DPP-4 Inhibitors

“Vildagliptin”

Between Guidelines and New

Evidence

Mesbah Said Kamel

MD

2

Diabetes in Egypt

1-http://www.who.int/diabetes/facts/world_figures/en/index2.html accessed 13-3- 2012 2-http://www.diabetesatlas.org/map cited 10-5-2011 3-The IDF Diabetes Atlas 5th Edition

4- IDF atlas 2012

In 2012: 7.5 million patients are diagnosed diabetic in Egypt

*

*

*

* Number of diabetic patients in millions

1 2 3

*

4

3

aHbA1c ≤6.5%.

HbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus.

Liebl A, et al. Diabetologia. 2002; 45: S23–S28.

• In the CODE study of a European cohort of over 7000 patients with

T2DM, ONLY 31% of patients had adequate glycaemic control

Pa

tie

nts

with

ad

eq

ua

te g

lyca

em

ic

co

ntr

ol (%

)

Approximately 70% of patients with T2DM do not

reach HbA1c goals

4

Impact of Uncontrolled Diabetes

p<0.001 age-adjusted death rates for linear trend.

Khaw K-T, et al. BMJ 2001; 322:1-6.

6

0

1

2

3

4

5

Re

lati

ve

ris

k O

f M

ort

ali

ty

HbA1C %

5 5.0-5.4 5.5-6.9 7

Diabetes Mellitus as Cardiovascular Disease Equivalent

Mortality risk is doubled with ≥7% HbA1c

The question now is not

whether to target

postprandial, fasting blood

sugar, or HbA1c but when,

how, and to what goals?

6

Legacy effect: early glycaemic control is key to

long-term reduction in complications

Bad legacy effect Achieving glycaemic control late in the disease, after a prolonged

period of poor control, does not improve long-term risk of

macrovascular complications2

Long-standing, preceding hyperglycaemia accounted for

the high rate of complications at baseline in VADT3

UKPDS=UK Prospective Diabetes Study; VADT=Veterans Affairs Diabetes Trial. 1Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589. 2Duckworth W, et al. N Engl J Med. 2009; 360: 129–139; 3Del Prato S. Diabetologia. 2009; 52: 1219–1226.

Good legacy effect Early, strict glycaemic control brings benefits,

reducing the long-term risk of microvascular and macrovascular

complications (UKPDS1)

Recent Guidelines

Recommend Patients Centered

Approach for Better Control

9

The General Goal is <7% in most patients

to reduce the

incidence of

microvascular disease

More stringent HbA1c targets might be

considered in selected patients (with short

disease duration, long life expectancy, no

significant CVD) if this can be achieved without

significant hypoglycemia or other adverse

effects of treatment

6.0– 6.5%

less stringent HbA1c goals are appropriate for

patients with a history of severe hypoglycemia,

limited life expectancy, advanced complications

especially CVD and extensive co morbid

conditions

7.5–8.0% or even

slightly higher

Individualized Goal

11

12

13 T2DM Antihyperglycemic Therapy: General Recommendations

Diabetes Care 2012;35:1364–1379

Diabetologia 2012;55:1577–

1596

Individualized Treatment

14

Current Oral Therapies do not Address

Islet Cell Dysfunction

Islet Dysfunction

Inadequate

glucagon

suppression

(-cell

dysfunction)

Progressive

decline of β-cell

function

Insufficient

Insulin secretion

(β-cell

dysfunction)

Sulfonylureas

Glinides

TZDs

Metformin

TZDs

Ins. Resistance

(Impaired insulin action)

TZD= Thiazolidinedione; T2DM= Type 2 Diabetes Mellitus

Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24-S40

15

Islet Cells are Targets for Incretin Hormones

GLP-1=Glucagon-Like Peptide-1

Adapted from Drucker D. Diabetes Care. 2003;26:2929-2940; Wang Q, et al. Diabetologia. 2004;47:478-487.

Incretin Response

Food

intake

α-Cell β-Cell

Islet

Incretin

16

HGO= Hepatic Glucose Output

Adapted from Unger RH. Metabolism. 1974;23:581.

Insulin

Glucagon

IMPROVED

GLYCEMIC CONTROL

Incretin

Activity

Prolonged

Improved islet

function

DPP-4 Inhibitor

Insulin

Glucagon

HYPERGLYCEMIA Incretin

Response

Diminished

Further impaired

islet function

T2DM

Blocking DPP-4 can Improve Incretin

Activity and Correct the Insulin/Glucagon

Ratio in T2DM

17

Role of Vildagliptin in

Glycemic Management

19

Vildagliptin add-on to metformin:

study design and objective

Objective: to demonstrate superior HbA1c reduction with vildagliptin

+ metformin vs metformin monotherapy

Target population: T2DM on maximal dose of metformin;

HbA1c 7.5–11%

HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus.

*Patient number refers to primary intention-to-treat population.

Bosi E, et al. Diabetes Care. 2007; 30: 890–895.

n=130: Placebo + metformin

n=143: Vildagliptin 50 mg twice daily + metformin

n=143: Vildagliptin 50 mg once daily + metformin

24 weeks

Metformin >1500 mg

(monotherapy, stable dose)

4 weeks

N=416*

20

Vildagliptin produces clinically meaningful,

decreases in A1C & FPG as add-on therapy to metformin.

Placebo + metformin (n=130) Vildagliptin 50 mg twice daily + metformin (n=143)

Vildagliptin 50 mg once daily + metformin (n=143) FPG=fasting plasma glucose; HbA1c=hemoglobin A1c.

*P <0.001; **P=0.003 vs placebo; ***P <0.001 vs placebo.

Primary intention-to-treat population.

Bosi E, et al. Diabetes Care. 2007; 30: 890–895.

7.2

7.4

7.6

7.8

8.0

8.2

8.4

8.6

−4 0 4 8 12 16 20 24

Time (Weeks)

Mean

Hb

A1c (

%)

−0.7% vs placebo

−1.1% vs placebo

*

*

Duration: 24 weeks

Vildagliptin add-on

to metformin

Time (Weeks)

Mean

FP

G (

mm

ol/L

)

−4 0 4 8 12 16 20 24

8

9

10

11

−0.8 vs placebo

= - 30.6mg/dL

**

***

Duration: 24 weeks

Vildagliptin add-on

to metformin

Add-on Treatment to Metformin (2.1 g Mean Daily)

Reduction in HbA1c Reduction in FPG

−1.7 vs

placebo

21

Vildagliptin: Enhances β-cell Function and Improves

PPG when Metformin Alone is not Sufficient

AUC=area under the curve; ISR=insulin secretion rate;

met=metformin; PBO=placebo; PPG=postprandial glucose; vilda=vildagliptin.

*P ≤0.001 vs PBO.

Bosi E, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin.

Diabetes Care. 2007; 30: 890–895.

Vilda 50 mg twice daily + met (n=57)

β-cell Function

Placebo-adjusted

values

Ad

jus

ted

Me

an

Ch

an

ge

in

IS

R A

UC

/ G

luc

os

e A

UC

* *

5.2 5.7

0.0

2.0

4.0

6.0

8.0

10.0

Ad

jus

ted

Me

an

Ch

an

ge

in

2-h

PP

G (

mm

ol/

L)

*

*

-1.9

-2.3

-3.0

-2.0

-1.0

0.0

Vilda 50 mg once daily + met (n=53)

Duration: 24 weeks

Vilda add-on to met 2-h PPG

Placebo-adjusted

values

-41.4mg/dL

-34.2mg/dL

22

Initial combination of vildagliptin and metformin

in drug-naïve patients is effective across the hyperglycemia spectrum

~9.9%

96

Change from BL to EP

~8.7%

285

Overall*

>9%

High BL Open-label

Sub-study b

Me

an

Ch

an

ge

in

Hb

A1

c (

%)

≥10%

~10. 6%

35

~9.2%

201

>8%

Subgroups by BL HbA1ca

*P <0.001 vs BL; **100 mg once daily is not a recommended dosing regimen. Intent-to-treat population. aRaw mean change from baseline; bLS (least-square) mean change from baseline. BL=baseline; EP=end point; HbA1c=glycosylated hemoglobin; met=metformin; vilda=vildagliptin. Bosi E, et al. Diabetes Obes Metab. 2009; 11: 506–515;

a Data on file, Novartis Pharmaceuticals, LMF237A2302 and LMF237A2302S1.

Vilda 100 mg once daily** + met 2000

mg daily open-label sub-study (P

<0.001 vs BL)d

High-dose vilda + met (50/1000 mg twice daily)c

BL mean=

n =

>11%

~12. 1%

86

*

Duration: 24 weeks

Vilda + met vs mono

Overall

At

Goal

< 7%

Vildagliptin Metformin

Combination Vs

SU/ Metformin

24

HbA1c=haemoglobin A1c; OAD, oral antidiabetic drugs.

Jacob AN, et al. Diabetes Obes Metab. 2007; 9:386–393;

Kahn SE, et al. N Engl J Med. 2006; 355: 2427–2443;

Wright AD, et al. J Diabetes Complications. 2006; 20: 395–401.

Risks of Hypoglycaemia

Weight gain

and

hypoglycaemia

Body w

eig

ht

HbA1c

Pla

sm

a g

lucose

Decreasing HbA1c is associated with

increased risks of hypoglycaemia and

weight gain

25

Risk Difference of Hypoglycemia with Different

Glucose-lowering Agents for T2DM

CI=confidence interval; Glyb=glyburide; Met=metformin; repag=repaglinide; SU=sulfonylurea; TZD=thiazolidinediones.

Bolen S, et al. Ann Intern Med. 2007;147:386–399

Met vs Met + TZD

Weighted absolute risk difference

0.2 0.15 0.15 0.5 0

3 (1557)

5 (1495)

6 (2238)

8 (2026)

3 (1028)

5 (1921)

8 (1948)

9 (1987)

Studies

(participated)

0.00 (-0.01 to 0.01)

0.02 (-0.02 to 0.05)

0.03 (0.00 to 0.05)

0.04 (0.0 to 0.09)

0.08 (0.00 to 0.16)

0.09 (0.03 to 0.15)

0.11 (0.07 to 0.14)

0.14 (0.07 to 0.21)

Pooled effect

(95% CI)

SU vs repag

Glyb vs other SU

SU vs Met

SU + TZD vs SU

SU vs TZD

SU + Met vs SU

SU + Met vs Met

Drug 1 more harmful Drug 1 less harmful

26

Health and economical consequences of

hypoglycemia

26

Hypoglycemia

CV complications2

Weight gain by defensive eating3

Coma2

Car accident4

Hospitalization costs1

Dizzy turn unconsciousness2

Seizures2

Death6

Increased risk of dementia5

Quality of Life7

1. Jönsson L, et al. Cost of Hypoglycemia in Patients with Type 2 Diabetes in Sweden. Value In Health. 2006;9:193–198

2. Barnett AH. CMRO. 2010;26:1333–1342 3. Foley J & Jordan. J. Vasc Health Risk Manag. 2010;6:541–548 4. Canadian Diabetes Association’s Clinical Practice Guidelines for Diabetes and Private and Commercial Driving. CanJ Diabetes. 2003;27(2):128 –140. 5. Whitmer RA, et al. JAMA. 2009;301:15655–1572 6. Zammitt NN, et al. Diabetes Care. 2005;28:2948–2961 7. McEwan P, et al. Diabetes Obes Metab. 2010;12:431–436

27

Pathophysiological cardiovascular consequences

of hypoglycaemia

CRP=C-reactive protein; IL-6=interleukin 6; VEGF=vascular endothelial growth factor.

Desouza CV, et al. Diabetes Care. 2010; 33: 1389–1394.

VEGF IL-6 CRP

Neutrophil

activation

Platelet

activation

Factor VII

Blood coagulation

abnormalities

Sympathoadrenal response

Inflammation

Endothelial

dysfunction

Vasodilation

Heart rate variability

Rhythm abnormalities Haemodynamic changes

Adrenaline

Contractility

Oxygen consumption

Heart workload

HYPOGLYCAEMIA

28

*P=0.01; **P=0.02; ***P <0.01.

CL=confidence limit; HDL-C=high-density lipoprotein cholesterol.

Abraira C. Oral Presentation. Presented at the 68th Scientific Sessions of the American Diabetes Association; 6–10 June 2008, San Francisco, USA.

HR (Lower CL, Upper CL)

Risk of death

Lower Higher

Hypoglycemia

HbA1c

HDL-C

Age

Prior event

4.042 (1.449, 11.276)*

1.213 (1.038, 1.417)**

0.699 (0.536, 0.910)*

2.090 (1.518, 2.877)***

3.116 (1.744, 5.567)***

Hypoglycemia was a strong predictor of CV death

in VADT study

0 2 4 6 8 10 12

Hazard Ratio

Oral Pharmacologic Treatment of Type 2

Diabetes Mellitus:

(A clinical Practice Guideline From the American College of Physicians)

Most diabetes medications had similar efficacy

and reduced HbA1c levels by an average of 1%

The guidelines essentially state that clinicians should use metformin

as a first-line agent to treat diabetes when diet and exercise are

insufficient, but they do not differentiate between the efficacy of

other diabetes treatments.

adapted from Ann Intern Med. 2012;156:218-231.

The preference from drug to drug will be based on safety and

tolerability

30

Vildagliptin vs. glimepiride as add-on to

metformin: study design and objective

Study purpose: To demonstrate long-term efficacy and safety of add-on therapy with

vildagliptin vs glimepiride in patients with T2DM inadequately controlled with ongoing

metformin monotherapy

Interim analysis: To demonstrate non-inferiority of vildagliptin vs glimepiride at 1 year

Target population: Patients with T2DM inadequately controlled on stable metformin

monotherapy (metformin minimum dose 1500 mg/day; baseline HbA1c 6.5–8.5%)

n=1393: Glimepiride up to 6 mg once daily + metformin

n=1396: Vildagliptin 50 mg twice daily + metformin

4 weeks

Metformin

HbA1c=haemoglobin A1c; SU=sulfonylurea; T2DM=type 2 diabetes mellitus.* Randomised population.

Ferrannini E et al. Diabetes Obes Metab 2009; 11: 157–166.

1-year interim

analysis

N=2789*

104 weeks

31

In patients uncontrolled with metformin monotherapy vildagliptin is as

effective as glimepiride over 1 year with low incidence of hypoglycaemia

and no weight gain

Glimepiride up to 6 mg once daily + metformin

Vildagliptin 50 mg twice daily + metformin

Number of hypoglycaemic events

Patients with 1 hypos (%)

Number of severe hypoglycaemic

events c

Inc

ide

nc

e (

%)

1389 1383 1389 1383 1389 1383 n =

No

. o

f e

ve

nts

No

. o

f e

ve

nts

16.2

1.7 39

554

Duration: 52 weeks, add-on to metformin: vildagliptin vs glimepiride

Mean HbA1c reduction a

Incidence of hypoglycaemia b

BL=baseline; CI=confidence interval

NI=non-inferiority; aPer protocol population ; bSafety population. cGrade 2 or suspected grade 2 events.

*P <0.001; adjusted mean change from BL to Week 52,

between-treatment difference and P value were from

an ANCOVA model containing terms for treatment,

baseline and pooled centre.

Ferrannini E et al. Diab Obes Metab 2009; 11: 157–166.

Me

an

Hb

A1

c (

%)

0.0

6.5

6.7

6.9

7.1

7.3

7.5

- 8 - 4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

NI: 97.5%

CI (0.02, 0.16)

−0.4%

−0.5%

Time (weeks)

Ad

juste

d m

ean

ch

an

ge in

bo

dy w

eig

ht

(kg

) fr

om

BL

(BL mean ~88.8kg)

1117 n = 1071

Change in body weight a

*

32

Vildagliptin vs glimepiride as add on to metformin:

No severe hypoglycemic events at 2 years

Safety population; * any episode requiring the assistance of another party

Vilda= vildagliptin; Glim= glimepiride; Met= metformin

Matthews DR et al Diab Obes Metab. 2010; 12:780-789

Glim up to 6 mg qd + Met (n=1546)

Vilda 50 mg bid + Met (n=1553)

Number of hypoglycemic

events

Number of Severe hypo

events*

Patients with one or more

hypoglycemic events (%)

Inc

ide

nc

e (

%)

Nu

mb

er

of

eve

nts

Nu

mb

er

of

eve

nts

This hypoglycemic profile was maintained in patients > 65 years

Discontinuation due to

hypoglycemia

0

Nu

mb

er

of

eve

nts

33

Vildaglipin improves alpha cell sensitivity in both

hyper and hypoglycemia

-cell Response to Hypoglycemia

(glucose clamp at 2.5 mmol/L)

Galvus (vildagliptin) 100 mg qd is not approved.

AUC=area under the curve; N=25 (completers population). *P=0.019; **P=0.039.

Ahrén B, et al. Poster 560-P. Presented at: 68th Scientific Sessions of the American Diabetes Association; June 6-10, 2008; San Francisco, CA; Thornberry NA, et al. Best Pract Res Clin Endocrinol Metab. 2009;23:479–486

Vildagliptin 100 mg once daily

Placebo

-cell Response to a Standard Meal

**

Ch

an

ge

in

Pla

sm

a

Glu

ca

go

n (

ng

/L)

0

10

20

30

40

50

60

+38%

Incre

men

tal G

lucag

on

AU

C0-6

0

(ng

/Lx

min

)

-41%

0

200

400

600

800

1000

1200

*

34

DPP-4 TZD MET AGI

MET

Dual therapy Dual therapy

TZD

Glinide or SU

MET +

GLP-1

or

DPP-4

AACE / ACE Diabetes Algorithm for Glycemic

Control: HbA1c Goal <6.5%*

Monotherapy

Triple therapy

MET +

MET +

Triple therapy

+

+ SU

+ TZD

Drug-naive Under treatment

Symptoms No symptoms

GLP-1 or DPP-4

TZD

Glinide or SU

GLP-1 or DPP-4

Colesevelam

AGI

MET

TZD

MET

+

+

+

HbA1c 6.5–7.5%** HbA1c 7.6–9.0%

+

Insulin + other agent(s) Insulin + other agent(s)

Insulin

+ other

agent(s)

Insulin

+ other

agent(s)

Robard HW, et al. Endocr Pract. 2009; 15: 540–559. *May not be appropriate for all patients; **For patients with diabetes and

HbA1c <6.5%, pharmacologic Rx may be considered.

GLP-1

or DPP-4

GLP-1 or

DPP-4

TZD

+ TZD

+ SU

GLP-1

or DPP-4

TZD

GLP-1

or DPP-4

GLP-1 or DPP-4

or TZD

Glinide or SU

Lifestyle modification

HbA1c >9.0%

Vilar, et al Arq Bras Endocrinol Metab. 2011;55(4):260-5

36

Addition of Vildagliptin 50 mg twice daily to T2DM Patients

nonresponsive to Combination Metformin+SU :

Study Design :

Uncontrolled Type 2 Diabetes Mellitus patients with mean HbA1c of

9.30 ± 1.38 .

Vildagliptin (50 mg bid) was prescribed for at least 6 months to

patients whose combination therapy with Metformin (1,700-2,550

mg/day) and a sulphonylurea − either gliclazide MR (30-90 mg/day),

glibenclamide (10-20 mg/day) or glimepiride (4 mg/day) − was not

able to maintain HbA1c levels < 7% .

Patients who achieved HbA1c levels < 7% after the addition of

Vildagliptin were labeled responsive, whereas those who did not

were considered nonresponsive.

Vilar, et al Arq Bras Endocrinol Metab. 2011;55(4):260-5

37

A statistically significant reduction in FPG (-45mg/dL) and

HbA1c(-1.6%) levels after the addition of Vildagliptin

Vilar, et al Arq Bras Endocrinol Metab. 2011;55(4):260-5

Results of patients achieved HbA1c levels

< 7%

-2.21 % -63mg/dL

Overall Reduction

38

T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care 2012;35:1364–1379

Diabetologia 2012;55:1577–

1596

Vildagliptin added to once or twice daily

insulin regimens improves glycemic control

without

increasing risk of hypoglycemia and weight

gain in patients with type 2 diabetes

40

Study Design

Patients with T2DM, HbA1c of ≥7.5% and ≤11.0%, fasting plasma glucose

(receiving a stable dose (≤1 U/kg/day) of basal long-acting, intermediate-

acting or pre-mixed insulin by daily injection(s), with (60%)or without (40%)

stable metformin treatment (≥1500 mg daily), for at least 12 weeks were

randomised in a 1:1 ratio to receive either vildagliptin 50 mg bid or placebo.

W. Kothny. Poster 857. Presented at the 48th European Association for the Study of Diabetes, 2012, 1-5th Oct, Berlin, Germany

41

Baseline Demographic

• There were no clinically relevant changes in insulin dose at study

end (–1.10 U/day and –0.19 U/day in the vildagliptin and placebo

groups, respectively).

W. Kothny. Poster 857. Presented at the 48th European Association for the Study of Diabetes, 2012, 1-5th Oct, Berlin, Germany

42

Results: Statistically significant sustained reduction

in HbA1c of -0.7% vs placebo after 24 weeks

W. Kothny. Poster 857. Presented at the 48th European Association for the Study of Diabetes, 2012, 1-5th Oct, Berlin, Germany

Vildagliptin is well

studied as add on to

insulin

Fonseca V et al. Vildagliptin Plus Insulin in T2DM … Horm Metab Res 2008 ; 40: 427 – 430

44

-0.5

-0.7

-0.2

-0.1

-0.8

-0.6

-0.4

-0.2

0.0

Vildagliptin Add-on to Insulin: Significant Reduction

in HbA1c and Fewer Hypoglycemic Events

>65 Years Mean BL = 8.4% Overall Mean BL = 8.4%

Ch

an

ge

in

Hb

A1c

(%

)

Add-on Treatment to Insulin

140

**

149 42 41 n =

*

Duration: 24 weeks

Add-on to insulin:

vilda vs PBO

PBO + insulin

Vilda 50 mg twice daily

+ insulin

PBO=placebo; vilda=vildagliptin; *P <0.001; **P <0.05 between groups.

Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155.

No. of Hypoglycemic Events No. of Severe Hypoglycemic Events

0

40

80

120

160

200

0

2

4

6

8

10 N

o. o

f S

eve

re E

ve

nts

113

185

0

6

*

**

No

. o

f E

ve

nts

45 Ved P, Shah S, Indian J Endocrinol Metab. 2012 Mar;16 Suppl 1

Significant Decrease in Hba1c and Insulin Dose When

Vildagliptin Is Added to Insulin

46

Vildagliptin is the only DPP-4i Shows

Comparable Efficacy to GLP-1As

Of 362 potential RCTs (≥12 weeks’ duration in T2DM), 80 were eligible for inclusion*

Mean baseline HbA1c ranged from 7.4% to 10.3% (GLP-1RA studies) and 7.2% to 9.3% (DPP-4

inhibitor studies)

The highest maintenance doses† of GLP-1RAs and DPP-4 inhibitors evaluated were associated

with changes from baseline in mean HbA1c of –1.1% to –1.6% and 0.6% to –1.1%, respectively

From Aroda VR, et al. Clin Ther 2012;34:1247–1258

*The majority of studies (85%) included ≥90 patients per treatment arm; †approved or tested: exenatide (10 µg bid), exenatide (2 mg qw),

liraglutide (1.8 mg qd), alogliptin (25 mg qd), linagliptin (5 mg qd), saxagliptin (5 mg qd), sitagliptin (100 mg qd), vildagliptin (50 mg bid)

GLP1-RA=GLP-1 receptor agonists; RCTs=randomized controlled trials

Exenatide BID

Exenatide QW

Liraglutide

Alogliptin

Linagliptin

Saxagliptin

Sitagliptin

Vildagliptin

Mean HbA1c difference (95% CI)

–1.10 (–1.22 to –0.99)

–1.59 (–1.70 to –1.48)

–1.27 (–1.41 to –1.13)

–0.69 (–0.85 to –0.84)

–0.60 (–0.75 to –0.46)

–0.68 (–0.78 to –0.57)

–0.67 (–0.75 to –0.60)

–1.06 (–1.48 to –0.64)

–2.0 –1.5 –1.0 –0.5

HbA1c change (%)

Mean FPG difference (95% CI)

–1.16 (–1.35 to –0.97)

–2.12 (–2.28 to –1.96)

–1.82 (–2.07 to –1.57)

–0.97 (–1.27 to –0.67)

–1.04 (–0.59 to –0.49)

–0.73 (–0.95 to –0.50)

–0.87 (–0.98 to –0.77)

–1.57 (–2.23 to –0.90)

–2.5 –2.0 –1.5 –1.0 –0.5

FPG change (mmol/L)

47

Vildagliptin treatment improves insulin sensitivity

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Duration: 6 weeks

Vildagliptin vs

placebo

Glu

co

se

Rd

(m

g/k

g•m

in)

Placebo (n=16)

Vildagliptin 50 mg twice daily (n=16)

Insulin infusion 80 mU/m2•min

Mean Rd difference=0.7 mg/kg•min

Rd=rate of disappearance.

*P <0.05.

Azuma K, et al. J Clin Endocrinol Metab. 2008; 93: 459–464.

* 6.1

5.4

Hyperinsulinemic Euglycemic Clamp

48

Reduced glucose toxicity: which is true for all drugs that

reduce FPG

Reduced glucagon during meals: increases

insulin/glucagon ratio in the liver which is true for all GLP-1

based therapies

Reduced lipo-toxicity as determined by improved insulin

mediated glucose oxidation in muscle

Due to reduced stored TG in muscle & liver

Due to decreased fasting lipolysis in fat cells which is

also true for TZDs

Improvement of inflammatory markers

Increase GLUT4 protein expression

Vildagliptin is associated

with reduced insulin resistance Due to

Ahrén B, Schweizer A, Dejager S, Villhauer EB , Dunning BE, Foley JE. Mechanisms of Action of DPP-4 Inhibitors in Humans. Diabetes Obesity &

Metabolism, 13: 775–783, 2011.

49

Rizzo et al 2012 Conclusions

• Nitrotyrosine levels correlated with MAGE (p<0.001) and PPG

(p=0.004)

• MAGE and PPG levels correlated with fasting plasma IL-6, IL-

18,TNFα, and inflammation score (p<0.001*)

• Activation of oxidative stress and increased activity of the innate

immune system can be reduced by the control of acute glucose

swings over a daily period in type 2 diabetics

• Despite similar plasma fasting hyperglycemia, HbA1c and

postprandial glucose, vildagliptin was associated with a greater

amelioration of MAGE and reduction of nitrotyrosine and

proinflammatory cytokines

Rizzo, et al Diabetes Care. 2012 Oct;35(10):2076-82.

50

Greater reduction of MAGE with Vildagliptin

treated patients within 3 months

P=NS vs BL P=,0.001

M. ROSARIA et al Diabetes Care. 2012 : 35(10):2076-82.

BL: Baseline

MAGE=Mean Amplitude of Glycemic Excursion

39%

51

Vildagliptin: Significantly reduces Inflammatory mediators,

Oxidative stress compared with other DPP-4 inhibitors

Pro-inflammatory cytokines

IL-6 (pg/ml)

Oxidative stress Nitrotyrosine µmol/L

*p<0.001 vs baseline

*p < 0.01 *p < 0.01

Vildagliptin

Sitagliptin Rizzo, et al Diabetes Care. 2012 Oct;35(10):2076-82.

¥ p<0.001 vs sitagliptin

¥ ¥

BL: 0.43 BL: 0.42 BL: 2.47

52

Management challenges can lead to cautious

prescribing in the elderly

1. Market research, data on file, Novartis.

2. schweizer A, et al. Diabetes Obes Metab. 2011; 13: 55–64

Hypoglycaemia

Other factors

Glycaemic targets

Ma

nag

em

en

t ch

alle

ng

es

Frequently and marked unawareness of

hypoglycemia in older patients, leading to more

frequent and severe episodes. 2

The presence of numerous comorbidities

and a high prevalence of polypharmacy, and

increased risk for drug–drug interactions.

And very limited availability of clinical trial data,

especially in the very elderly subgroup 2

There is a difficult balance to strike between

HbA1c levels and safety.1

53 53

54

Vildagliptin: very elderly patients from

pooled analysis

Pooled safety and efficacy analysis of all randomised, double-blind

studies that:

• Dosed vildagliptin 50 mg twice daily

• Included patients ≥75 years

• Duration ≥24 weeks

• 10 studies were included seven Mono-therapy and three add on , total

n=12,326

No. patients receiving vildagliptin

<75 years ≥75 years

Safety

population

5984 132

Monotherapy Add-on therapy Monotherapy Add-on therapy

Efficacy

population 2303 910 62 25

Vildagliptin is approved for 50 mg once or twice daily in combination with metformin or a TZD,

and vildagliptin 50 mg once daily in combination with a sulfonylurea.

Schweizer A, et al. Diabetes Obes Metab. 2011; 13: 55–64.

55

Vildagliptin Monotherapy in Patients ≥ 75 years: Efficacious Without Hypoglycemia

BL

< 75 years

8.7

≥ 75 years

8.3

-2

-1

0

Mean

ch

an

ge f

rom

BL

(%

)

HbA1c #

* *

≥ 75 years < 75 years

Any

events 0.0 % 0.3 %

Severe

events 0.0 % 0.0 %

Hypoglycemic events ##

#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 Diabetes Obes Metab. 2011; 13: 55–64.

-2

-1

0

Mean

ch

an

ge f

rom

BL

(m

mo

l/L

)

FPG #

* *

BL

< 75 years

10.5

≥ 75 years

9.7

-0.9

-1.2 -1.1

-1.2

Vildagliptin 50 mg twice daily

< 75 years

≥ 75 years

20mg/dL 22mg/dL

56

≥50% of elderly patients achieving a target HbA1c

A1C ≤7% in monotherapy

Schweizer A et al Diabetes Obes Metab. 2011; 13: 55–64.

T2DM in older individuals is known to be associated with relative

hyperglucagonaemia and elevated postprandial glucose.

Vildagliptin treatment appears to address both these defects

57

-2

-1

0

Mean

ch

an

ge f

rom

BL

(kg

)

BL

< 75 years

86.1

≥ 75 years

74.9

Body weight #

* -0.9

-0.4

#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 Diabetes Obes Metab. 2011; 13: 55–64.

Vildagliptin did not induce weight gain in older or

younger patients as monotherapy

Vildagliptin did not induce weight gain

This modest weight loss may explain the positive trends seen for blood

pressure and the fasting lipid profile.

58

Cardiovascular endpoint studies with

Vildagliptin are ongoing, but so far a variety

of markers have been already used to

assess cardiovascular benefits of

Vildagliptin

This data may have off- label information

Endothelial Dysfunction

Blood Pressure

Lipid Profile

Vildagliptin Improves

Endothelium-Dependent

Vasodilatation in Type 2 Diabetes

Pleun C.M. van Poppel, Diabetes Care. 2011 Sep;34(9):2072-7.

Four weeks treatment with vildagliptin improves endothelium-dependent

vasodilatation in subjects with type 2 diabetes.

This observation might have favorable cardiovascular implications.

This data may have off- label information

60

Vildagliptin: Mean Change in BP in T2DM Patients

with SBP >140 mmHg and DBP >90 mmHg

-7.5

-9.1

-4.2

-5.3

-10.0

-5.0

0.0

DBP SBP

BL=baseline; BP=blood pressure; DBP=diastolic blood pressure; met=metformin;

SBP=systolic blood pressure; T2DM=type 2 diabetes; vilda=vildagliptin

*P <0.05 vs met.

Bosi E, et al. Presented at ADA Annual Meeting, June 22-26, 2007; Chicago, IL. Abstract 521-P.

Ch

an

ge

fro

m B

L (

mm

Hg

)

n= 89 53 150 84

BL= 94 94 149 150

*

*

Duration: 52 weeks

Vilda vs met

Met 1000 mg twice daily

Vilda 50 mg twice daily

This data may have off- label information

61 This data may have off- label information

Am J Cardiol 2012;110:826 – 833

Safety of Vildagliptin

63

In meta – analysis of 38 clinical trials include more

than 14.000 patients

Vildagliptin shows no increased risk of:

Pancreatitis-related AEs

ALT / AST or Bilirubin elevation

Renal AEs and SAEs in patients with normal renal

function and mild renal impairment patients

Infection and skin related adverse events

vs. comparators (placebo, insulin and other OAD)

Ligueros-Saylan et al. DIABETES, OBESITY AND METABOLISM Volume 12 No. 6 June 2010

64

The incidence of any hepatic or renal AE was also

lower with vildagliptin than with comparators

Age ≥ 75 years

N (%)

Age < 75 years

N (%)

Vilda 50 mg

bid

Comparators Vilda 50 mg

bid

Comparators

Hepatic safety

Any hepatic

AE 1 (0.8) 2 (1.2) 84 (1.4) 91 (1.5)

ALT or AST ≥

3× ULN

0 (0.0) 1 (0.6) 51 (0.9) 40 (0.6)

Renal Safety

AEs in mild

renal

impairment

51 (62.2) 67 (68.4) 1216 (70.7) 1278 (70.2)

AEs : adverse events, ULN: upper limit of normal, ALT: Alanine aminotranferease , AST : aspartate aminotransferase

Schweizer A et al Diabetes Obes Metab. 2011; 13: 55–64.

65

Today’s Conclusion

• Approximately 70% of patients with T2DM do not reach HbA1c

goals

• Achieving early glycemic control may generate a good legacy

effect. Patients initially received intensive therapy had a lower

incidence of any complication

• Vildagliptin produces extra clinically meaningful, decreases in A1C

-1.1%when added to metformin

• Vildagliptin is as effective as mostly common used SU with low risk

of hypoglycemia and without severe hypoglycemic events

• Vildagliptin improves beta and Alpa cell function

• Vildagliptin safety is well established in a meta-analysis of 38

clinical trials with about 14.000 patients and with very elderly

patients.

66

1. Glucagon suppression

2. GLP-1 raising

3. MAGE reduction

4. DPP-4 activity inhibition during 24 hrs

Differentiate Vildagliptin as Best-in-class efficacy

to support -1.1% A1C reduction message.

Vilda stronger efficacy in 4 dimension: