%
()

+
TZD
MET +
GLP-1 DPP-4
SU GLIN

2-3
>7%

+
TZD
MET +
GLP-1 DPP-4
SU GLIN

+ +/-

2-3
>7%

A1c<8%

A1c<8%
A1c>8%

+
TZD + SU
MET +
GLP-1 DPP-4 2 + SU
GLP-1 DPP-4 + TZD
2-3
>7%

1.

2.

3.

DPP
DPP--4 ()

+ +

A1c>8%

2-3
>7%