-

E
-



21%

2*

37%

HbA1c

(, )*

1%

14%

*P<.0001
**P=.035
Stratton IM et al. UKPDS 35. BMJ 2000; 321: 405412

43%

12%

**

 Standard ?

American Diabetes
Association1

IDF2

AACE3

HbA1c (%)

<7.0

<6.5

6.5

FPG mmol/L
(mg/dL)

70-130

<110

<110

PPG mmol/L
(mg/dL)

<180

<145

<140

*Treatment targets for non-pregnant adults.

AACE = American Association of Clinical Endocrinologists; FPG = fasting plasma glucose; IDF = International Diabetes Foundation;
PPG = postprandial plasma glucose.
1. American Diabetes Association. Diabetes Care. 2012;35(Suppl 1):S11-S63. 2. International Diabetes Federation (IDF). Available at:
http://www.idf.org/webdata/docs/GGT2D%2006%20Glucose%20control%20levels.pdf. Accessed 9 March 2012. 3. Handelsman Y,
et al. Endocr Pract. 2011;17(Suppl 2):1-53.
Company Confidential
2012 Eli Lilly and Company

Lilly Diabetes

E
HbA1c
target

6.0%

7.0%

8.0%

-
Higher motivation, knowledge
Greater self-care capacity, insight, support

Less motivated, non-adherent,

Limited self-care capacity, insight support

None

Early Microvascular CV

Advanced Microvascular

Ismael-Beigi F. Ann Intern Med. 2011;154(8):554-559.

Company Confidential
2012 Eli Lilly and Company

Lilly Diabetes




(%)

100

PPG
FPG

80
60
40
20
0

<7.3

7.3-8.4

8.5-9.2

9.3-10.2

>10.2

HbA1c Range (%)

HbA1c
FPG = fasting plasma glucose.
Monnier L, et al. Diabetes Care. 2003;26(3):881-885.

Company Confidential
2012 Eli Lilly and Company

 HbA1c < 7%
~ 85 % 12

HbA1c

7%

H -
(91) IFG 2
( )
3.0

-Cell Volume (%)

2.5

40 %*

2.0
1.5

**

1.0

63 %*

0.5
0.0

NGT
(n=31)

Company Confidential
2012 Eli Lilly and Company

IFG
(n=19)

Type 2
Diabetes
(n=41)

*P.05 vs NGT; **P.01 vs NGT.

Butler AE, et al. Diabetes. 2003;52(1):102-110.


2
1.

2.

3. /

4.

65
95 - BMI = 31
2 10

:

/
50/1000 x 2
4mg 2 mg

 mg/dl:

FBG

PPG
(
)

PPG
(

)

170

220

150

200

<130

<180

<130

<180

HbA1c = 8,8 %

ADA-EASD Position Statement: Management of

Hyperglycemia in T2DM

Advancing to triple combination therapy

2 ,

,
(.. 8.5%)

,

INSTIGATE
Characteristics of patients with type 2 diabetes mellitus
initiating insulin therapy: baseline data from the INSTIGATE
study
Stephen Jonesa, Marian Benroubi , Conxa Castell,
Albert Goday, Andreas Liebl, Louise Timlin,
Claudia Nicolay, Alexander Simpson and Aodan Tynan

, ,
6 ,

2

Curr Med Res Opin 2009; 25(3) , 691700

5
1172

176

253

253

UK
GERMANY

224

GREECE

SPAIN

254

254

FRANCE

263

176

224

263

Curr Med Res Opin 2009; 25(3) , 691700


(Baseline)

263

(% )

54,0

(SD)

65,8 (10,45)

BMI (SD) Kg/m2

28,1 (4,7)

(SD)

11,5 (7,0)

HbA1c (SD) (%)

9,4 (1,8)

HbA1c (SD) %

9,6 (1,6)

(%)

17,5

Curr Med Res Opin 2009; 25(3) , 691700

(Baseline)
HbA1c %

11,5

9,6

10,5

9,5

8,6

8,6

8,7

8,7

6 to 9

3 to 6

8,5
7,5
6,5
12 +

9 to 12

0 to 3

n=263

HbA1c
Curr Med Res Opin 2009; 25(3) , 691700

Conclusion
INSTIGATE

2

Curr Med Res Opin 2009; 25(3) , 691700

Statement ADA/EASD 2012

Management of Hyperglycemia in T2DM
Table 1. Properties of anti-hyperglycemic agents

Class

Mechanism

Advantages

Insulin

Activates insulin
receptor
peripheral
glucose uptake

Universally effective
Unlimited efficacy
Microvascular risk

1.
2.
3.
4.

5. ?
6.

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

If you dont take better care of your

diabetes, you will end up on insulin

Insulin
(U/mL)

40
30
20
10
0

Basal Insulin
50%

Modified from Liu G et al. Metabolism 1983;32:754-756.

Statement ADA/EASD 2012

1

10 0,1 - 0, 2 U / kg

(glargine detemir - tresiba )

NPH,

Treat to Target Trial: A1C Results

N=756 T2DM, aged 30-70, A1C 7.6-10.0%,

glargine vs. NPH for 24 wks

p<0.05
60

58.0%

A1C 7%

57.3%

A1C 7% and no nocturnal

hypoglycemia

Patients (%)

50

40

33.2%

26.7%

30
20

Glargine

> 40 %

A1C ?

NPH

1 or 2 oral agents continued at pre-study doses, forced titration to target FBG 5.6 mmol/L

Adapted from Riddle MC, et al. Diabetes Care 2003;26(11):30803086.




2
15
15

250 mg%

Treatment: Glibenclamide + Metformin

BG (mmol/l)

14
14

Age: 57.38.1 yrs

Oral treatment duration: 6.55.7 yrs

13
13

180mg /dl

12
12

Disease duration:
9.16.4 yrs

215 mg%

11
11
10
10
99
88
77
6:00
6:00

HbA1c(%) 9.7 1.8,

8:00
8:00

10:00 12:00
22:00
10:00
12:00 14:00
14:00 16:00
16:00 18:00
18:00 20:00
20:00 22:00

Data derived from Milicevic Z et al.

Diabetologia 2002;45 (Suppl 2):A246.

0:00
0:00

2:00
2:00

4:00
4:00

24-hr day (time)

*Compiled data from 6 European countries (135 patients)

6:00
6:00

 (Glargine)
2
160

Insulin (mU/mL)

140
120
100
80
60
Early Type 2

40

20

Type 2 diabetes

0
0800

1200

1600
2000
Clock time (hours)

2400

0400

130 mg/dL excursion

400

22.0

300

16.5

85 mg/dL
200

11.0

100

5.6

Breakfast Lunch
0
6AM 10AM

T2D=type 2 diabetes.

2PM

Dinner
6PM

aBasal

Derived from Hirsch et al. Clin Diabetes 2005;23(2):78-86.

10PM

Plasma Glucose (mmol/L)

(mg/dL)

Without basal insulin

Treated with basal insulina

0
2AM

6AM

insulin is neutral protamine hagedorn insulin or insulin glargine.

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

HbA1c (9.0%),
2

Sequential Insulin Strategies in T2DM

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

24-
2
160

Insulin (mU/mL)

140
120
100
80
60

40
Type 2 diabetes

20
0
0800

1200

1600

2000

2400

0400

 vs
:
4 RCTs
Insulin
Insulin
Glargine, Detemir,
BIAsp
BIAsp

8.25

Insulin
Glargine,
LM25

Insulin
Glargine,
LM25

Basal insulin
Premixed insulin

HbA1C (%)

8.00
7.75
7.50

**

**

**p<0.001

7.25

*p<0.01
*

7.00
6.75
6.50

Raskin
et al.

Holman
et al.

Malone
et al. 04

Malone
et al. 05b

Insulin: 25-30% Rapid-Acting Analog bInsulin-experienced patients.

RCT=randomized controlled trial; HbA1C=hemoglobin A1C; BIAsp=biphasic insulin aspart 70/30; LM25=insulin
lispro mix 25.

aPremixed

Derived from Raskin et al. Diabetes Care 2005;28:260-5; Holman et al. N Engl J Med 2007;357(17):1716-30;
Malone et al. Diabet Med 2005;22:374-81; Malone et al. Clin Ther 2004;26:2034-44.

Humalog Mix25 (BID) + Met vs

Lantus (OD) + Met :

Humalog Mix25
.

Episodes/patient/30 days

Overall hypoglycemia

p=0.041
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

Nocturnal hypoglycemia
p=NS
0.25
0.20
0.15
0.10
0.05
0

Lantus +
Met

Mix25 +
Met

Lantus +
Met

Mix25 +
Met

N=101

N=100

N=101

N=100

Data derived from Malone JK et al. Clin Ther 2004;26:2034-2044.

30 50 IU

26 43

Humalog-mix 25

~ 40%
30 50 U

37 61

 Humalog Mix25

:
10 10

:

1,5 - 2 g/
:

: 2- 4 U

: 2- 4 U

*OAM to be used in accordance with the locally approved package insert. Some OAMs may be contraindicated.
Physicians and patients should decide if additional BG measurements may be needed. Abbreviations: BG = blood glucose.

Recommendations

Guidelines

Glycaemic
target

Intermediate- or long-acting

ADA/EASD <7.0% basal insulin

IDF

AACE

NICE

Long-acting or NPH insulin, HbA1c (
>9,0% -
or twice-daily premix insulin
<6.5%

(biphasic insulin) particularly

with higher HbA1c
-
2

<6.5% Basal, premix, or basal bolus


Intermediate acting insulin
<7.5%

(NPH) with consideration of

premix once- or twice-daily if
HbA1c 9.0%

 11
.

HbA1c = 8,2%
11 +

44
Lantus

63
90
BMI = 31
11


FBG

PPG
( )

PPG

130

200

170

180

<130

<180

<130

<180

(
)

;
1.
: ( )
2.

1. ADA. Diabetes Care. 2006;29(suppl 1):S4-S42.

H
HbA1c
UKPDS 1 1
HbA1c

Upper limit of HbA1c

Years from Randomisation

39

2. Wright G, et al. Diabetes Care. 2002;25(2):330-336. 3. Raccah D, et al. Diabetes Care. 2003;26(11):3080-3086.



?

1. E (
)

2.
3.
Note:

Dunning. Diabetes Voice 2004;49(1):30-3. Meece. Diabetes Educ 2006;32(Suppl 1):S9-18.



?
:

1.
2.
3.

Kunt and Snoek. Int J Clin Pract Suppl 2009;63(164):6-10.

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

:
1. ( >180 mg /dl )
HbA1c

.
2.
0.5 U kg1 day1
Sequential Insulin Strategies in T2DM

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of

print]


?
1.
1
( Basal Plus )
2.
2
- ( +
Humalog-mix 25 )
3. ( basal bolus) :
1 + 3
(Humalog )

Basal-bolus insulin treatment: matching

insulin administration to insulin needs
Rapid-acting insulins
100

Basal insulins

U/ml

80
60
40

Normal pattern

20

0600

0800

1200

1800

2400

0600

Time of day
B = breakfast; L = lunch; D = dinner
Riddle MC. CADRE Core Slide Kit. 2003
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239

Basal-Bolus:

:
, 4
( 6-7)

(
/ )

Data from Skyler JS: Insulin Treatment. In Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders. 3 rd ed. ADA, 1998:186-203.

ADA-EASD Position Statement:

Management of Hyperglycemia in T2DM

2

.
,
1

Basal - Plus

Journal Issue Endocrine Practice,

Volume 17, Number 5 / SeptemberOctober 2011
The Step-Wise Randomized Study

2
Insulin Aspart
2
1
Detemir

 (bolus) :
Extra STEP :

Simple STEP :


60%
55%

40%

Endocrine Practice, Volume 17, Number

. 5 / September-October 2011

 ( 48 ) ,
75%
3

,
.

Diabetes Care , March 2014 37:604-610

Does a Patient-Managed Insulin Intensification Strategy

With Insulin Glargine and Insulin Glulisine Provide Similar
Glycemic Control as a Physician-Managed Strategy?

Results of the START (Self-Titration With Apidra to Reach

Target) Study
( This study was sponsored by Sanofi Canada)

The primary outcome was the achievement of an HbA1c

level of 7% without severe hypoglycemia 24 weeks
after randomization

characteristics by
titration algorithm, all randomized patients (n =
316)

 21% 28%
( HbA1c 7%
) ,
bolus



. 1 , . 1 , . 2
1 ..

2 ..

26 , 15 - 17 2012

 189 , 158 (83,5%)

.

Percent of population (%)

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Sequential Insulin Strategies in T2DM

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Sequential Insulin Strategies in T2DM

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin

CE Diabetes Care Plan Guidelines

Endocr Pract. 2011; 17( suppl 2 ) p. 22

Premixed Insulins:
Insulin therapy is initiated as a basal, basal-bolus, prandial, or premixed
regimen

Premixed insulins are available as 70% NPH/30% regular, 70% insulin aspart


2 /
.
protamine/30%
insulin aspart,
75% insulin lispro
protamine/25% insulin
lispro,
or 50%
insulin
lispro protamine/50%
insulin lispro.
These mixtures
provide

elements of both postprandial and intermediate-release glucose control. The
2
analogue premixed insulins are preferred over human 70/30 given the faster
onset of action, more consistent

PPG control, and. less variability in activity.

Premixed insulin may be administered at the largest meal once daily or at the 2
largest
meals twice
daily. Adjustments are
on the
basis of the
predinner
(

made

glucose level if administered prebreakfast and the fasting blood glucose level if

)
administered
predinner.
Some patients
are more
suitable for this less complex
regimen, and their DM can be well controlled with 2 injections of premixed
insulin.

Insulin:Premix 75/25

Humalog

75/25

Prandial 25%
Basal 75%

Humalog

NPL

25%

75%


Humalog Mix25
/ 2
: 50% - : 50%

3-4
<80 mg/dL

-2 units

80-130
mg/dL

No change

130-160
mg/dL

+2 units

160-200
mg/dL

+4 units

200 mg/dL

+6 units

(8.00 )

( 8.00 )

Insulin lispro low mixture twice daily versus basal insulin

glargine once daily and prandial insulin lispro once daily
in patients with type 2 diabetes requiring insulin
intensification: a randomized phase IV trial

2
glargine ( +
/ pioglitazone )
D Volume 16, Issue 10, October 2014, Pages: 963970

Glycaemic control throughout the study receiving insulin lispro low

mixture (LM2 25%) twice daily or basal insulin glargine once daily and
prandial insulin lispro once daily (IGL )
H
0.22

LM25
IGL
(p=0.010).

. 963970
D Volume 16, Issue 10, October 2014, Pages:

Diabetes Care Publish Ahead of Print,

published online October 29, 2013

Initiation and Gradual Intensification of Premixed

Insulin Lispro Therapy vs. Basal Mealtime
Insulin in Patients with Type 2 Diabetes

Eating Light Breakfasts ( consuming <15% daily

calories at breakfast )

Brazil (13, 3.8%), Canada (7, 2.0%), Egypt (64, 18.6%), India (58, 16.9%),
Mexico (71, 20.6%), Portugal (15, 4.4%), Romania (50, 14.5%), Spain (40,
11.6%), and Turkey (26, 7.6%).

 3 lispro mix 25
glargine + 3 lispro
LM25 QD, progressing to TID (n=171)
Randomization

N=344
G+L Treatment (n=173)

-12

12

24

36

48

Weeks
Randomized, open-label, 48-week study
Diabetes Care Publish Ahead of Print, published online November 1, 2013

Insulin Lispro Mix 25 (LM25) vs Basal/Bolus

Therapy (BBT): HbA1C
48
Mean HbA1c at
baseline was 8.93%
in the Premix arm

and 9.08% in the

Basal+ arm

G+L=insulin glargine+insulin lispro; HbA1C=hemoglobin A1C.

Diabetes Care Publish Ahead of Print, published online November 1, 2013

 HbA1c 48
(
48 )

60%

48,%

HbA1c < 7 %

HbA1c < 6,5 %

Diabetes Care Publish Ahead of

Print, published online November 1,
2013

Conclusions

2,


2

Premix < 7.0%

Humalog Mix25

Humalog
Humalog Mix50

: 3
:
Humalog* Humalog Mix25 Humalog Mix50

AACE/ACE 2009, Diabetes Care, Vol. 32, Suppl. 2, S253, Nov 2009, NICE 2009
Diabetes Care 2008; 31: 20-25, *JAMA 2003; 289 (17): 2254-2264

 : 3
: Humalog

N
(mg/dL)

140-180

+2U

4U

6U

180-220

+4 U

6U

8U

221-260

+6U

8U

10 U

260-300

8U

10 U

12 U

300

10 U

12 U

15 U

AACE/ACE 2009, Diabetes Care, Vol. 32, Suppl. 2, S253, Nov 2009, NICE 2009
Diabetes Care 2008; 31: 20-25, *JAMA 2003; 289 (17): 2254-2264


Humalog Mix50
2 2 /

1. HbA1c >7% ( )
2. : 1,2;
3. , (

)
4.

1Rosenstock
3Hirsch

J, et al. Diabetes Care 2008; 31:20-25

HIB, et al. Clinical Diabetes 2005; 23:78-86

2Robbins

DC, et al. Clin Ther 2007; 29(11):2349-2364

Humalog Mix50 2 3 /

1. Humalog Mix 25 Humalog Mix50 ,

2. Humalog Mix50 / + Humalog Mix25

3. Humalog Mix50 2 3

Basal/Bolus

Diabetes Care 2005; 28: 260-265

1-2-3 Study

Diabetes Obesity and Metabolism 2006; 8: 58-66

PRESENT

Int Clin Pract 2008; 62(7): 1013-1018

IMPROVE

Int J Clin Pract 2009; 63(6): 966-972

PREFER

Diabetes Obesity and Metabolism 2009; 11: 45-52

OnceMix

Curr Med Res Opin 2009; 25(12): 2887-2894

4T Study

N Egl J Med 2009; 361: 1736-47

Diabetes Care 34: 510-517, 2011

16 :

2
HbA1c< 7%


1.

2.
- HbA1C
3.

4. FPG
PPG
HbA1C