: SGLT2 DPP-4;

, MD, MSc, PhD

&
-

SGLT2
inhibitor

DPP-4
inhibitor

:
HbA1c .

CDA (Canada)
HbA1c <7,0%
ADA (US)
HbA1c <7,0%

49%

NICE (UK)
HbA1c 6,5%-7,5%

60%
58%

IDF (Western Pacific)

HbA1c <6,5%

78%

ALAD (Latin America)

HbA1c <6,0%-7,0%

75%

48%
Australia
HbA1c <7,0%

1.Harris et al. Diabetes Res Clin Pract 2005;70:90-7 2.NCQA 2006 (Heidis measures) 3.UNIFESP and Fiocruz Study 2006, 4.EUCID 2008 5.JDDM-CODIC 2007 6.Nitiyanant et al.
CMRO 2002;18(5):317-327 7.http://www.glycomate.com/changingdiabetes/AUS, 8. Liatis et al, Exp Clin Endocrinol Diabetes 2009

:
7% 2. 37%
63% 54%
.

4.906

2013.
2
.

585

714

2035

22
%

585

2013

2035

36,6%

214 .
2013

54%

( HbA1c)*
200 . 2013 (34,2% )

International Diabetes Federation.IDF Diabetes Atlas, 6th edn.Brussels, Belgium: IDF 2013.www.idf.org/diabetesatlas
* Liatis et al, Exp Clin Endocrinol Diabetes 2009 / Athanasakis K. et al. Diabetes Medicine 2010;27:679-684

2013

75gr
[OGTT]
B
iv
10
C
C-

20 60%

Diabetes Metab Res Rev 2005;21:91-117.- ,

20

15
10
5
0
10 5

IR
(mU/L)

80

60

120

15
10
5
0
10 5

60

40

40

* * * * * *
*
60

120

60

120

180

120

180

80

60

0
10 5

20

180

20

2 (n=14)

(mmol/L)

(n=8)

per os (50 g/400 ml)

IR
(mU/L)

(mmol/L)

20

180

()

0
10 5

*p0.05 vs.
IR=
Nauck M et al Diabetologia 1986;29:4652.

* *

60

()

 GLP-1
L-

GLP-1 :
&
GLP-1
5-10
L-
GLP-1
,

GLP-1

J. J Meier, MA Nauck. Diabetes Metab

Res Rev 2005; 21:91-117

More than 50% of Secreted GLP-1 is

Degraded
Before Plasma
Absorption
GLP-1
(green) released

into intestinal
capillaries is
immediately exposed
to DPP-4 (red)1

> 50% of secreted GLP-1

is already degraded before

it reaches the general circulati

,
GLP-1
GLP-1
>
40%
of circulating

,

is already
degraded
before

DPP-4,
2
it
reaches -cells


t : GLP-1 = 2min,
GLP-1 = 5min

. Hansen L, et al. Endocrinology. 1999;140:53565363;

. Deacon CF, et al. Am J Physiol. 1996;271(3 pt 1):E458E464.
Histochemistry by C. rskov, Panum Institute, Copenhagen. Copyright 1999, The Endocrine Society.
1
2

 DPP-4

Drucker DJ. Exp Opin Invest Drugs. 2003;12:87100; Ahrn B. Curr Diab Rep. 2003;3:365
372.

Effects of saxagliptin on -cell stimulation and

insulin secretion in patients with type 2 diabetes.

1.

18%

(p=0.04)
2. 27.9%

(p=0.02)
3.

AUC

-21.8%

(p=0.03)
Henry RR et al. Diabetes Obes Metab 2011;13:850-8

: -, -

Non-diabetic control Des-F-sitagliptin

Anti-insulin antibody

-cell / Total Islet Area

Insulin-positive -Cell: Total Islet Area

0.9
*Ratio
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

Rosiglitazone

Glipizide

Anti-glucagon antibody

Glucagon-positive -Cell: Total Islet

Area
-cell / Total Islet Area

Diabetic control

0.5
0.4

0.3
0.2

0.1
0.0

Diabetic control

Des-F-sitagliptin

Non-diabetic control

Glipizide

Rosiglitazone

Diabetic control

Des-F-sitagliptin

Non-diabetic control

Glipizide

Rosiglitazone

*p<0.003 vs. the diabetic control group, #p=0.011 vs. diabetic control, n=40 islets in each group.
Mu J et al. American Diabetes Association, 2006.

: -

Vildagliptin
60 mg/kg
21

120

P <0,001

100
80
60
40
20
0

Vilda

2,5
2,0
1,5

P <0,05

1,0
0,5
0,0

Vilda

- (mg)

BrdU- (%)

ApopTag- (%)

0,14
0,12
0,10
0,08
0,06
0,04
0,02
0,00

P <0,05

Vilda

21
Duttaroy A et al. Diabetes 2005.

(A) ge,
(B) ody weight,
(C) omplications
(D) uration of disease

5 :

Pozzilli P, et al. Diabetes Metab Res Rev 2010;26:239-244

Vildagliptin: -

HOMA - IR

Pmol/min/m2/mmol/L

pmol/l

* p<0,001

* p<0,016

met=, vilda=vildagliptin
*P 0,001 .

Vilda 50 mg + met (n=40

320mg + met (n=41

Filozof C et al, (2010), 27:

5 mg - proinsulin:insulin 24 1

proinsulin: insulin3
placebo

proinsulin:insulin

24

placebo

HOMA-%B [mU/mmol]
24

HOMA-%B2

22.2

: +5.0 mU/mmol
Placebo: 17.2 mU/mmol

134.0

-0.04

: 0.02
Placebo: +0.02

p < 0.05

p < 0.05

33% HOMA-%B4

20% proinsulin:insulin4

1. SE. 24, FAS OC.

2. n = 157 ( 66.9 mU/mmol); Placebo n = 57 ( 62.3 mU/mmol).
3. n =142 (baseline 0.20); Placebo n = 47 ( 0.18).
4. ( ) .
: Del Prato S, et al. Diabetes Obes Metab. 2011;13:258267.

:
52
( ~1.5 g)
..
.. ~8,5%

M
HbA1c
(%)
0.81%

0.85%

( 52 )
Filozof C et al, Diabetic Medicine 2010;27:318-26

 Vildagliptin :
HbA1c
Vilda 50 mg + met (, ITT n=42)
PBO + met (, ITT n=29)
Vilda 50 mg + met ( , ITT n=56)
PBO + met ( , ITT n=51)

8,4

HbA1c (%)

8,0
P <0,0001

1,1 0,2%

7,6

P <0,0001

7,2

6,8

4 0

12 16 20 24 28 32 36 40 44 48 52

n ITT .
HbA1c= A1c, ITT= , met=, PBO= , vilda=vildagliptin
Ahrn B, et al. Diabetes Care 2004; 27: 2874-2880.

HbA1c ( placebo effect

Metformin
International* ineligible**

-0,7%

Japan

Add-on
to met*

-0,6%

-0,6%

Add-on
to SU**

-0,5%

Add-on to
met + SU*

With metformin With metformin

(Low dose)*
(High dose)*

-0,6%

-0,9%

p <0.0001 for all studies vs. baseline, for initial

combination vs. respective monotherapy

-1,3%
-1,7%

* 24 weeks treatment duration

**
18 weeks treatment duration
Del
12Prato,
weeksettreatment
duration
al. Diabetes
Obes Metab. 2011;13:258-267 (International); Barnett, et al. EASD 2010, Poster 823-P (Metformin ineligible);
Kawamori et al. EASD 2010 , Poster 696-P (Japan); Taskinen et al. Diabetes Obes Metab. 2011;13: 65-74 (Add-on to metformin); Lewin et al.
EASD 2010, Poster 821-P (Add-on to SU); 3. Owens DR, et al. ADA 2010, Poster 548-P (Add-on to metformin + SU); Haak T., et al. ADA 2011
oral presentation 279-OR (Initial combi with met).

Change from
baseline
HbA
1c
( 8,1%)
(mean 8.1%)

0%

HbA1c reduction

(Mean change from baseline 8.1%
SEM)
2
Placebocontrolled
, doubleblind

HbA1c

Openlabel
extension

HbA1c :
-0,8%3

-0.5%

(
102
)1

-1.0%
-1.2%
0
(n=15
31)

12
(n=146
3)

18 24

30

(n=142 (n=140
9)
0)

42

54

66

(n=130
(n=118
(n=109
2)
3)
0)

Treatment duration in weeks

78

90

102

(n=100
7)

(n=948)

(n=903)

Linagliptin in monotherapy, dual combination, triple combination - monotherapy, or combination with metformin SU, or initial combination
with pioglitazone

Owens et al; Oral Presentation EASD Lisbon 2011

HbA1c(%)
24

HbA1c
> 1 to 5
1

> 5
p
p
p
<0,000
<0.000
<0,000
1
1
1

n=

120

261

8,2

8.1

227

570

8,0
8,1
Mean baseline HbA1c
(%)

381

1045

8,2

8,2

Placebo

placebo-corrected

Pre-specified sub-group analysis on pooled data from 4 pivotal phase III

randomized placebo-controlled trials: treatment in monotherapy, add-on to
metformin, add-on to metformin + SU, initial combination with
pioglitazone.
p-values for between group difference (versus placebo)
Source: data on file

 HbA1c

HbA1c(%)
24

HbA1c 1
(%) 24

50
years

51 to 64
years

65 to 74
years

p
<0.000
0.02
1

p
<0,0001

p
<0,000
1

-0.02

-0,54-0.56

75
years
p
=0,000
0,03 2

-0.09

-0,60
-0,69

-0,66-0,64

n = 194

442

363

970

8,2

8,2

8,2

8,2

-0,80-0,83

152

398

19

66

8,1

8,1

8,1

8,0

Mean baseline HbA1c (%)

Placebo

placebo-corrected

Pre-specified sub-group analysis on pooled data from 4 pivotal phase III

randomized placebo-controlled trials: treatment in monotherapy, add-on to
metformin, add-on to metformin + SU, initial combination with
pioglitazone.
p-values for between group difference (versus placebo)
Source: data on file

 ,

HbA1c
HbA1c < 7%
2

(n = 271)

(n = 233)

,.
: Gallwitz B, et al. Int J Clin Pract. 2013;67:317321.

: ,

20% SUs
6
SUs



!!
Amiel S. Diabet Med 2008

(ADA. Clinical Practice Recommendations. Diabetes Care 2013).

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

1-

2-

1-

-,

ST

QT

Dead in bead =

 vs :

>1 .
(%)

n=

1389
1383

1389
1383

1389
1383

(%)

50 mg bid
+

6 mg qd +
Data on file, Novartis Pharmaceuticals, LAF237A2308 52-week interim analysis



Overall incidence of hypoglycaemia
Patients (%)

Monotherapy1

Add-on to
metformin2

Overall hypoglycaemic event rate was

8.2% with linagliptin, 5.1% with placebo 7
Hypoglycaemic event rate was very
low (<1%) with linagliptin when used
without sulphonylureas, even in
elderly and renally impaired patients
when treated without sulphonylureas
background7

Metforminineligible3

Add-on to
Add-on to
4
sulphonylurea metformin plus
sulphonylurea5

Add-on to
insulin6

1. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258267; 2. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:6574; 3. Barnett AH, et al.
Diabetes Obes Metab. 2012. doi: 10.1111/dom.12011; 4. Lewin AJ, et al. Clin Ther. 2012;34:19091919.e15; 5. Owens DR, et al. Diabetic Med.
2011;28:13521361; 6. Yki-Jrvinen H, et al. Diabetes Care. 2013 ;doi: 10.2337/dc12-2718 ; 7. Schernthaner G, et al. Diabetes Obes Metab.
2012;14:470478.



DPP-4
(
)
.

DPP-4
,
,
GLP-1
AACE October 2009



Adjusted mean (SE) change in body weight from baseline to study end*
Kilograms

Linagliptin baseline
BMI Kg/m2 (SD)
Placebo baseline BMI
Kg/m2 (SD)

29.04 (4.80) 1
Monotherapy

Metformin29.1 (5.6)2
ineligible

Add-on to
29.85 (4.84)3
metformin

29.08 (4.84)

30.2 (5.0)

30.5 (5.01)

Add-on to
metformin
Add-on to
plus
sulphonylure sulphonylure
4
5
28.4a(5.0)
28.4a(4.8)
28.2 (5.1)

28.2 (4.5)

Add-on to
6
30.8
(5.4)
insulin
31.2 (4.9)

Linagliptin is weight neutral as monotherapy or as add-on to

other glucose-lowering agents

Note: Add-on to SU is not approved in Europe.

* Adjusted mean change in body weight from baseline to study end is reported for all studies, except for the metformin-ineligible study, which reports change from
baseline to Week 18 (end of placebo versus linagliptin phase of study).
1. Data on file; 2. Barnett AH, et al. Diabetes Obes Metab. 2012. doi: 10.1111/dom.12011; 3. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:651374; 4. Lewin AJ, et
al. Clin Ther. 2012;34:19091919.e15; 5. Owens DR, et al. Diabetic Med. 2011;28:13521361; 6. Yki-Jrvinen H, et al. Diabetes Care. 2013 (submitted);

 vs
:

(~1.9 g )

(kg)

* p< 0.01

1.6
1

1.8 kg

-0.2
-1
VILDA 50 mg bid + metformin
Glimepiride up to 6 mg qd + metformin

Ferrannini E et al, Diabetes Obes Metab. 2009 Feb;11(2):157-66


52
(~1.5 g )

(kg)

* p< 0.001

1.4

1.3 kg

+0.08
-1
VILDA 50 mg bid + metformin
Gliclazide up to 320 mg daily + metformin

Filozof C and Gaultier J, DiabetIic Medicine. 2010 (27):318-26


()

()

per os

0,75

1,13

+/per os

1,22

1,29

0,93

1,21

()

*365

339,5

30%
: 2011

441,5

2011

HbA1c

(
)

123,5

185,4

209,3

416,4

35

35

31,1

38,9

23
68%

: 2011

35,1

9,4

2011

 QALYs

( )
20

Elgart et al. Health Economics Review 2013, 3:11

 QALYs
QALYs LYG
20

LYG-Life years
gained

Elgart et al. Health Economics Review 2013, 3:11

Retrospective cohort study of medical and pharmacy claims database

(786,656 patients aged 18-63 years)
Kaplan-Meier estimate

1.000

Diabetes

0.998

Non-diabetic
control

0.996
0.994
0.992
0.990
0.988

HR 2.1 (95% CI 1.7-2.5)

P<0.001
0 30 60 90 12 15 180 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75
0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Days to pancreatitis
Cox proportional hazard model controlling for diabetes, age, pre-existing pancreatic disease, alcohol intake, biliary stone
disease and chronic disease score. The overall diabetic group combined exenatide, sitagliptin and diabetic control

Patients with diabetes are twice as likely to have acute pancreatitis

than patients without diabetes
Garg R, et al. Diabetes Care 2010;33:2349-2354

 Ca
2
Cumulative incidence (%)

1.0

Diabetes

0.8

Non-diabetics

RR for pancreatic cancer for new-onset

diabetics vs non-diabetics:
2.17 (95% CI 1.84 2.56)

0.6
0.4
0.2
0.0
0

Follow-up (years)
Cumulative incidence over 6 years in patients with new-onset diabetes: 0.5%
Average incidence: 83.8/100,000 patient-years
RR=rate ratio
Gupta S, et al. Clin Gastroenterol Hepatol 2006;4:13661372

-: DPP-4

First author (ref)

MH-OR
(95% confidence intervals)

Raz 2006 (41)

0.089
NCT00575588 (1)
0.200
NCT00722371 (1)
0.250
Scherbaum 2008 (65)
0.318
NCT00614939 (1)
0.329
NCT01289119 (21)
0.333
Pfutzner 2011 (21)
0.335
Bergenstal 2010 (52)
0.389
NCT00700817 (1)
0.677
NCT01204294 (1)
0.831
Williams-Herman 2010 (45)
0.980
NCT00482729 (1)
0.994
Rosenstock 2010 (10)
1.000
Hollander 2011 (26)
1.455
NCT00996858 (1)
1.496
DeFronzo 2012 (5)
1.496
Ferrannini 2009 (89)
1.498
Pan 2008 (53)
1.505
Rosenstock 2009 (6)
1.509
Garber 2008 (60)
1.562
NCT00954447 (1)
2.000
NCTC00328172 (1)
2.345
Wainstein 2012 (50)
2.954
Seck 2010 (49)
2.985
Russell-Jones 2012 (51) 7.560
OVERALL
0.933

0.004
0.010
0.010
0.013
0.013
0.014
0.021
0.019
0.027
0.034
0.061
0.062
0.041
0.059
0.060
0.061
0.250
0.061
0.061
0.063
0.181
0.095
0.120
0.121
0.306
0.515

2.192
4.178
6.152
7.878
8.202
8.221
5.366
8.141
16.675
20.523
15.708
15.920
24.668
35.881
37.080
36.796
8.978
37.098
37.291
38.554
22.113
58.033
72.849
73.416
186.538
1.688

Relative
weight (%)

0.114
0.30
0.40
0.48
0.50
0.50
0.44
0.54
0.81
0.91
0.99
1.00
1.00
0.82
0.81
0.81
0.66
0.80
0.80
0.79
0.57
0.60
0.51
0.50
0.22
0.817

3.42
3.81
3.43
3.42
3.40
3.42
4.57
3.80
3.43
3.42
4.57
4.57
3.42
3.42
3.41
3.43
10.97
3.43
3.42
3.42
6.09
3.42
3.42
3.43
3.42
100.00

0.001 0.01

0.1

1.0

10.0

100.0

DPP-4 inhibitors

Comparators

Events Patients

Events Patients

0
0
0
0
0
0
1
0
0
1
1
1
1
1
1
1
3
1
1
1
2
1
1
1
1
20

411
428
922
156
85
252
978
166
219
450
551
625
491
381
186
1.038
1.396
440
260
305
631
170
261
588
163
11.553

1
2
1
1
1
1
1
2
1
0
1
1
0
0
0
0
2
0
0
0
1
0
0
0
0
16

110
430
693
150
85
253
328
325
446
124
540
621
163
184
92
517
1.393
220
130
158
630
132
256
584
409
8.973

Overall risk of pancreatitis and pancreatic cancer did not differ between
DPP4 inhibitors and comparators (MH-OR [95% CI]: 0.93 [0.511.69]; p=0.82)
Monami et al. Diabetes Obes Metab 2014;16:4856

 &
52, , ,
2
( NYHA)
50mg
(=128) (=126)
(LVEF).




NYHA
.

Vildagliptin in Ventricular Dysfunction Diabetes Trial(VIVIDD)

No difference in risk of HF hospitalization with vildagliptin:

VIVIDD study

Krum H, et al. No significant difference in risk of heart failure hospitalization with vildagliptin in diabetic patients with systolic chronic
heart failure: VIVIDD study. Poster presented at the 74th Scientific Sessions of the American Diabetes Association, San Francisco, USA,
June 13-17 2014.

 DPP-4 &
Ref: SPCs

NYHA

I NYHA

II NYHA

V NYHA

(50mg x 2)

(50mg x 2)

(50mg x 2)

SPC


(I-IV)

SPC


(I-IV)

SPC


(I-IV)

SPC


(I-IV)

.

-IV.

.

-IV.

.

-IV.

.

-IV.

 DPP-4
(Vipidia)
- 1 (1x25mg)

- Vipidia
18
2



,

, ,
,

-

-
.

:
- .
: - . (12,5
: mg)
**: - . (6,25
mg)
-

-

(Trajenta)
- 1 (1x5mg)
- *
-

-

-

-
.
-


,
- ,

* . ** : ,

 :
- (19 )

Incidence rate
(per 1,000 patient-years)

Incidence rate of primary CV events*

Number and percentage of patients
- 19

Hazard ratio 0.78

[95% CI 0.55, 1.12]
No significant difference
62 events
out of
3,612
patients

Comparator
(pooled active and
placebo comparators)

60 events
out of
5,847
patients

Linagliptin

(1.03%) (1.35%)
*Primary endpoint; composite of occurrence or time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization
for unstable angina.
Source: Linagliptin EU SmPC, May 2013; Johansen O-E, et al. ADA 2013, Abstract 376-OR.

 :

UKPDS 33:

(%)

-34

-67
-74

1. UKPDS Group (UKPDS 33). Lancet 1998;352:83753.

 (%) GFR<60 ml/min

20%

U.S. Renal Data System, USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage
Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive
and Kidney Diseases, Bethesda, MD, 2013.

 (%) GFR<60 ml/min

23%

BMC Nephrology 2012, 13:87

 (%) GFR<60 ml/min

65

44,2 %

BMC Research Notes 2014, 7:415



eGFR (mL/min/1.73 m2)
60-89

45-59

30-44

15-29

<15

sitagliptin

100 mg

50 mg

50 mg

25 mg

25 mg

vildagliptin

100 mg

50 mg

50 mg

50 mg

50 mg

saxagliptin

5 mg

2,5 mg

2,5 mg

2,5 mg

linagliptin

5mg

5mg

5mg

5mg

alogliptin

25mg

12,5 mg

12,5 mg

6,25 mg

1000 mg,

25

GLP1

Dapaglifozin

5mg


75

Mean change from BL (%)

BL

-1

HbA1c #

FPG #

75 years

< 75 years

8.3

8.7

-0.9

-1.2

*
-2

Mean change from BL (mmol/L)

75 years

< 75 years

9.7

10.5

BL

-1

-1.1

BL

< 75 years

74.9

86.1

Hypoglycemic events ##

75 years

< 75 years

Any
events

0.0 %

0.3 %

Severe
events

0.0 %

0.0 %

Mean change from BL (kg)

-0.4
-1

-0.9

*
-2

-2

Body weight #
75 years

-1.2

Vildagliptin 50 mg twice daily

Pooled monotherapy efficacy population up to Week 24 (7 studies; n=62 ( 75 years) and n=2303 (< 75 years)); ##Monotherapy (excluding open-label)
safety population up to Week 24 ((n=71 ( 75 years) and n=2553 (< 75 years)); unadjusted mean changes; *p<0.05 vs baseline; BL= baseline
Schweizer A et al DOM 2011; 13:55-64.
#


HbA1c

HbA1c
(%)

Placebo

Linagliptin

78

160

Mean age (SD)

74.9 (4.2)

74.9 (4.4)

Baseline HbA1c
(%)

7.82

7.70

Subjects

-0.64%,
p < 0.0001

Week

12

18

24

Linagliptin should be used with caution when treating patients aged >80 years, as experience in this patient group is limited (Trajenta EU summary of product
characteristics).
* Full analysis set (last observation carried forward).
Source: Barnett A, et al. Lancet. 2013 doi: 10.1016/S0140-6736(13)61500-7.



Investigator-defined hypoglycaemia
(% patients with 1 episode)

39 13
162 79

10

67 36

29

95 43

45 22

22 14

Patients with
hypoglycaemia
Total number of patients

Note: Add-on to SU is not approved in Europe.
*Odds ratio for linagliptin versus placebo = 1.58 [95% CI 0.78, 3.78], p = 0.2083. The slightly higher overall incidence of hypoglycaemia, although not
statistically significant, was mainly due to increased incidence in patients receiving sulphonylurea.

Confirmed plasma glucose concentration 39 mmol/L and/or symptoms attributed to hypoglycaemia.

Source: Barnett A, et al. Lancet. 2013, doi:10.1016/S0140-6736(13)61500-7.

Mean (SE) change in HbA1c over time, %; FAS (OC)

6

12

18

24

32

40

52

64

76 Treatment
weeks

0.07
(0.08)%
*

Free insulin
dose

Stable insulin
dose
-0.58
(0.08)%
*

Placebo, n

617

606

565

537

493

440

370

301

163

76

Linagliptin, n 618
611
593
568
527
496
426
386
Basal insulin dose, IU/day, mean Mean (SD) change in basal insulin
dose
(SD)

233

122

Baseline

Week 24

Week 52

41.5 31.9

+0.1 (0.2)

+2.6 (0.8)

Placebo
40.1 27.3
+0.4 (0.2)
*Adjusted mean (SE) change in HbA1c from baseline.

+4.2 (0.8)

Linagliptin

Source: Yki-Jrvinen H, et al. Diabetes Care. 2013;doi: 10.2337/dc12-2718.

Frequency of investigator-defined hypoglycaemia (%)

Source: Yki-Jrvinen H, et al. Diabetes Care. 2013;doi: 10.2337/dc12-2718.

 Vildagliptin :
(SBP >140
mmHg DBP >90mmHg)
(2.0 g )
DBP
BL (mmHg)

n=

57

SBP
59

57

59

*
*

Vilda 50 mg
+ met
PBO + met
*

BL= , DBP= , met=, PBO= , SBP= , vilda=vildagliptin. *P <0,05

BL.

Bosi E, et al. Presented at ADA Annual Meeting; June 22-26, 2007; Chicago, IL. 2165-PO.

 HbA1c

*
Adjusted mean (SE) HbA1c (%) change from baseline to Weeks 18 and 24

Week 18

Week 24

Placebo
Linagliptin
Placebo-adjusted
linagliptin
95% CI
-0.75, -0.39
p < 0.0001
Linagliptin, n = 366; placebo, n = 146
Baseline HbA1c %: linagliptin, 8.3 (0.9); placebo, 8.4 (0.9)

95% CI
-0.80, -0.39
p < 0.0001

Linagliptin provides reliable HbA1c reductions in patients at high risk for renal
and CV disease
*Pooled analysis of patients with baseline microalbuminuria (UACR 30300 mg/g) and hypertension (SBP >40 mmHg, and/or DPB >90 mmHg) who
participated in any of six randomized placebo-controlled trials of 1824 weeks duration.

Pooled analysis of six clinical trials.

Pooled analysis of four clinical trials.

Source: von Eynatten M, et al. Cardiovasc Diabetol. 2013:12:60. doi: 10.1186/1475-2840-12-60.



DPP-4 HbA1c 0.5-0.8%
FPG PPG
DPP-4 FPG
DPP-4 PPG

-
DPP-4

 ... !

 DPP4

Peptidomimetic* DPP4
inhibitors

Nonpeptidomimetic* DPP4 inhibitors

DPP4 inhibitors mimicking dipeptides

F
F

NH2 O
F

F
F

N
N

N
N
N

F
O
N

HO

N
NH2
OH

N
H

DPP4 inhibitors directly binding to active site of the

enzyme

N
O

NH2

Linagliptin belongs to the small

molecule class (MW: 473 Da) and is
much smaller than the DPP4 enzyme
(MW: 85,400 Da)
Based on the chemical structure of
linagliptin and the DPP4 enzyme, it fits
perfectly to the active centre of the
enzyme

Indicates peptide-like structure

*Small protein-like chain designed to mimic a peptide.

Licensed in the US.

Source: Adapted from Deacon CF. Diabetes Obes Metab. 2011;13:718.

 ,
GLP-1
,
DPP-4,


t : GLP-1 = 2min,
GLP-1 = 5min

SUs, TZDs, DPP-4 Is, GLP-1 RAs, Insulin

(, , )


GLP-1

GLP-1

GLP-1
DPP-IV

 (GLP-1, GIP)
DPP-4

GLP-1 GIP

DPP-4

GLP-1

DPP-4

GLP-1 GIP
GLP-1 = glucagon-like peptide-1. GIP = glucose-dependent insulinotropic
polypeptide. DPP-4 = dipeptidyl peptidase-4.
Adapted from Drucker DJ. J Clin Invest. 2007;117:24-32.

GLP-1

GLP-1

GIP

GIP

 GLP-1:

GLP-1

5. :

2. -:

3. :

1. -

4. :

GLP-1=glucagon-like
peptide-1
Adapted from 1Nauck
MA, et al. Diabetologia 1993;36:741744; 2Larsson H, et al. Acta Physiol Scand 1997;160:413422; 3Nauck
MA,
etetal.
1996;39:15461553;
Flint
J Clin
Invest
1998;101:515520;
et al.
2002;359:824830.
1. Nauck
MA,
al.Diabetologia
Diabetologia 1993;36:741744;
2. Larsson
H,A,
et et
al.al.
Acta
Physiol
Scand
1997;160:413422; 3.Zander
Nauck MA,
et Lancet
al. Diabetologia
1996;39:15461553;
4. Flint A, et al. J Clin Invest 1998;101:515520; 5. Zander et al. Lancet 2002;359:824830
4

DPP-4

Food intake
DPP-4 inhibitor
-cells
Stomach

Increases and prolongs GLP1 and GIP effect on -cells:

Insulin release

Pancreas
DPP-4

GI tract

Net effect:
Blood glucose

Incretins
Increases and prolongs
-cells GLP-1 effect on -cells:
Glucagon secretion

Intestine

DPP-4 = Dipeptidyl peptidase-4; GIP = Glucose-dependent insulinotropic polypeptide; GLP-1 = Glucagon-like peptide-1
1. Kulasa K, Edelman S, et al. Core Evidence 2010;5:2337

McIntosh et al. Open Medicine 2011;5(1):e39




11%

(: ,

Grant RW Diabetes Care

1. Cade WT. Phys Ther. 2008;88:13221335.;2. Centers for Disease Control and Prevention, 2007.
http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf; 3. Fowler MJ. Clinical Diabetes. 2008;26:7782 .

 .
(
)

*p<0.001
*p<0.05

90

60

45
GFR

30

15

. Deacon CF. Diabetes, Obes Metab. 2011;13(1):718