Achieving Treatment Outcome With DPP4i for Diabetic Patient "Efficacy Beyond Sugar Control”

Achieving Treatment Outcome

With DPP4i for Diabetic Patient

“Efficacy Beyond Sugar

Control”

1

Riwayat Hidup :

Nama : Dr Eddy Supriadi, Sp.PD, FINASIM

Tempat/ Tgl. Lahir : Jakarta, 19 Feb 1968

Pendidikan : Dokter FKUI 1993, Penyakit Dalam

FKUI 2006

Tempat Kerja : RS Dr H. MARZOEKI MAHDI

Pengalaman :

- Inspire Diabetes Program. PERKENI Indonesia-

STENO Denmark. Jakarta 2013.

- Workshop and Symposium on the Diabetic Foot.

Noordwijkerhout, The Netherlands, 2011

- dll.

The Prevalence of Diabetes Mellitus Worldwide

(IDF 2013) Diabetes Atlas 3

PART I

DIABETES UPDATE

4

ADA Diabetes Care 2015

5

Classification and Diagnosis of Diabetes

6

A1C ≥6.5%

OR

Fasting plasma glucose (FPG)≥126 mg/dL (7.0 mmol/L)

OR

2-h plasma glucose ≥200 mg/dL(11.1 mmol/L) during an OGTT

OR

A random plasma glucose ≥200 mg/dL(11.1 mmol/L)

ADA. 2. Classification and Diagnosis. Diabetes Care 2015;38(suppl 1):S9; Table 2.1

Categories of Increased Risk for Diabetes

(Prediabetes)*

7

FPG 100–125 mg/dL (5.6–6.9 mmol/L): IFG

OR

2-h plasma glucose in the 75-g OGTT140–199 mg/dL (7.8–11.0 mmol/L): IGT

OR

A1C 5.7–6.4%

*For all three tests, risk is continuous, extending below the lower limit of a range and becoming disproportionately greater at higher ends of the range.

ADA. 2. Classification and Diagnosis. Diabetes Care 2015;38(suppl 1):S10; Table 2.3

Approach to the Management of

Hyperglycemia

8ADA. 6. Glycemic Targets. Diabetes Care 2015;38(suppl 1):S37. Figure 6.1; adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

Antihyperglycemic Therapy in

Type 2 Diabetes

9

If not controlled

in

3 months

3 months

3 months

ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015;38(suppl 1):S43. Figure 7.1; adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015;38:140-149

PERKENI 2015

10

Konsensus PERKENI, 2011

Perkeni Guideline for T2DM Management (2011)

11

PART II

Incretins and DPP-4

Inhibition

12

Different Binding Kinetics within DPP-4 Class

Natural

substrate:(GLP-1)

GLP-1

+

DPP-4

K-1

K1

GLP-1: DPP-4

complex

K2

Fast(~1 sec)

DPP-4Inactive

GLP-1

+

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.

Burkey BF, et al. Poster 0788 presented at EASD 2006; Deacon CF, Holst JJ. Adv Ther. 2009; 26: 488–499;

Miller SA, St Onge EL. Ann Pharmacother. 2006; 40: 1336–1343; Neumiller JJ. J Am Pharm Assoc. 2009; 49: S16–S29;

Potashman MH & Duggan ME. J Med Chem 2009; 52: 1231-1246. White JR. Clin Diabetes. 2008; 26: 53–57.

Substrate

acting as

inhibitor:(vildagliptin,

saxagliptin) Substrate-like

enzyme blocker

+

DPP-4

K-1

K1

Substrate-like

enzyme blocker:

DPP-4 complex

K2

Slow

(~ 1 h)

DPP-4Inactive

substrate-like

enzyme blocker

+Slow dissociation

Inhibitor

+

DPP-4

K-1

K1

Inhibitor: DPP-4

complex

Competitive

inhibitor:(sitagliptin,

alogliptin) Fast dissociation

13

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1. Burkey BF, et al. Poster 0788 presented at EASD 2006; Deacon CF, Holst JJ. Adv Ther.

2009; 26: 488–499; Miller SA, St Onge EL. Ann Pharmacother. 2006; 40: 1336–1343; Neumiller JJ. J Am Pharm Assoc. 2009; 49: S16–S29; Potashman

MH, Duggan ME. J Med Chem 2009; 52: 1231–1246; White JR. Clin Diabetes. 2008; 26: 53–57.

Fast dissociation Slow dissociation

GLP-1

GLP-1

GLP-1

DPP-4

Competitive

inhibitor

GLP-1

GLP-1

GLP-1DPP-4

Vildagliptin

Tight substrate-like binding of vildagliptin leads to

potent DPP-4 inhibition

Duration of sitagliptin binding: <5 seconds Duration of vildagliptin binding: 55 minutes

14

0

20

40

60

80

100

120

-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Vildagliptin 50 mg twice daily

Sitagliptin 100 mg once daily

Relationship between Drug Exposure and GLP-1 Levels

with Vildagliptin and SitagliptinD

rug

Le

ve

ls

Drug exposure1

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1. *P <0.05 vs vildagliptin group.

Plasma levels during 24-h sampling comprising three standardized meals after 3 months of treatment in type 2 diabetic patients. 1He YL, et al. Clin Pharmacokinet. 2007; 46: 577–588; 1Herman GA, et al. Clin Pharmacol Ther. 2005; 78: 675–688; 2Marfella R, et al. J Diabetes Complications. 24: 79-83, 2009.

Inta

ct

GL

P-1

(p

mo

l/L

)

Time (hours)

0 2 4 6 8 10 12 14 160

5

10

15

20

25

30

Breakfast Lunch Dinner

Vildagliptin 50 mg twice daily

Sitagliptin 100 mg once daily

Time (hours)

GLP-1 levels2

15

Comparison of Plasma Glucagon Levels following

3 Months’ Treatment with Vildagliptin or Sitagliptin

Sitagliptin 100 mg once

daily + metformin (N=20)

Vildagliptin 50 mg

twice daily + metformin (N=18)

*P <0.05 vs vildagliptin group; Plasma levels during 24-h sampling comprising three

standardized meals after 3 months of treatment in type 2 diabetic patients.

Marfella R, et al. J Diabetes Complications. 24: 79-83, 2009.

90

80

70

60

50

40

30

20

Breakfast Lunch Dinner

Pla

sm

a G

lucag

on

(m

g/d

L)

-20 0 15 30 60 90 120 180 240 300 0 15 3060 90 120 180 240 300 0 15 3060 90 120 180 240 300 min

16

Dysglycaemia of Diabetes

Vascular complications in diabetes are mainly or partly dependent

on dysglycaemia

2 components:

• Sustained chronic hyperglycaemia

• Acute glucose fluctuations

Both component lead to diabetes complication through:

• Excessive protein glycation

• Activation of oxidative stress

Monnier L et al. J Diabetes Sci Technol 2008;2:1094-1100 17

Glycaemic variability

Glycaemic variability – an important parameter

used to resolve potential clinical problems in

diabetic patients

Acts as independent risk factor for diabetic

complications, although HbA1c values were

intensely treated

Zaccardi F et al. J Diabetes Sci Technol 2008;2:1061-5 18

Glucose variability: Should we prevent it?

Activation of

oxidative stress

FPG

PPG HbA1c (glycation)

Acute glucose fluctuations

(MAGE)

Adapted from Monnier L, Colette C. Diabetes Care 2008;31(Suppl2):S150-4

Correlated with

urinary excretion rate

of 8-iso-PGF2α

Reflects the level of

FPG and PPG

↑ production of

free radicals

Proportional to

magnitude of PPG

excursion

↑ formation

and urinary

excretion

rate of 8-iso-

PGF2α

Significantly

higher in

T2DM

(p<0.01)

8-iso-PGF2α is a parameter of activation of oxidative stress

19

Glucose Tetrad ConceptGlucose fluctuations and activation of oxidative stress contribute to

progression of vascular complications

Monnier L et all. Diabetes Metab Res Rev 2009;25:393-402 20

MAGE

Simple arithmetic average of the “amplitudes” of all glycaemic excursions

Amplitudes can be estimated by the magnitude of either the upward shifts

or the downward shifts of each excursion

• Upward excursion: MAGE+

• Inward excursion: MAGE-

• Average excursion: MAGE.avge

Baghurst PA. Diabetes Technol Ther 2011;13:296-301 Example of final MAGE calculation

2 main advantages of MAGE

• The parameter is not dependent on the mean

glucose value

• It is designed to quantitate major glucose swings

and exclude minor ones

Monnier L et al. J Diabetes Sci Technol 2008;2:1094-1100 22

OPTIMA study: Vildagliptin vs. SitagliptinVildagliptin provides 24-hours better glucose fluctuation control

Guerci B et al. Diabetes Metab 2012;38:359-66 23

OPTIMA study: Vildagliptin vs. Sitagliptin

917 872

1139

958

0

400

800

1200

Vildagliptin Sitagliptin

Baseline Week 8

Vildagliptin provide 24-hours better glucose fluctuation control and give

longer blood glucose ideal range significantly than Sitagliptin

Min

ute

s

Adapted from Guerci B et al. Diabetes Metab 2012;38:359-66

Conclusion

Addition of DPP-4 inhibitor significantly reduced glycaemic variability with

no difference between the two drugs

However vildagliptin induced better circadian glycaemic control than

sitagliptin with a significant decrease on over all hyperglycaemia

Time takes to stay in ideal blood glucose range

24

Objective:

Evaluate the effects of two dipeptidyl peptidase-IV (DPP-4) inhibitors,

sitagliptin and vildagliptin, known to have different efficacy on :

Mean amplitude of glycemic excursions (MAGE)

Oxidative stress

Systemic inflammatory markers in patients with type 2 diabetes

Rizzo MR et al. Diabetes Care 2012;35:2076-82 25

Design and Methods:

Prospective, randomized, open-label (PROBE) design (parallel group

with a blinded end point) in 90 patients with T2DM inadequately

controlled by metformin

The study assigned 45 patients to receive sitagliptin (100 mg once daily;

sitagliptin group) and 45 patients to receive vildagliptin (50 mg twice

daily; vildagliptin group) for 12 weeks

MAGE, evaluated during 48 h of continuous subcutaneous glucose

monitoring (CSGM), allowed an assessment of daily glucose fluctuations

at baseline and after 12 weeks in all patients

Assessment of oxidative stress (nitrotyrosine) and systemic levels of

inflammatory markers interleukin (IL)-6 and IL-18 were performed at

baseline and after 12 weeks in all patients


Vildagliptin, compared to Sitagliptin, is significantly better in MAGE reduction,

hence better in reduction of oxidative stress

Rizzo MR et al. Diabetes Care 2012;35:2076-82

Conclusion:

MAGE reduction is associated with reduction of oxidative stress and

markers of systemic inflammation in type 2 diabetic patients.

These effects were greater in the vildagliptin group than in the sitagliptin

group


PART III

Vildagliptin Concept In

T2DM Therapy

29

Vildagliptin and GLP-1 inactivation

• Vildagliptin 50 mg once daily: blocks GLP-1 inactivation during the

three daily meals, resulting in reduced PPG and its associated

reduction in FPG1

• Vildagliptin 50 mg twice daily: blocks GLP-1 inactivation over

24 hours, providing an additional reduction in FPG due to a direct

effect on overnight HGP1

• In moderate and severe renal impairment (RI):

‒ vildagliptin 50 mg once daily expected to block GLP-1 inactivation over

24 hours2

• reductions in HbA1c in patients with RI given qd dose comparable with bid

dose in similar patient population with preserved renal function and similar

baseline HbA1c2

qd=once daily; bid=twice daily1Ahrén B, et al. Diabetes Obes Metab 2011;13:775–83; 2Lukashevich V et al. Diabetes Obes Metab 2011;13:947–54

30

REAL WORD EFFECTIVENESS DATA

31

32

Europe

Austria, Belgium, Czech Republic, Germany, Greece, Netherlands,

Portugal, Slovakia, Sweden, Bulgaria, Luxembourg, Russia

Latin America

Mexico, Venezuela,

Argentina, Colombia,

Ecuador

Middle East

Jordan, Palestine, Lebanon,

Bahrain, Kuwait, Oman

United Arab Emirates

India

East Asia

South Korea

Philippines

27 Countries participating in EDGE

32

Total Enrolled Population: 45,868

Adapted from Mathieu C, et al. Effectiveness and tolerability of second-line therapy with vildagliptin vs. other oral agents in type 2

diabetes: A real-life worldwide observational study (EDGE). Int J Clin Pract. 2013 Oct;67(10):947-56.

One of the largest T2DM observational studies ever conducted in a real-world setting

12-month observational, multicenter, post-authorisation, prospective cohort study, which included

45,868 patients from 27 countries worldwide

Overall HbA1c reductions Patients who achieved HbA1c <7%,

without hypoglycaemia and weight gain

The EDGE Study

35.1%

23.2%

0.0%

10.0%

20.0%

30.0%

40.0%

Vildagliptin Comparators

Patients at goal (HbA1c <7%)

-1.19

-0.99

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Vildagliptin Comparators

HbA1c drop (%)

Vildagliptin n = 29759; Comparators n = 16078

BL 8.17% BL 8.16%

Adapted from Mathieu C, et al, Int J Clin Pract 2013;67:947-56

BL=baseline

OAD comparators used: metformin, SU, TZD, AGI, glinide; other DPP-4 inhibitors and GLP-1 analogues are

excluded

One of the largest T2DM observational studies ever conducted in a real-world setting

12-month observational, multicenter, post-authorisation, prospective cohort study, which included 45,868

patients from 27 countries worldwide

33

Vildagliptin as add-on metformin in real-life setting:

-1.1% HbA1c reductionBroadly consistent with the decrease seen in randomized controlled trial settings

-1.19

-0.99

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0HbA1c change (%)

Vildagliptin

Comparator

Vildagliptin was consistently effective

in reducing HbA1c

12-month-therapy in real-life setting

(Baseline 8.17±1.3%)1

-0.7

-1.1-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Vilda 50 mg qd

Vilda 50 mg bid

Vildagliptin as add-on metformin

24-week-therapy

in randomized controlled trial settings

(Baseline 8.4±0.1%)2

Consistent efficacy

1 EDGE Study. Mathieu C, et al, Int J Clin Pract 2013;67:947-56

2 Bosi E, et al, Diabetes Care 2007;30:890–5 34

EDGE study Conclusion

In conclusion, EDGE demonstrated in a real-life setting

that T2DM patients in whom second-line oral glucose-

lowering therapy is initiated:

• vildagliptin can succeed in lowering HbA1c to < 7%,

(without weight gain, hypoglycaemia or peripheral

oedema) in a higher proportion than comparator OADs

• No differences in the reported number of AEs or SAEs

between Vildagliptin and comparator OAD.

• This information is consistent with data from RCTs with

vildagliptin

35

36

GUARD STUDY: data from >19,000 patients with T2DM

pooled from 4 different regions

Asia: Bangladesh; India; Pakistan; Philippines

Middle East: Bahrain; Kuwait; Lebanon; Oman; Qatar; UAE

Central America: Dominican Republic; El Salvador; Honduras; Panama

Africa: Egypt; Kenya; Nigeria; South Africa

T2DM=type 2 diabetes mellitus. Patients from Saudi Arabia were excluded from this analysis due to non-compliance with the study protocol.

Rosales et al. Poster 314 presented at the Australian Diabetes Society and the Australian Diabetes Educators Association Annual

Scientific Meeting, Melbourne, Australia, 27–29 August 2014.

Rosales et al. 2015. Clinical effectiveness and safety of vildagliptin in >19,000 patients with type 2 diabetes: the GUARD study. Diabetes Obes Metab.

2015 Jan 14. doi: 10.1111/dom.12436 In press.

Adapted from Rosales et al. 2015. Clinical effectiveness and safety of vildagliptin in >19,000 patients with type 2 diabetes: the GUARD study. Diabetes

Obes Metab. 2015 Jan 14. doi: 10.1111/dom.12436 In press.

Adapted from Rosales et al. Poster 314 presented at the Australian Diabetes Society and the Australian Diabetes Educators Association Annual

Scientific Meeting, Melbourne, Australia, 27–29 August 2014.

GUARD: prospective, multinational, ‘real-world’

study design

*As a free-dose combination or single-pill combination

Vildagliptin or vildagliptin add-on to metformin*

Data collection

(Visit 3)

Data collection

(Visit 2)Data collection

(Visit 1)

Observational period of 24±6 weeks

Adult patients

with T2DM

Day 1 (baseline) Week 24 (final visit)Week 12

• Non-interventional study conducted under an umbrella protocol in four geographic regions

(Asia, Middle East, Africa and Central America)

‒ Treatments prescribed according to the physician’s judgment and clinical indication based on the

prescribing information in the respective countries, and was clearly separated from the decision to

include the patient in the study

‒ Only data from routine clinical practice collected

37

GUARD: significant reductions from baseline to Week 24 in

mean HbA1c

–1.29*–1.17*

†At baseline, the mean overall HbA1c was 8.20 ± 0.88% (n=3,345) in the vildagliptin treatment group and 8.44 ± 0.85 (n=15,424) in the

vildagliptin plus metformin group.

BL, baseline; HbA1c, glycated haemoglobin; SD, standard deviation. Full analysis set, patients from vildagliptin and vildagliptin + metformin

treatment groups with a value for baseline HbA1c and at least one post-baseline HbA1c value available, last observation carried forward.

*p<0.0001 vs. baseline (twosided t-test)

Rosales et al. 2015. Clinical effectiveness and safety of vildagliptin in >19,000 patients with type 2 diabetes: the GUARD study. Diabetes Obes

Metab. 2015 Jan 14. doi: 10.1111/dom.12436 In press.

Mea

n c

ha

ng

e in H

bA

1c

from

baselin

e (

%)†

Vildagliptin Vildagliptin + metformin

0

–2

–4

0

–2

–4

n=3,216 n=14,807

38

GUARD: proportion of patients achieving target

HbA1c ≤7.0% at Week 24

47.2

0

20

40

60

80

100

42.8

0

20

40

60

80

100


Pro

po

rtio

n o

f p

atie

nts

at

targ

etH

bA

1c ≤

7.0

% a

tW

ee

k 2

4

(%)

HbA1c, glycated haemoglobin; Full analysis set, patients from vildagliptin and vildagliptin + metformin treatment groups with a value for

baseline HbA1c and at least one post baseline HbA1c value available, last observation carried forward

n=3,511 n=15,820


Metab. 2015 Jan 14. doi: 10.1111/dom.12436 In press.39

GUARD: significant reductions from baseline to Week 24 in

mean HbA1c across baseline HbA1c


–3.06*

–0.81*

–1.89*

–1.26*

–3.30*

–0.84*

–1.30*

–1.84*

–1

–3

–5

–1

–3

–5

≤8 >8–9 >9–10 >10BL HbA1c

category, %‡

Me

an

ch

an

ge

in H

bA

1c

fro

m b

ase

line

(%

)

Mean change in HbA1c at Week 24 according to baseline HbA1c level. Corresponding mean (SD) HbA1c values at baseline for vildagliptin group

respectively were:7.47, 8.51, 9.45, 11.40 and and vildagliptin added to metformin group were: 7.56, 8.54, 9.45, and 11.02.

BL, baseline; HbA1c, glycated haemoglobin. Full analysis set, patients from vildagliptin and vildagliptin + metformin treatment groups with a value for

baseline HbA1c and at least one post-baseline HbA1c value available, last observation carried forward. *p<0.0001 vs. baseline (twosided t-test).

Rosales et al. 2015. Clinical effectiveness and safety of vildagliptin in >19,000 patients with type 2 diabetes: the GUARD study. Diabetes Obes Metab. 2015

Jan 14. doi: 10.1111/dom.12436 In press.

n=1,427 n=1,298 n=464 n=27 n=4,686 n=7,173 n=2,634 n=314

≤8 >8–9 >9–10 >10

–2

–4

00

–2

–4

40

GUARD: significant reductions from baseline to Week 24 in mean HbA1c

with vildagliptin monotherapy regardless of obesity status and age

Me

an

ch

an

ge

in H

bA

1c

fro

m b

ase

line

(%

)†

*P<0.0001 vs baseline (two-sided t-test). †At baseline, mean overall HbA1c was 8.21 ± 0.86% (non-obese; n=2,355) and 8.18 ± 0.94% (obese;

n=646); 8.22 ± 0.87% (aged <65 years; n=3,129) and 7.93 ± 1.01% (aged ≥65 years; n=187)

Full analysis set (consisting of all patients who provided informed consent and entered into the study); analysis conducted in patients with a value for

baseline (BL) HbA1c and at least one post-BL HbA1c value (if Week 24 value was missing, the last post-BL observation was carried forward).

BMI=body mass index

n=2,269 n=632

–1.16*

0

–1

–2

–3

–4

–1.27* –1.17*

0

–1

–2

–3

–4

–1.11*

n=3,016 n=174

Non-obese

BMI <30 kg/m2

Obese

BMI ≥30 kg/m2

Age

<65 yearsAge

≥65 years

41Rosales et al. 2015. Clinical effectiveness and safety of vildagliptin in >19,000 patients with type 2 diabetes: the GUARD study. Diabetes Obes


GUARD: significant reductions from baseline to Week 24 in mean HbA1c

with vildagliptin + metformin regardless of obesity status and age

Me

an

ch

an

ge

in H

bA

1c

fro

m b

ase

line

(%

)†

*P<0.0001 vs baseline (two-sided t-test). †At baseline, mean overall HbA1c was 8.43 ± 0.84% (non-obese; n=9,316) and 8.49 ± 0.88% (obese;

n=4,398); 8.45 ± 0.85% (aged <65 years; n=14,289) and 8.37 ± 0.96% (aged ≥65 years; n=1,007)

Full analysis set (consisting of all patients who provided informed consent and entered into the study); analysis conducted in patients with a value for

baseline (BL) haemoglobin A1c (HbA1c) and at least one post-BL HbA1c value (if Week 24 value was missing, the last post-BL observation was

carried forward). BMI=body mass index

Non-obese

BMI <30 kg/m2

Obese

BMI ≥30 kg/m2

Aged

<65 yearsAged

≥65 years

–1.26*

0

–1

–2

–3

–4

–1.41* –1.29*

0

–1

–2

–3

–4

–1.35*

n=13,751 n=953n=8,967 n=4,218

42Rosales et al. 2015. Clinical effectiveness and safety of vildagliptin in >19,000 patients with type 2 diabetes: the GUARD study. Diabetes Obes


GUARD: changes in body weight and BMI from baseline to

Week 24

Mean c

hange in b

ody

weig

ht

from

baselin

e (

kg)


–1.1*–1.5*

Mean body weight and BMI at baseline: 75.7 kg and 27.4 kg/m2 for vildagliptin monotherapy; 78.6 kg and 28.5 kg/m2 for

vildagliptin + metformin.

• At Week 24, mean body mass index (BMI) decreased from baseline by 0.4 kg/m2 with vildagliptin

and 0.5 kg/m2 with vildagliptin + metformin (both P<0.0001 vs baseline)

0

–1

–2

–3

–4

0

–1

–2

–3

–4

Adapted from Rosales et al. 2015. Clinical effectiveness and safety of vildagliptin in >19,000 patients with type 2 diabetes: the GUARD study.

Diabetes Obes Metab. 2015 Jan 14. doi: 10.1111/dom.12436 In press. 43

*P<0.0001 vs baseline

GUARD: AEs and SAEs

44

Vildagliptin

(n=3,511)

Vildagliptin + metformin

(n=15,820)

Total AEs, n (%)* 143 (4.1) 556 (3.5)

Hypoglycaemia† 12 (0.3) 55 (0.3)

Nausea 6 (0.2) 43 (0.3)

Diarrhoea 7 (0.2) 34 (0.2)

Gastritis 7 (0.2) 23 (0.1)

Urinary tract infection 6 (0.2) 22 (0.1)

Dyspepsia 10 (0.3) 16 (0.1)

Peripheral neuropathy 10 (0.3) 3 (0.0)

Total SAEs, n (%) 8 (0.2) 14 (0.1)

*Occurring in ≥0.2% of any treatment group; †The number of patients with HEs was greater when data were recorded on a specific reporting form (vildagliptin: n=18;

vildagliptin + metformin: n=78) versus AE records; the dedicated HE form is more likely to capture non-symptomatic HEs (based on blood glucose measurements) as

well as symptomatic HEs

Full analysis set (consisting of all patients who provided informed consent and entered into the study); analysis conducted in patients with a value for baseline

(BL) haemoglobin A1c (HbA1c) and at least one post-BL HbA1c value; AE=adverse event; HE=hypoglycaemic events; SAEs=serious adverse events



GUARD was a large prospective study assessing vildagliptin with/without

metformin in a real-world setting: more than 19,000 patients with T2DM were

pooled across Asia, Middle East, Central America and Africa

Vildagliptin with/without metformin was associated with statistically significant

and clinically relevant HbA1c reductions from baseline

This effect was observed irrespective of patient age or obesity status and was

seen across baseline HbA1c categories

Vildagliptin without/without metformin was generally well tolerated

Overall, the findings from the real-world GUARD study are generally consistent

with other real-world studies and interventional controlled clinical trials with

vildagliptin with/without metformin

GUARD study: conclusions

45



Safety and Efficacy Profile in

T2DM Patiens With Moderate and

Severe Renal Impairment

Analysis of data from 102 prospective studies on diabetes morbidity and

mortality comparing those with and without diabetes in 698 782 pts

Rank Conditions Hazard

ratio

95% CI

1. Renal disease 3.02 2.39 – 3.82

2. Infection 2.39 1.95 – 2.93

3. Death from vascular causes 2.32 2.11 – 2.56

4. Coronary death 2.31 2.05 – 2.60

5. Liver disease 2.28 1.90 – 2.74

6. Ischemic stroke 2.27 1.95 – 2.65

7. Coronary heart disease 2.00 1.83 – 2.19

8. Mental disorder 1.64 1.45 – 1.92

9. Haemorrhagic stroke 1.56 1.19 – 1.61

10. Death from cancer 1.25 1.19 – 1.31

Sanwar N et al. Lancet 2010:2215-2222

Seshasai SR et al. N Engl J Med 2011: 829-841 47

Renal dysfunction is common in patients with type 2

diabetes mellitus

Russo E et al. Diabetes Metab Syndrome Obes Target Ther 2013;6:161-70

48

Considerations for management of T2DM in renal impairment

GLP-1 analogue (exenatide)2

Metformin2

Sulphonylurea (glimepiride)3,4

Pioglitazone5

DPP-4 inhibitors (e.g. saxagliptin, sitagliptin, vildagliptin, linagliptin)2

Repaglinide, Nateglinide6,7

Insulin2

Acarbose2

SGLT-2 inhibitor (dapagliflozin)1

1. SmPC: Forxiga 5 mg & 10 mg film coated tablets (dapagliflozin); 2. Russo et al. Diabetes Metab Syndr Obes 2013;6:161–70; 3. SmPC: glimepiride 2 mg

tablets; 4. Product monograph, Amaryl, September 2013; 5. SmPC: Actos tablets (pioglitazone); 6. SmPC: repaglinide 2 mg tablets and nateglinide 60/120 mg

tablets; 7. Yale. J Am Soc Nephrol 2005;16:S7–10

Renal function

Normal Mild RI Moderate Severe Terminal

GFR (mL/min) >90 60–90 <60 <30 <15

SGLT-2=sodium/glucose cotransporter 2

Is There Evidence of Any Safety Differences Among

DPP-4 inhibitors in Treatment of People with T2DM and

CKD?

• DPP-4 inhibitors have been shown to be associated with no further decline in

estimated glomerular filtration rate (eGFR) when treating patients with CKD

• Vildagliptin 50 mg efficacy is maintained when the frequency of dosing is reduced

from twice daily in patients with normal renal function to once daily in patients

with moderate or severe RI

• The dose adjustments thus require regular monitoring of renal function, which is

also good clinical practice because in these patients it is important to closely

monitor renal disease progression.

• Other than the specifications for modifications in dose or dose frequency, there

appears to be no difference between each DPP-4 inhibitor with respect to their

safety and tolerability in patients with T2DM and CKD

• Study in which vildagliptin was dosed at either 50 mg once or twice daily in

patients with ESRD, both dosing regimens were well tolerated, with no clinically

important differences noted between doses with respect to adverse events. Thus,

any concern that accumulation of vildagliptin (or its renally excreted metabolites)

results in an increase in renal or other toxicities is not supported by data.

Evans, et al, Diabetes Ther (2015) 6:1–5

Vildagliptin data in renal impairment

UACR=urinary albumin-to-creatinine ratio ; RI = renal impairment

The prescribing information may vary from country to country. Before prescribing, please refer to your local country’s full prescribing information for

locally approved indications and full details.. In general, no dose adjustment is required for vildagliptin in patients with mild renal impairment (creatinine

clearance ≥ 50 ml/min). In patients with moderate or severe renal impairment or with end-stage renal disease (ESRD), the recommended dose of

vildagliptin is 50 mg once daily. There is limited experience in patients with ESRD on haemodialysis and hence should be used with caution in these

patients

1. Tani S et al, Am J Cardiovasc Drugs 2013;13:443–450; 2. Banerji et al. Diabetes Res Clin Pract. 2010;90:182-90; 3. Novartis data on file;

4. Lukashevich et al. Diabetes Obes Metab 2011;13:947–54; 5. Kothny et al. Diabetes Obes Metab 2012;14:1032–9;

6. Lukashevich et al. Vasc Health Risk Manag 2013; 9:21–8; 7. Ito et al. Diabetes Ther 2013;4:321–9;

8. Haidinger et al. Am J Transplant 2014;14:115–23; 9. He et al. J Clin Pharmacol Ther 2013; 51:693–703

Mild Moderate Severe

Pharmacokinetic data in mild, moderate and severe RI9

UACR at 8

weeks1

Mild RI at 24

weeks3

Add-on to MET in

mild RI at 12 weeks2

Moderate RI

at 24 weeks4

Moderate RI

at 52 weeks5

Elderly

≥75 years

at 24 weeks3

Severe RI

at 24 weeks4

Add-on to

insulin at 24

weeks6

Severe RI

at 52 weeks5

Efficacious and well tolerated in T2DM patients with

MILD Renal Impairment As well as patients with normal GFR

Vildagliptin 100 mg daily as monotheraphy

effectively lowers HbA1c

Meta analysis, ≥ 12-week duration, baseline HbA1c ≥

8.6%

Vildagliptin is well tolerated in patients

with normal GFR and mild Renal Impairment

Meta analysis, ≥ 12-week duration

Reference

Thuren T, et al, EASD 2008. Poster, 88

52

Active Comparator: metformin, pioglitazon, rosiglitazon

-1.1%

-1.0%

Stages of chronic kidney disease / guideline

Chronic kidney disease is defined as either kidney damage or GFR <60 mL/min/1.73m2 for

≥3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, including

abnormalities in blood or urine tests or imaging studies.

Stage DescriptionCurrently accepted values

GFR (mL/min/1.73m2)^

1 Kidney damage with normal or ↑ GFR ≥90

2 Kidney damage with mild ↓ GFR 60–89

3 Moderate ↓ GFR 30–59

4 Severe ↓ GFR 15–29

5 Kidney failure <15 (or dialysis)

^National Kidney Foundation. KDOQI, Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification.

CKD, chronic kidney disease; GFR, glomerular filtration rate

Am J Kidney Dis 39:S1-S000, 2002 (suppl 1).

53

Pharmacokinetic parameters of Vildagliptin

in Various Renal Condition

Adapted from He YL et al. Int J Clin Pharmacol Ther. 2013; 51:693–703.

ParameterHS

(n=46)

Mild RI

(n=16)

Controls

to mild RI

(n=16)

Moderate

RI

(n=16)

Controls to

moderate RI

(n=16)

Severe RI

(n=18)

Controls to

severe RI

(n=14)

Plasma

Cmax, ng/ml 251 (79) 326 (77) 245 (83) 343 (139) 258 (96) 361 (137) 253 (58)

tmax, h 1.5 (0.5, 3.0) 1.5 (0.5, 2.0) 1.5 (0.5, 3.0) 2.0 (0.5, 3.0) 1.5 (0.5, 3.0) 1.8 (1.0, 3.0) 1.5 (1.0, 2.0)

AUC0–24h, ng*h/ml 990 (237) 1323 (291) 954 (215) 1810 (688) 1038 (264) 2113 (1130) 980 (240)

t½, h 2.8 (2.1) 2.7 (1.2) 2.9 (2.2) 3.1 (1.0) 2.1 (0.6) 3.6 (1.3) 3.3 (2.9)

Data are mean (SD) unless specified otherwise.

Ae0-24h, amount of vildagliptin excreted in the urine during the interval of 0–24 hours, AUC0–24h, area under the plasma concentration time curve

from 0–24 hours, Cmax, maximum plasma concentration; CLR, renal clearance; CL/F, oral clearance; HS, healthy subjects; RI, renal imapirment;

t1/2, terminal elimination half-life; tmax, time to maximum plasma concentration. For tmax median (min, max) is presented.

Vildagliptin AUC increased on average 1.4, 1.7 and 2-fold in patients with mild, moderate and severe RI, respectively, compared with

normal healthy subjects.

AUC0–24h, ng*h/ml 990 (237) 1323 (291) 954 (215) 1810 (688) 1038 (264) 2113 (1130) 980 (240)

54

Conclusions

• The pharmacokinetic results from this study indicate that no dose adjustment for

vildagliptin is necessary in patients with mild RI (50 mg bid).

• In patients with moderate or severe RI, vildagliptin 50 mg qd is considered

appropriate and recommended.

bid, twice daily; qd, once daily; RI, renal impairment

He YL et al. Int J Clin Pharmacol Ther. 2013; 51:693–703.

55

Aim: To assess the effects of vildagliptin 50 mg qd in patients with advanced type 2 diabetes and

moderate or severe RI whose hyperglycemia was not adequately controlled with insulin alone or in

combination with an oral anti-diabetic agent at baseline.

Study design: This was a 24-week, multicenter, randomized, double-blind, parallel group, placebo-

controlled trial of vildagliptin in adult patients (age 18–85 years) with T2DM and moderate or severe RI

(eGFR by the MDRD formula ≥ 30 to <50 and <30 ml/min/1.73 m2, respectively).

Effecicay of Vildagliptin in MODERATE and

SEVERE Renal Disease

eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease; RI, renal impairment

Lukashevich V et al. Diabetes Obes Metab. 2011; 13:947–54.

Placebo + current therapy (N=226)

N=525

Vildagliptin 50 mg qd + current therapy (N=289)

Placebo run-in plus stable

dose of current therapy*

Period I Period II

24-week, double-blind treatment2 weeks

*Randomized patients must remain on their current anti-diabetic therapy (stable dose for at least 4 weeks prior to visit 1 or remain

untreated for the duration of the study if patient is not on anti-diabetic therapy at study entry (unless patient meets criteria for rescue

medication). Total of 525 includes 10 patients with mild RI revealed during re-classification by MDRD method: 7 were randomized to

vildagliptin, 3 to placebo, but data from mild RI patients are not reported.

Study design figure was prepared based on the data provided in the article

56

Patient demographics and background

characteristics were comparable at baseline

Mean ± SD or n (%)

Moderate RI patients Severe RI patients*

Vildagliptin 50 mg qd

(n=165)

Placebo

(n=129)


(n=124)

Placebo

(n=97)

Age (years) 67.7 ± 8.8 69.7 ± 7.3 64.1 ± 9.2 64.5 ± 10.8

eGFR [MDRD (ml/min/1.732)] 39.3 ± 6.0 40.3 ± 5.8 21.9 ± 5.7 20.9 ± 6.4

Age group, n (%)

≥65 y 114 (69.1) 102 (79.1) 64 (51.6) 48 (49.5)

≥75 y 36 (21.8) 35 (27.1) 14 (11.3) 20 (20.6)

Gender, male 96 (58.2) 80 (62.0) 65 (52.4) 53 (54.6)

Race, n (%)

Europid 116 (70.3) 94 (72.9) 61 (49.2) 49 (50.4)

Asian (Indian subcontinent) 24 (14.5) 15 (11.6) 22 (17.7) 21 (21.6)

Asian (non-Indian subcontinent) 0 (0.0) 0 (0.0) 2 (1.6) 0 (0.0)

Hispanic or Latino 21 (12.7) 16 (12.4) 36 (29.0) 26 (26.8)

Black 2 (1.2) 0 (0.0) 2 (1.6) 0 (0.0)

Other 2 (1.2) 4 (3.1) 1 (0.8) 1 (1.0)

Mean BMI (kg/m2) 30.2 ± 5.1 30.0 ± 5.0 30.2 ± 5.6 29.5 ± 5.0

Mean HbA1c (%) 7.8 ± 1.0 7.8 ± 0.9 7.7 ± 1.0 7.7 ± 1.0

≤8.0%, n (%) 98 (59.4) 80 (62.0) 87 (70.2) 66 (68.0)

Mean FPG (mmol/l) 9.1 ± 3.3 8.4 ± 2.7 8.1 ± 2.8 8.6 ± 3.4

Mean duration of T2DM (years) 15.0 ± 9.1 15.2 ± 10.0 17.3 ± 8.6 19.0 ± 9.6

Randomized set. Demography and duration of T2DM was collected on day of screening (week -2). Baseline HbA1c and FPG were collected on

Day 1 or the sample obtained at an earlier visit closest to Day 1, if Day 1 measurement was missing. *Two patients in each group had end stage

renal disease. BMI, body mass index; GFR, glomerular filtration rate; T2DM, type 2 diabetes mellitus; RI, renal impairment


57

Concomitant anti-diabetic therapy at baseline

were comparable between treatment groups

Moderate RI patients Severe RI patients*


(n=165)

Placebo

(n=129)


(n=124)

Placebo

(n=97)

Current anti-diabetic therapy, n (%)

None 6 (3.6) 5 (3.9) 5 (4.0) 1 (1.0)

Any 159 (96.4) 124 (96.1) 119 (96.0) 96 (99.0)

Insulin monotherapy 95 (57.6) 68 (52.7) 87 (70.2) 66 (68.0)

Insulin & OAD 18 (10.9) 20 (15.5) 13 (10.5) 12 (12.4)

OAD monotherapy 39 (23.6) 33 (25.6) 18 (14.5) 14 (14.4)

OAD combination therapy 7 (4.2) 3 (2.3) 1 (0.8) 4 (4.1)

*Two patients in each group had end stage renal disease

OAD, oral anti-diabetic drug


58

Vildagliptin sustained HbA1c reduction over 24

weeks in both moderate and severe RI patients

RI, renal impairment


Time-course of mean HbA1c (±SE) during rescue-free treatment in patients with moderate or severe RI

6.7

6.9

7.1

7.3

7.5

7.7

7.9

8.1

-4 0 4 8 12 16 20 24M

ea

n H

bA

1c

(%

)

Weeks of Treatment


Placebo

Moderate RI patients Severe RI patients

6.7

6.9

7.1

7.3

7.5

7.7

7.9

8.1

-4 0 4 8 12 16 20 24

Me

an

Hb

A1

c (

%)

Weeks of Treatment

00

Moderate RI patients

59

Overall safety and tolerability of vildagliptin was similar to

placebo in moderate/severe RI patient

Event category, n (%)


Vildagliptin 50 mg

qd (n=163)

Placebo

(n=129)

Vildagliptin 50 mg

qd (n=124)

Placebo

(n=97)

Any adverse event 110 (67.5) 94 (72.9) 90 (72.6) 72 (74.2)

Any serious adverse event 15 (9.2) 11 (8.5) 23 (18.5) 20 (20.6)

Any adverse event leading to

discontinuation4 (2.5) 7 (5.4) 11 (8.9) 6 (6.2)

Deaths* 1 (0.6) 1 (0.8) 3 (2.4) 4 (4.1)

*None of the deaths were suspected to be related to study drug. A patient with multiple occurrences of an adverse event under one treatment

is counted only once in the adverse event category for that treatment. RI, renal impairment


60

Incidences of common AEs (≥5%) were similar between

groups in moderate / severe RI patients

Preferred term, n (%)

(Common AEs ≥5% in any group)



(n=163)

Placebo

(n=129)


(n=124)

Placebo

(n=97)

Asthenia 9 (5.5) 6 (4.7) 7 (5.6) 6 (6.2)

Back pain 3 (1.8) 5 (3.9) 1 (0.8) 5 (5.2)

Blood glucose decreased 13 (8.0) 4 (3.1) 7 (5.6) 3 (3.1)

Diarrhea 8 (4.9) 5 (3.9) 11 (8.9) 8 (8.2)

Dizziness 14 (8.6) 14 (10.9) 12 (9.7) 10 (10.3)

Dyspnea 2 (1.2) 2 (1.6) 4 (3.2) 5 (5.2)

Fatigue 6 (3.7) 3 (2.3) 7 (5.6) 2 (2.1)

Hyperhidrosis 12 (7.4) 12 (9.3) 13 (10.5) 8 (8.2)

Hyperkalemia 4 (2.5) 4 (3.1) 13 (10.5) 4 (4.1)

Hypertension 3 (1.8) 3 (2.3) 6 (4.8) 9 (9.3)

Hyperuricemia 2 (1.2) 3 (2.3) 3 (2.4) 6 (6.2)

Hypoglycaemia 28 (17.2) 15 (11.6) 19 (15.3) 12 (12.4)

Influenza 4 (2.5) 2 (1.6) 8 (6.5) 1 (1.0)

Nasopharyngitis 9 (5.5) 13 (10.1) 4 (3.2) 5 (5.2)

Nausea 5 (3.1) 4 (3.1) 7 (5.6) 6 (6.2)

Edema, peripheral 18 (11.0) 13 (10.1) 21 (16.9) 18 (18.6)

Tremor 11 (6.7) 10 (7.8) 6 (4.8) 1 (1.0)

Urinary tract infection 5 (3.1) 5 (3.9) 6 (4.8) 5 (5.2)

Vomiting 0 (0.0) 4 (3.1) 7 (5.6) 4 (4.1)

A patient with multiple occurrences of an AE under one treatment is counted only once in the AE category for that treatment. Coded using MedDRA version 13.1.

AE, adverse event; RI, renal impairment


61

Incidence of Hypoglycemia in T2DM Patient with Moderate and severe RI receiving Vildagliptin

62Adapted from Lukasevich V., et al, Diabetes, Obesity and Metabolism 13: 947–954, 2011

15.3% 15.6%

1.6%

12.4%

18.8%

2.1%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

14.0%

16.0%

18.0%

20.0%

HE HE in elderly ≥ 65 years

SevereHypoglycemia

Incidence of Hypoglycemic Event in Severe RI

Vildagliptin 50 mg qd Placebo

The number of patients experiencing HE in moderate RI were 28 (17.2%) for vildagliptin and

15 (11.6%) for placebo. In the severe RI group, the number of patients experiencing HE was

19 (15.3%) for vildagliptin group and 12 (12.4%) for placebo.

RI = Renal Impairment, HE = Hypoglycemic Event

17.2%

11.5%

1.2%

11.6% 11.8%

1.6%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

14.0%

16.0%

18.0%

20.0%

HE HE in elderly ≥ 65 years old

Severe Hypoglycemia

Incidence of Hypoglycemic Event in Moderate RI


Vildagliptin is efficacious and well tolerated in

T2DM patients with MODERATE and SEVERE RI

-0.7

-0.9

-0.2-0.3

-1

-0.8

-0.6

-0.4

-0.2

0

Vildagliptin

Placebo

Effectively reduced HbA1c

24-week treatment

67.5

72.672.9 74.2

60

65

70

75

Vildagliptin

Placebo

Proven good tolerability24-week treatment

Any Serious Adverse Events (SAE’s) (%)

9.2

18.5

8.5

20.6

0

10

20

30

Vildagliptin

Placebo

Any Adverse Events (AE’s) (%)

Vildagliptin 50 mg qd, placebo qd

Moderate: eGFR ≥ 30 - < 50 ml/min/1.73 m2; severe Renal Impairment: eGFR < 30 ml/min/1.73 m2, RI = Renal Impairment

Adapted from Lukasevich V., et al, Diabetes, Obesity and Metabolism 13: 947–954, 2011 63

Moderate Severe

7.9% 7.8% 7.7% 7.7%Baseline

p<0.0001 vs. placebo

110 94 90 72

Moderate Severe

15 11 23 20

Moderate Severe

(n)

(n)

Conclusions

• Treatment with vildagliptin (50 mg qd) added to ongoing anti-diabetic therapy was

well-tolerated, with a safety profile comparable to placebo.

• In patients with moderate or severe RI, vildagliptin added to current therapy elicited

robust improvements in glycemic control with HbA1c reductions of ∼0.7% (from

baseline 7.9% in moderate RI) and ∼0.9% (from baseline of 7.7% in severe RI).

• It may be concluded that vildagliptin treatment is well-tolerated and effective in

patients with T2DM and moderate or severe RI and did not cause deterioration of

renal function.

RI, renal impairment; T2DM, type 2 diabetes mellitus


64

Long-term Safety and Efficacy in Moderate

and Severe Renal Disease

● Aim: To assess long-term safety and efficacy of vildagliptin 50 mg qd in patients with T2DM and

moderate or severe RI.

● Design: This was a long-term extension of a randomized, double-blind, parallel-group, placebo-

controlled 24-week clinical trial. Adult patients (age 18–85 years) having T2DM and moderate or

severe RI (eGFR by the MDRD formula ≥ 30 to <50 mL/min/1.73 m2 and <30 mL/min/1.73 m2,

respectively) were included in this study.

N=515

Placebo + current therapy

(N=226)

Placebo + current therapy

(N=153)

Vildagliptin 50 mg qd +

current therapy (N=216)

Placebo run-in plus

stable dose of

current therapy*

2 weeks 24-week, double-blind treatment 28-week, double-blind treatment

Vildagliptin 50 mg qd +

current therapy (N=289)

Core Period I Core Period II Extension

Patients remained on their current anti-diabetic therapy or remained untreated for the duration of the study if patient was

not on anti-diabetic therapy at study entry (unless patient met criteria for rescue medication). Study design figure was

prepared based on the data provided in the article.

eGFR, estimated glomerular filtration rate; qd, once daily; RI, renal impairment; T2DM, type 2 diabetes mellitus

Kothny W et al. Diabetes Obes Metab. 2012; 14:1032–9.

65

Time-course of mean HbA1c (SE) during rescue-free treatment

in patients with moderate or severe RI

Vildagliptin maintained HbA1c reduction over 52 weeks in both

moderate and severe RI patients

6.8

7.2

7.6

8.0

8.4

-2 BL 4 8 12 16 20 24 40 52 EP

Me

an

Hb

A1

c (

%)

Time (week)

6.4

6.8

7.2

7.6

8.0

-2 BL 4 8 12 16 20 24 40 52 EP

Me

an

Hb

A1

c (

%)

Time (week)



Placebo

Absolute mean change in HbA1c (%) from baseline to rescue-censored extension endpoint. Extension full analysis set. BL, baseline; EP, end point; RI, renal

impairment; SE, standard error


66

Vildagliptin Has Comparable Safety Profile Compared to Placebo

Over 52 Weeks in T2DM patients with Moderate and Severe RI

Overall Summary

Moderate Severe

Vildagliptin

50 mg qd

(N=122) n (%)

Placebo

(N=89) n (%)

Vildagliptin

50 mg qd

(N=94) n (%)

Placebo

(N=64) n (%)

Any AE 103 (84.4) 76 (85.4) 80 (85.1) 56 (87.5)

Any suspected

drug-related AE31 (25.4) 22 (24.7) 24 (25.5) 18 (28.1)

Any SAE 26 (21.3) 17 (19.1) 23 (24.5) 16 (25.0)

Any AE leading to

discontinuation6 (4.9) 5 (5.6) 9 (9.6) 4 (6.3)

67Kothny et al, Diabetes obes Metab 14: 1032-1039, 2012

Incidence of Hypoglycemia in T2DM Patient with

Moderate and severe RI receiving Vildagliptin

There was a slightly higher incidence of mild hypoglycaemia in patients with moderate RI treated with

vildagliptin than with placebo.

Rates of hypoglycaemia in patients with severe RI were similar across treatment groups.

Very few events of severe hypoglycaemia, and more with placebo than vildagliptin.

incidence of hypoglycaemia with vildagliptin in the present study (∼26% in patients with moderate RI and

∼18% in those with severe RI) appears to be lower than that expected (≥50%) in patients with

longstanding T2DM and low baseline A1C (∼7.6%).

68

26.2%

18.5%

1.6%

16.9% 17.1%

3.4%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%


SevereHypoglycemia

Incidence of Hypoglycemic Event in Moderate RI


18.1%15.6%

1.1%

17.2%

26.5%

4.7%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%


Severe Hypoglycemia

Incidence of Hypoglycemic Event in Severe RI


Adapted from Kothny et al, Diabetes obes Metab 14: 1032-1039, 2012

The number of moderate RI patients experiencing HE in vildagliptin group is 32 (26.2%) , in placebo group 15 (16.9%) , with 2 patients

(1.6%) in vildagliptin group has severe Hypoglycemia and 3 (3.4%) in placebo group. In the severe RI patient, there are total of 17

(18.1%) patient experiencing HE in vildagliptin group and 11 (17.2%) patients in placebo group.

HE = Hypoglycemic event ; RI = Renal Impairment

Vildagliptin maintained HbA1c reduction over 52 weeks in

T2DM patients with moderate and severe RI

85.4

19.1

84.4

21.3

0

20

40

60

80

100

Placebo

Vildagliptin 50mg OD

Safety Data In Moderate RI (%)

Safety Data In Severe RI (%)

87.5

25

85.1

24.5

0

50

100

Placebo

Vildagliptin 50mg OD

-0.6

-0.2

-0.4

-0.8

-0.1

-0.7

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Adjusted mean HbA1c change from baseline in 52 weeks in patients with

moderate or severe Renal Impairment

Moderate

Severe

In patients with T2DM and moderate or severe Renal

Impairment, vildagliptin added to ongoing antidiabetic therapy

had a safety profile similar to placebo during 1-year

observation. Furthermore, relative to placebo, a clinically

significant decrease in A1C was maintained throughout 1-year

treatment with vildagliptin.

RI = Renal Impairment

Adapted from Kothny et al, Diabetes obes Metab 14: 1032-1039, 2012 69

103 76 26 17

Any AE Any SAE

(n)

(n)80 56 23 16

Any AE Any SAE

Vildagliptin Placebo Between Treatment

Difference7.8 7.7 7.7 7.5

Baseline

*p=0.005 vs placebo; **p<0.0001 vs placebo

*

**

Conclusions

This is the largest long-term study with a DPP-4 inhibitor in patients with T2DM and

moderate or severe RI.

Vildagliptin maintained the robust efficacy throughout 52 weeks with HbA1c

reductions of ~0.6% and ~0.8% from baselines of 7.8% and 7.7% in moderate and

severe RI, respectively.

Safety profile of vildagliptin 50 mg qd was similar to placebo when added to anti-

diabetic therapy during 1-year observation.

The incidence of hypoglycemia with vildagliptin (26% in moderate and 19% severe RI

groups) was lower than expected in patients with longstanding T2DM receiving

insulin ± OADs and achieving significantly tighter glycemic control at low baseline

HbA1c (~7.6%). The risk of severe hypoglycemia was very low.

These data support the long-term safety and efficacy of vildagliptin 50 mg qd added

to ongoing anti-diabetic therapy in patients with moderate or severe RI.

OAD, oral anti-diabetes drug; qd, once daily; RI, renal impairment; T2DM, type 2 diabetes mellitus


70

Thank You

71

OPTIMA study: Vildagliptin vs. SitagliptinVildagliptin provide 24-hours better glucose fluctuation control and give

longer blood glucose ideal range significantly than Sitagliptin

Guerci B et al. Diabetes Metab 2012;38:359-66

Achieving Treatment Outcome With DPP4i for Diabetic Patient "Efficacy Beyond Sugar Control”

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