How to treat

55
55

:
:

:
: 170cm,
170cm, :
: 120Kg,
120Kg, BMI:
BMI: 41.5,
41.5,

:
: 2
2 (
(
),
),

:
: 135cm
135cm

:
:

:
:

LDL:
LDL: 130mg/dl,
130mg/dl,
HDL:
HDL: 45mg/dl,
45mg/dl,

,
2
2
6,
6,,
.:
.: 280mg/dl
280mg/dl
,
,

SGOT:50mg/gl
SGOT:50mg/gl
,
,

:
:
HbA1c:
HbA1c: 9%,
9%,

SGPT:72mg/dl
SGPT:72mg/dl
:
: 160-100mmHg,
160-100mmHg,

.
. (FPG):
(FPG): 150-190
150-190 mg/dl,
mg/dl,
..
.. (PPG):
(PPG): 215-330
215-330 mg/dl
mg/dl

.:
.:
1000mg
1000mg xx 2,
2,

Ins
Ins Glargine
Glargine 210
210
U/
U/

:86/min
:86/min
GFR:78ml/min
U/S

GFR:78ml/min
U/S :
:

.:
.:
160mg
160mg qd,
qd,

10mg
10mg qd,
qd,
mg/
mg/

Salospir
Salospir 100
100

 (HbA1c)

<45

45-65

>65

>75

HbA1c

(<6.5%)

(~
(~7%)

<10

(6.5-7 %)

>10

(~
(~7%)

(7-8%)

<10

(~
(~7%)

>10

(7-8%)

(~
(~8%)

(~
(~8%)

Beigi F., Maghissi E., Tiktin M., Hirsch I., Inzucchi S. Gennth S. Ann. Int. Med. 2011;154:554-559

Guidelines ADA - 2015

 M HbA1c
LifeStyle inter.
, .

Oral Agents

1-2

A1c (%)*

Sulfonylureas

1-2

Diguanides (metformin)

1-2

Glinides

0.5-1.5

Thiazolidinediones

0.5-1.4

DPP-IV inhibitors

0.5-0.8

a-glucosidase inhib.

0.5-0.8

SGLT 2 inh.

0.6-0.9

Parenteral

()

A1c (%)

A1c (%)

Insulin

1.5-3.5

GLP analogues

0.8-1.5

monotherapy

Metabolism Clin. And experimental 2011;60:1-23,

Clinical Therapeutics 2011;33:528-76 lancet diab ndocrinol 2013;1:
140-51,,
2013;1:140-51
Cobble M. Diabetology & Metabolic Syndrome, 2012;4:8,1-10

 HbA1c

 HbA1c

102 cm
88 cm
()

.
.

150 mg/dl

HDL .
HDL

<40 mg/dl
<50mg/dl

130 mmHg
/ 85 mmHg

100 mg/dl

Alberti KG, Zimmet P, Shaw J. The metabolic syndrome: a new worldwide definition. Lancet 2005;366:1059-1062

..

Journal of the American College of Cardiology Vol. 47, No. 6, 2006

2006 by the American College of Cardiology Foundation ISSN 0735-1097/06/$32.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2005.11.046

-
-

CVD
CVD

NASH
NASH

Ca
Ca

Handelsman Y et al, Endocr Practice 2011

,
.

Bergman RN et al. J Clin Invest. 1981;68:1456-1467

Bergman RN et al. J Clin Invest. 1981;68:1456-1467

- - iv.


<25
<25 kg/m
kg/m 70%
70%
25-29
25-29 kg/m
kg/m 25%
25%

>30
>30 kg/m
kg/m 5%
5%

<25
<25 kg/m
kg/m 48%
48%
25-29
25-29 kg/m
kg/m 35%
35%

>30
>30 kg/m
kg/m 17%
17%

<25
<25 kg/m
kg/m 16%
16%
25-29
25-29 kg/m
kg/m 48%
48%
>30
>30 kg/m
kg/m 35%
35%


: 84% /
16% /

: 30% /
70% /

: /

Diab. Vasc. Dis Res 2005 Oct: 2(3):105-12

JM Despres, Nature 14 Dec 2006

 -



,
,

(2,
)
2,
-

 2
,

 2
Diabetes
Obesity

Controllable
Hyperglycemia
or
Diabetes
Remission

Controllable
Hyperglycemia

Prediabetes

Relative Function (%)

Uncontrolled
Hyperglycemia

250

Insulin Resistance

200
150

Diabetes Remission

100
50

-cell function

0
-10

-5

Years before Diabetes

10

15

20

Years of Diabetes

25

30

 2 (UKPDS)

100

Rx: Insulin, Metformin, Sulfonylurea

75

-Cell
Function
(%)

50
IGT

25

Postprandial Type 2
HyperglycemiaDiabetes
Phase I

0
-12

-10

-6

-2

Type 2
Diabetes
Phase II
6

Type 2
Diabetes
Phase III

10

14

Years From Diagnosis

Dashed line shows extrapolation forward and backward from years 0 to 6 based on
HOMA data from UKPDS.

Adapted from Lebovitz H. Diabetes Rev. 1999;7:139-153.

UKPDS 16. Diabetes. 1995;44:1249-1258.

CRP (high TNF-a, IL-6, PAI-1)



TG VLDL, HDL


C-

 sc

~ 0,3 U/kg :

~ 0,4 U/kg :

~ 0,5 U/kg :

> 0,6 U/kg :

> 1 U/kg :

( FFA)
()
2

stress

Insulin
Resistance

Hamdy O. Curr Diab Rep. 2005;5(5):317-9.

TZDs
Insulin

GLP-1

./

GLP-1
SGLT2-I

Insulin

Hamdy O. Joslin Diabetes Center, 2014

2
Metformin
TZDs
SGLT-2 inhibitors
GLP-1


/
(BMI 30)
(BMI 25 )

E a:

C
C

.
.

2
2

NAFL
NAFL
Guidelines 2013, Assesment and Lifestyle Management of patiens with Obisity, JAMA


: ,
.

: 150 /
: , , ,

Guidelines 2013, Assesment and Lifestyle Management of patiens with Obisity, JAMA

 2

Duration in Months

Weight Loss (%)

-3.5%

-6.4%

-9.0%
***

***

14% 2
21%
50-60% .
*** p<0.001 (group 1 vs. group 2)
Total Group n=129
Group 1 n=61 (Participants maintained <7% weight loss at 1 year)
Group 2 n=68 (Participants maintained > 7% weight loss at 1 year)

Joslin - Why WAIT Program/

Program/adc 2014,Boston

Change From Baseline (%)

/ +/ 2

WGT, weight; BMI, body mass index; W-H, waist-to-hip ratio; IS, insulin sensitivity.
*P<0.001. Hamdy O. Diabetes Care. 2003;26:2119-2125
7% loss of WGT

/ +/ 2

Change (%)

NS
P<0.05

NS

NS

P<0.001P<0.01

IL, interleukin; TNF, tumor necrosis factor; hCRP, human C-reactive protein;
PAI, plasminogen activator inhibitor. Hamdy O. Diabetes Care. 2003;26:2119-2125; Monzillo LU. Obes Res.
Res.
2003;11(9):1048-1054.
7% loss of WGT

Visceral
Visceral Fat
Fat

,
BP
BP &
& lipids
lipids
Metabolic
Metabolic Control
Control
Physical
Physical Fitness
Fitness &
& QOL
QOL

Maintenance
of

Maintenance
of Weight
Weight
Loss
Loss

Vascular
Vascular

Resistance
Resistance

BMI 30 BMI 25

(Orlistrat 120mg tid)
(.. Benzphetamine 25-50 mg
qd)
- FDA
Lorcaserin 10mg bid
Phentermine/Topiramate ER 7.5/46mg qd bid
Naltrexone SR/Bupropione SR 90/80mg bid
Liraglutide 3mg/day sc

> 5% ,
.
< 5% ,
.

 - 16 (lifestyle
interversions) 2,
.

BMI
-0.29:95%CI,
BMI -0.29
:95%CI, -0.52
-0.52
-0.06
-0.06 P=0.014
P=0.014

HbA1c
HbA1c -0.37:95%CI,
-0.37:95%CI, -0.59
-0.59
-0.14
-0.14 P=0.001
P=0.001

SBP
-0.03 P=0.016
SBP -0.16:95%CI,
-0.16:95%CI, -0.29
-0.29
-0.03
P=0.016

DBP
-0.012 P<0.001
DBP -0.27:95%CI,
-0.27:95%CI, -0.41
-0.41
-0.012
P<0.001

:
: Naltrexone /Bupropione
, , :
: Phentermine/Topiramate, Naltrexone/Bupropione
: Lorcaserin
2 GLP-1 :
: Liraglutide 3mg/day sc
: Lorcaserin


BMI 40 BMI 35


:

10-15kg/m BMI 2

2 77% (
)

GLP-1, . , (
bypass r-n-y), ( sleeve)

, (
Fe, Ca , B12, )

Dumping

->

40-50% 3-5 (
-)

Lee CW et al. Curr Opin Gastroenterol. 2007;23(6):636-643.

, 6
2 15

, ,
2

, >50%

, 30%

 5-10%
5-10%
HbA1c 0.5%
0.5% ..
..
HbA1c

~5mmHg
~5mmHg
AA

Tg
Tg 40mg/dl
40mg/dl ,, HDL
HDL 5mg/dl
5mg/dl

- C-PAP
C-PAP

5-10%

Look AHEAD
AHEAD study)
study)



!!!!
!!!! ((Look

Guidelines ADA - 2015





(,
(,
,)
,)

,
,
,
,

GLP-1
GLP-1


HbA1c:
HbA1c: 1-2%
1-2%

FPG
FPG

TC,
(
(TC,
TC, HDL,
TG, FFA)
FFA)
HDL, LDL,
LDL, TG,



(TC,



,
,

(UKPDS)
(UKPDS)
A
A
??

De Fronzo, Ann Int Med 2000, Inzucchi JAMA 2002

N Engl J Med. 1995 Aug 31;333(9):550-4.


/ ~4%
12
GFR 30-45ml/min
GFR<30ml/min

NYHA >III
.

De Fronzo, Ann Int Med 2000, Inzucchi JAMA 2002

DPP-IV inh





--

,
,

HbA1c:
HbA1c: 0.5-0.8%,
0.5-0.8%,
baseline
baseline

DPP4-in
DPP4-in ((


/
/
/).
/).


PPG
PPG




(
(TC,
TC,
HDL,
HDL,
LDL,
LDL,
TG
TG))

(
(

)
)

-
- ?

SGLT2 inh
,

-
-


HbA1c:
HbA1c: 0.5-0.9%,
0.5-0.9%,

baseline
baseline

,
,

FPG
FPG
PPG
PPG

(
(
)
)

SGLT2 inh -

(
)

( )

/,

( )
/ () ,
ACE inhibitors, ARBs, Diuretics.
LDL
GFR<60 ml/min

TZDs



(,
(, , )

HbA1c:
HbA1c: 0.5-1.4%,
0.5-1.4%,

(durability)


FPG
FPG


(
(TG,
TG,HDL, LDL)

,
,

,
, CRP,
CRP, TNFa
TNFa

GFR
GFR
5ml/min
5ml/min

TZDs

TZDs

:

, :
( )

TZDs (durability)
:o

Change in HbA 1c(%)

0
PIO

Rosiglitazone
PIO

-1

Hanefeld (n=250)
(n=250)
Tan (n=297)

PIO

PERISCOPE (n=181)

PIO

Chicago (n=230)
ADOPT (n=1.441)

TIME (Years)
-2

ADOPT, NEJM 355:2427-43,2006, Chicago JAMA 296:2572-81,2006, Hanefeld, Cur Med Res Open 22:1211-15,2006
Tan, Diabetic Care 28:544-50,2005, Periscope, JAMA 299:1567-73,2008

10

TZDs

TZD

TZDs

+15%

+14%

+10%
+5%

-5%
-10%

+4 kg

-10%

-15%
-20%
-25%

-25%
Miyazaki Y, Mahankali A et al Diabetes 49, suppl 1, A299, 2000

TZDs -

A NYHA I-IV







> ..




Ca
Ca

(
( ,
, )
)

TZDs

(kg)

-1.28

7.5 mg 15 mg 30 mg 45 mg
-0.59

1.30

1.29

1.91
2.30

0.95
2.92
3.73

-1.36
-0.77
-0.04

Mathisen A, et al. Diabetes 2000;49:A117.

2.82

GLP-1
Glp-1 (Glucagon Like Peptide)




-

 Glp-1

Nature 2009;8:369-381

 Glp-1

Meier, J.J.Nat.Rev.Endocrinol. 8, 728-742 (2012): published online 4 Sept 2012

GLP-1



HbA1c:
HbA1c: 0.8-1.5%,
0.8-1.5%,




FPG PPG
PPG




(
(TG,HDL,
HDL, LDL
LDL))


((hsCRP)
hsCRP)
(
( )
)
uptake ,

,
,

 2
Glp-1

Glp1 HbA1c

Glp1 ,

Medscape Education : Lipid and Metabolic session

Glp-1 :
, , : 20-40%

Glp-1 :

Ca 2

Glp-1

Glp-1
Exenatide bid

GFR (mL/min/1.73 m2)

30-50 :
<30 :

Lixisenatide

30-50 : !
<30 :

Liraglutide

<60 :

Exenatide LAR

<50 :

 DRI012

Ratner R et al. Dabet Med 2010, 27:1024-1032

GLP-1 head to head Clinical Studies

Ther Adv Endocrinol Metab 2015, Vol 6(1) 19-28

 GLP-1

Glp-1 +

Glp-1







15-63%

JIten Vora Dia Care 2013:36 : s226-s232

Glp-1 +

Annals of Intern. Med. 2011;154:103-113

Glp-1 +

GetGoal-L Trial - Riddle et al. Abstract 983-P; Presented at ADA 2012, Philadelphia, PA

Glp-1 +
Liraglutide 1.8 + ins Degludec (n=199)

HbA1c (%)

Ins Degludec (n=199)

HbA1C

EOT

0.89%

8.0%

1.90%

6.9%

p<0.0001

0.0
Time (weeks)

DUAL II: ins Degludec+ Metformin vs ins Degludec+Liraglutide 1.8 + Metformin

Ins Degludec maximum dose was 50 units per day, Data are mean SE, EOT, end-of-trial,
Buse et al. Diabetes Care 2014;37:292633

Glp-1 +
( HbA1c)

N=

78

69

53

41

62

84

199 199

HbA1c
10.0

9.7

HbA1c
9.5

8.8

9.0

8.7 8.8

HbA1c (%)

8.1
8.0

8.3

7.4
7.6

7.0

6.0

8.0

7.9
7.2

6.6

6.5

ns

7.5

6.7
*

>7.58.5

Liraglutide 1.8+
Ins Degludec

6.9

6.7

*
*

>8.59.0

Baseline HbA1c category (%)

>9.0

Ins Degudec
(max. 50 U)

Total trial
population

DUAL II: ins Degludec+ Metformin vs ins Degludec+Liraglutide 1.8 + Metformin

Rodbard et al. Diabetes 2014;63(Suppl. 1):A18, Abstract #67-OR , *p<0.01

(Glp-1 + basal insulin) (basal bolus)

Diabetes Obesity and Metabolism 16: 636-644, 2014



/ 3

.:
.:

M 1000 mg bid

ins Glargine

inj Liraglutide sc,

0.6 1.2 1.8 mg

..

Standards of Care (ADA)

HbA1c <7.0 (- 8.0 )

BP < 140 / <80 mmg (140/90 JNC-8)
LDL <100mg/dl (< 70mg/dl )



/ 3

.:
.:

.:
.:

/
/
360/12.5
360/12.5 mg
mg

100
100 mg
mg qd
qd

20
20mg
mg

M 1000 mg bid

ins Glargine

inj Liraglutide sc,

0.6 1.2 1.8 mg

10
10mg
mg

.follow up (2 )
:
:
:
: 120Kg,
120Kg, BMI:
BMI: 41.5
41.5

HbA1c:
HbA1c: 9%,
9%,

~5%

HbA1c:
HbA1c: 7.2%
7.2%

.
. (FPG):
(FPG): 108-132
108-132 mg/dl,
mg/dl,
..
.. (PPG):
(PPG): 145-178
145-178 mg/dl
mg/dl

:
: 114Kg,
114Kg, BMI:
BMI: 39.4
39.4

.:
.:

1000mg
1000mg xx 2,
2,

iins
ns Glargine
Glargine 210
210 U
U

ins
ins Glargine
Glargine 158
158 U
U

inj
inj Liraglutide
Liraglutide 1.8mg/d
1.8mg/d
LDL:
LDL: 130mg/dl,
130mg/dl,
97mg/dl
97mg/dl

.:
.: /
/
.:
.: 280mg/dl,
280mg/dl,
182mg/dl
182mg/dl
:
: 160/100mmHg,
160/100mmHg,
140/70mmHg
140/70mmHg

320/12.5mg
320/12.5mg
20mg,
20mg,

10mg
10mg
mg
mg

GFR:80ml/min
GFR:80ml/min

..

Salospir
Salospir 100
100

GLP-1

FPG
FPG

PPG
PPG

Balena et al. Diabetes Obes Metab 2013; 15:485502; Inzucchi et al. Diabetologia 2012;55:157796

GLP-1RA
FPG
FPG

PPG
PPG



2.

GLP-1

(, , )
o GLP-1 +

o GLP-1 +