Galvus® (vildagliptin) Introduction

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• Before local implementation, you must ensure compliance with all applicable laws and regulations, including local industry codes, as well as local Novartis companies’ policies.

IMPACT slide content

1) The legacy effect: the importance of early control

1.1) How low should we go and when?: The legacy effect

Relative risk*

Microvascular complications 37%

Any diabetes-related endpoint 21%

Diabetes-related death 21%

All-cause mortality 14%

Fatal and non-fatal MI 14%

Glycaemic exposure and complications of diabetes: decrease in risk for 1% reduction in HbA1c

HbA1c=haemoglobin A1c; MI=myocardial infarction. *P <0.0001.Observational analysis of relationship between glycaemic exposure and complications of diabetes as estimated by decrease in risk per 1% reduction in HbA1c concentration.Stratton IM, et al. BMJ. 2000; 321: 405–412.

Incidence of microvascular complications increases with mean HbA1c with no evidence of a threshold

HbA1c=haemoglobin A1c.Incidence rates and 95% confidence intervals for myocardial infarction and microvascular complications by category of mean HbA1c concentration, adjusted for age, sex and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean duration of diabetes of 10 years.Stratton IM. et al. BMJ. 2000; 321: 405–412.

80

60

40

20

0

Ad

jus

ted

in

cid

ence

p

er 1

000

per

son

yea

rs (

%)

5 6 7 8 9 10 11

Mean HbA1c (%)

Myocardial infarction

Microvascular endpoints

VADT1

(n=1700)

ACCORD2

(n=10250)

ADVANCE3

(n=11140)

HbA1c – Std vs. Intensive 8.4 vs. 6.9 7.5 vs. 6.5 7.3 vs. 6.5

Primary outcome

Non-fatal MI

Non-fatal stroke

CVD death

Hospitalization for CHF

Revascularization

Non-fatal MI

Non-fatal stroke

CVD death

Non-fatal MI

Non-fatal stroke

CVD death

Hazard Ratio for primary outcome (95% CI)

0.87

(0.730 – 1.04)

0.90

(0.78 – 1.04)

0.94

(0.84 – 1.06)

Hazard Ratio for mortality (95% CI) 1.065 (0.801 – 1.416) 1.22 (1.01 – 1.46) 0.93 (0.83 – 1.06)

*P=0.041W. Duckworth et al presented at EASD Annual Meeting, 2008; 2The ACCORD Study Group NEJM 2008;358:2545;

3The ADVANCE Collaborative Group NEJM 2008,358:2560

*

Three studies assessed the association between intensive glycemic control and long-term CV complication

Reaching target in late stages of the disease does not reduce vascular complications

P=0.14.Primary outcome: first occurrence of a major cardiovascular event (a composite of myocardial infarction, stroke,death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronarydisease, and amputation for ischaemic gangrene).Duckworth W, et al. N Engl J Med. 2009; 360: 129–139.

1.0

0.8

0.6

0.4

0.2

0.0

0 2 4 6 8

Pro

bab

ilit

y o

f su

rviv

al

Years

Standard therapy

Intensive therapy

892899

774770

707693

No. at riskIntensiveStandard

639637

582570

510471

252240

6255

00

VADTPrimary outcome

HbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus. Adapted from Del Prato S. Diabetologia. 2009; 52: 1219–1226.

Achieving late glycaemic control may generate a bad legacy effect increasing risk of complications

• Hypothetical representation of the natural history of diabetic patients in the VADT study: initial poor glycaemic control increases risk of complications later in disease course

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Ideal HbA1c

Generation of a ‘bad glycaemic legacy’ drives

risk of complicationsHb

A1c

(%

)

Time since diagnosis (years)

Before entering VADT intensive treatment arm

After entering VADT intensive treatment arm

Early glucose control not only reduces complications but has a long-term legacy effect

Aggregate endpoint 1997 2007

Any diabetes-related endpoint RRR =P =

12%0.029

9%0.040

Microvascular disease RRR =P =

25%0.0099

24%0.001

MI RRR =P =

16%0.052

15%0.014

All-cause mortality RRR =P =

6%0.44

13%0.007

After median 8.5 years’ post-trial follow-up

MI=myocardial infarction; RRR=relative risk reduction; P=log rank.Diabetes Trials Unit. UKPDS Post Trial Monitoring. UKPDS 80 Slide Set. Available at: http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/. Accessed 12 September, 2008; Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589; UKPDS 33. Lancet. 1998; 352: 837–853.

Acheiving early glycaemic control may generate a good legacy effect

HbA1c=haemoglobin A1c.Diabetes Trials Unit. UKPDS Post Trial Monitoring. UKPDS 80 Slide Set. Available at: http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/. Accessed 12 September, 2008; Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589; UKPDS 33. Lancet. 1998; 352: 837–853.

Med

ian

Hb

A1c

(%

)

06

7

8

9

UKPDS 1998

ConventionalMetformin

Holman et al 2008

Legacy effect

1997

Difference in HbA1c was lost after first year but patients in the initial intensive arm

still had lower incidence of any complication:• 24% reduction in microvascular complications

• 15% reduction in MI• 13% reduction in all-cause mortality

2007

2011 ADA recommendations

• Lowering A1C < 7% has been shown to reduce microvascular and neuropathic complications and, if implemented early, is associated with long-term reduction in macrovascular disease

• Analyses from several randomized trials suggest a small but incremental benefit in microvascular outcomes with A1c values closer to normal, more stringent A1c goals for selected patients* are recommended, if this can be achieved without significant hypoglycemia or other adverse effects of treatment

• Less stringent A1c goals may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with longstanding diabetes in whom the general goal is difficult to attain

* Such patients might include those with short duration of diabetes, long life expectancy, and no significant CVD Executive summary: Standard of Medical care in diabete 2011. Diabetes Care 2011: 34 (1):S4-S7

2) Islet dysfunction

2.1) Both insulin resistance and islet dysfunction contribute to the onset of type 2 diabetes

Roles of insulin and glucagon in normal glucose homeostasis

*Insulin and glucagon secretion are also influenced by other nutrients, hormones, and neural input. Adapted from Berne RM, Levy MN, eds. Physiology. St. Louis, Mo: Mosby, Inc; 1998: 822–847.

+

Glucagon*

(plasma concentration)

–

–

Insulin*

(plasma concentration)

+Glucose(plasma

concentration)

Pancreatic islet dysfunction leads to hyperglycemia in T2DM

↑ Glucose

Fewer -cells

-cellsHypertrophy

Insufficient Insulin

Excessive Glucagon

–+

↓ Glucose Uptake

↑ HGO

+

HGO=hepatic glucose output.Adapted from Ohneda A, et al. J Clin Endocrinol Metab. 1978; 46: 504–510; Gomis R, et al. Diabetes Res Clin Pract. 1989; 6: 191–198.

CI=confidence interval; IGT=impaired glucose tolerance; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus.Adapted from Weyer C, et al. J Clin Invest. 1999; 104: 787–794.

Inadequate -cell compensation for insulin resistanceIn

sulin

sec

reti

on

Insulin resistance

T2DM

IGT

NGT

Nonprogressors (n=23)

Progressors (n=11)

NGTNGT

NGT

95% CI

Resistant Sensitive

250

200

150

100

50

Insulin secretion deteriorates with progressive impairment of glucose tolerance

IGT=impaired glucose tolerance; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus. Adapted from Stumvoll M, et al. Horm Metab Res. 2000; 32: 230–232.

Time (min)

Glu

cose

(m

g/d

L)

500

400

300

200

100

0

Time (min)

Insu

lin

(p

mo

l/L

)

N=58Plasma Glucose

Insulin Response

NGT IGT T2DM

Hyperglycemic Clamp

–20 0 20 40 60 80 100 120 140 –20 0 20 40 60 80 100 120 140

HOMA=homeostasis model assessment; T2DM=type 2 diabetes mellitus. *Tolbutamide, metformin.Adapted from Levy J, et al. Diabet Med. 1998; 15: 290–296.

N=432

2–4 5–7 8–10Diet only

Years in which progression necessitated adding oral hypoglycemic* or insulin

β-cell function declines while insulin sensitivity remains stable over course of T2DM—Belfast Diet Study

80

60

40

20

00 2 4 6

HO

MA

%B

Years from Diagnosis

β-cell Function

80

40

20

00 2 4 6

HO

MA

%S

Years from Diagnosis

Insulin Sensitivity

IFG=impaired fasting glucose; IGT=impaired glucose tolerance; NGT=normal glucose tolerance.Adapted from International Diabetes Center. Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center; 2000.

Prediabetes(IFG / IGT)

NGT Diabetes

Insulin resistance

Islet cell functionDiabetes onset

Treatment targets: deteriorating islet cell function in the setting of insulin resistance

Age,life style, environmental factors

2.2) α-cells sensitivity to glucose is impaired in T2DM, resulting in excessive glucagon secretion, leading to excess glucose production from the liver

Roles of insulin and glucagon in normal glucose homeostasis

*Insulin and glucagon secretion are also influenced by other nutrients, hormones, and neural input. Adapted from Berne RM, Levy MN, eds. Physiology. St. Louis, Mo: Mosby, Inc; 1998: 822–847.

+

Glucagon*

(plasma concentration)

–

–

Insulin*

(plasma concentration)

+Glucose(plasma

concentration)

Pancreatic islet dysfunction leads to hyperglycemia in T2DM

↑ Glucose

Fewer -cells

-cellsHypertrophy

Insufficient Insulin

Excessive Glucagon

–+

↓ Glucose Uptake

↑ HGO

+

HGO=hepatic glucose output.Adapted from Ohneda A, et al. J Clin Endocrinol Metab. 1978; 46: 504–510; Gomis R, et al. Diabetes Res Clin Pract. 1989; 6: 191–198.

Glucagon

25

30

35

40

45

pm

ol/L

Time (min)-60 0 60 120 180 240 300

NGTIGT

0

Insulin

200

400

600

pm

ol/L

Glucose

Glucose

50

100

150

200

250

mg

/dL

NGTIGT

NGTIGT

Elevated glucagon not only in T2DM but in IGT as well ( insulin / glucagon ratio)

IGT T2DM

CHO=carbohydrate; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus.Adapted from Müller WA, et al. N Engl J Med. 1970; 283: 109–115.

IGT=impaired glucose tolerance; NGT=normal glucose tolerance.Adapted from Mitrakou A, et al. N Engl J Med. 1992; 326: 22–29.

CHO meal

0

NGTT2DM

-60

Time (min)

0 60 120 180 240

Glucose100

200

300

400

mg

/dL

0

Insulin50

100

150

μU

/mL

NGTT2DM

Glucagon

75

100

125

150

pg

/mL

NGTT2DM

NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus.Adapted from Kelley D, et al. Metabolism. 1994; 43: 1549–1557.

Suppression of endogenous glucose production is impaired in T2DM

Time (min)

–30 –15 0 30 60 90 120 150 180 210 240 270 300

Meal

2

6

10

14

18

En

do

gen

ou

s G

luco

se(µ

mo

l/min

/kg

)

NGT (n=12)T2DM (n=18)

2.3) β-cells mass progressively declines, loses sensitivity to glucose leading to insufficient insulin secretion

Roles of insulin and glucagon in normal glucose homeostasis

*Insulin and glucagon secretion are also influenced by other nutrients, hormones, and neural input. Adapted from Berne RM, Levy MN, eds. Physiology. St. Louis, Mo: Mosby, Inc; 1998: 822–847.

+

Glucagon*

(plasma concentration)

–

–

Insulin*

(plasma concentration)

+Glucose(plasma

concentration)

Pancreatic islet dysfunction leads to hyperglycemia in T2DM

↑ Glucose

Fewer -cells

-cellsHypertrophy

Insufficient Insulin

Excessive Glucagon

–+

↓ Glucose Uptake

↑ HGO

+

HGO=hepatic glucose output.Adapted from Ohneda A, et al. J Clin Endocrinol Metab. 1978; 46: 504–510; Gomis R, et al. Diabetes Res Clin Pract. 1989; 6: 191–198.

CI=confidence interval; IGT=impaired glucose tolerance; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus.Adapted from Weyer C, et al. J Clin Invest. 1999; 104: 787–794.

Inadequate -cell compensation for insulin resistanceIn

sulin

sec

reti

on

Insulin resistance

T2DM

IGT

NGT

Nonprogressors (n=23)

Progressors (n=11)

NGTNGT

NGT

95% CI

Resistant Sensitive

Compensatory increase in β-cell insulin secretion fails during progression of T2DM

T2DM=type 2 diabetes mellitus.Protocol: 3H-3-glucose administered for 2 hours in control group (n=72) and 3 hours in diabetic group (n=77).Adapted from DeFronzo RA, et al. Metabolism. 1989; 38: 387–395.

Fas

tin

g P

lasm

a In

sulin

(µ

U/m

L)

Fasting Plasma Glucose (mg/dL)

N=149

0

25

20

15

10

5

060 100 140 180 220 260 260

β-cell function continues to decline regardless of intervention in T2DM

T2DM=type 2 diabetes mellitus.*β-cell function measured by homeostasis model assessment (HOMA).Adapted from UKPDS Group. Diabetes. 1995; 44: 1249–1258.

0

20

40

60

80

100

–5 –4 –3 –2 –1 0 1 2 3 4 5 6

Years since Diagnosis

β-c

ell F

un

ctio

n (

%)*

Progressive Loss of β-cell Function Occurs prior to Diagnosis

Metformin (n=159)

Diet (n=110)

Sulfonylurea (n=511)

Glucagon

25

30

35

40

45

pm

ol/L

Time (min)-60 0 60 120 180 240 300

NGTIGT

0

Insulin

200

400

600

pm

ol/L

Glucose

Glucose

50

100

150

200

250

mg

/dL

NGTIGT

NGTIGT

Insufficient or impaired insulin not only in T2DM but in IGT as well ( insulin / glucagon ratio)

IGT T2DM

CHO=carbohydrate; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus.Adapted from Müller WA, et al. N Engl J Med. 1970; 283: 109–115.

IGT=impaired glucose tolerance; NGT=normal glucose tolerance.Adapted from Mitrakou A, et al. N Engl J Med. 1992; 326: 22–29.

CHO meal

0

NGTT2DM

-60

Time (min)

0 60 120 180 240

Glucose100

200

300

400

mg

/dL

0

Insulin50

100

150

μU

/mL

NGTT2DM

Glucagon

75

100

125

150

pg

/mL

NGTT2DM

3) Burden of T2DM

3.1) T2DM causes significant clinical complications and financial burden

Type 2 diabetes mellitus is associated with a high and increasing burden

· Diabetes is estimated to be responsible for almost 1/10 of deaths in most developing countries among people aged 35–64 years1

· The complications of type 2 diabetes include microvascular disease (e.g. diabetic retinopathy, nephropathy) and macrovascular disease (e.g. CHS)

· Diabetes accounts for 2–19% of the healthcare budget in countries in Europe2

· Type 2 diabetes is associated with a high burden for the patient, patients’ families and carers, and society

· Nearly 1/5 hospitalizations were related to Diabetes (US) 3

1. Roglic G et al. Diabetes Care 2005; 28: 2130-5. 2. Federation of European Nurses in Diabetes. Diabetes. The policy puzzle: Is Europe making progress? 2nd edition, 2008. http://www.fend.org.

Spending on diabetes is predicted to triple between 2009 and 2034

Huang ES et al. Diabetes Care 2009; 32(12): 2225-9.

68

16545

171

0

50

100

150

200

250

300

350

400

2009 2034

Sp

end

ing

on

peo

ple

wit

h d

iab

etes

(U

S$b

illi

on

)

Non-Medicare population Medicare-eligible populationUS data

113

336

Eyes (retinopathy, glaucoma,

cataracts)

Brain and Cerebral Circulation(stroke, TIA)

Heart and Coronary Circulation(angina, MI, CHF)Kidneys

(nephropathy, ESRD)

Peripheral Nervous System

(peripheral neuropathy) Peripheral Vascular Tree(peripheral vascular disease, gangrene, amputation)

Serious long-term complications in T2DM

CHF=congestive heart failure; ESRD=end-stage renal disease; MI=myocardial infarction; TIA=transient ischemic attack; T2DM=type 2 diabetes mellitus.Adapted from International Diabetes Federation. Complications. Available at: http://www.eatlas.idf.org/complications. Accessed April 14, 2006.

Microvascular and macrovascular complications are the key drivers of the costs associated with type 2 diabetes

Source: CODE-2 Study. Williams R et al. Diabetologia 2002; 45: S13-S17.

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Microvascular & Macrovascular

3.5x

Macrovascular

2.0x

Microvascular

1.7x

No Complications

1.0x

Effect of Complications on Average Cost per Patient

Cost

Imp

act

Facto

r

Costs were assessed retrospectively for 6 months

Incremental cost due to complicationsBase cost without complications

Breakdown of Pharmacotherapy for Diabetes Patients

Breakdown of Direct Diabetes Costs per Patient

Diabetes-related healthcare expenditures

Other

Cardiovascular and lipid lowering

Oral antidiabetic

Insulin

Gastrointestinal

Anti-infectives

26%

42%

13%

11%

6%

2%

Source: Jonsson B et al. Diabetologia 2002; 45: S5-S12.

7%

18%

Hospitalizations

55%

Other medications

21%

Antidiabetic drugs

Ambulatory

Economic burden of type 2 diabetes continues to rise in both developed countries and emerging markets

• Direct costs for diabetes-related care are projected to reach USD 376 billion globally in 2010 and USD 490 billion by 2030

22

5

28

17

8

Japan

China

Germany

France

UK

US

198

3'125

115

3'7514'141

3'574

7'383

Japan

China

Germany

France

UK

US

Estimated 2010 Total Costs for Diabetes (US$ Bn)

Estimated 2010 Cost per Patient (US$)

Source: IDF Diabetes Atlas 2009 www.eatlas.idf.org

Vildagliptin is a cost effective alternative vs. pioglitazone

“In summary, the gliptins and the glitazones appear roughly equivalent in glycaemic effect, but the former have an advantage in avoidance of weight gain, which,

together with their lower (at present) costs may give them an edge.”

Waugh N et al. Health Technol Assess. 2010 Jul;14(36):1-248

No Complications With Complications

Vildaglilptin Pioglitazone Net Vildaglilptin Pioglitazone Net

UKPDS QALYS 8.561 8.590 -0.029 8,353 8,378 -0.025

8.468 8.479 -0.011 8,262 8,269 -0.007

Direct drug cost (£) 5371 5824 -453 5220 5665 -445

Total cost (£) 15,731 16,180 -449 16,309 16,756 -446

ICER (£) 39,846 66,799

4) Unmet need and limitations of current treatments

4.1) T2DM is a progressive disease and most patients do not achieve HbA1c goals

ADOPT study: progression of hyperglycemia in T2DM

*Significant difference rosiglitazone vs other treatment groups with Hochberg adjustment.Kahn SE, et al. N Engl J Med. 2006; 355: 2427–2443.

Time (Years)

6.0

7.6

8.0

6.8

0 1 2 3 4 5

Hb

A1c

(%

) 7.2

0

Rosiglitazone, 0.07 (0.06 to 0.09)Metformin, 0.14 (0.13 to 0.16)*Glyburide, 0.24 (0.23 to 0.26)*

6.4

No. of Patients 4012 3308 2991 2583 2197 822

Treatment difference (95% CI)Rosiglitazone vs metformin, 0.13 (0.22 to 0.05); P=0.002Rosiglitazone vs glyburide, 0.42 (0.50 to 0.33); P <0.001

Annualized slope (95% CI)

Percentages of Adults reaching targets

(Data from European countries)

Most patients with T2DM do not achieve HbA1c goals

A1C <6.5%

7.6% < A1C

6.5<= A1C <=7.6%

% p

ati

en

ts r

each

ing

targ

et

Alvarez Guisasola F. et al. Diab Metab Obes. 2008. 10 (suppl 1): 8-15

Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) study

4.2) Mechanism of action of different anti-diabetic treatments

Pharmacologic targets of current drugs used inthe treatment of T2DM

-glucosidase inhibitorsDelay intestinal carbohydrate absorption

ThiazolidinedionesDecrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liver

SulfonylureasIncrease insulin secretion from pancreatic -cells

GLP-1 analogsImprove pancreatic islet glucose sensing, slow gastric emptying, improve satiety

BiguanidesIncrease glucose uptakeand decreases hepatic glucose production

DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus.Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226. Ahrén B, Foley JE. Int J Clin Pract. 2008; 62: 8–14.

GlinidesIncrease insulin secretion from pancreatic -cells

DPP-4 inhibitorsProlong GLP-1 action leading to improved pancreatic islet glucose sensing, increase glucose uptake

4.3) Use of SUs is associated with hypoglycemia and weight gain

Pancreatic b cell

Sulphonylureas do not work in glucose-dependent manner increasing risk of hypoglycemia

Adapted from: Cheng AYY, et al CMAJ. 2005; 172: 213–216.* Levy AR et al. Health and Quality of Life Outcomes 2008, 6:73

• Increased secretion of insulin independently of glucose level• Increased risk of hypoglycemia• Chronic effect: weight gain due to defensive eating*

SU

K+X

Release of insulin

Pancreas Insulin

Risk of hypoglycemia with different sulfonylureas

*<50 mg/dL.Tayek J. Diabetes Obes Metab. 2008; 10: 1128–1130.

0

5

10

15

20

25

30

Gliclazide0.85

Glipizide8.70

Glimepiride0.86

Tolbutamide3.50

Chlorpropamide16.00

Glyburide16.00

Severe hypoglycemia*n/1000 person years =

Rel

ativ

e R

isk

(%)

Short-term consequences: unpleasant symptoms (and potential risky situations) related with the actual episode

Long-term consequences: pattern of “fear of hypoglycemia” with negative impact on patients´ HRQOL”

Hypoglycemia and QoL:The impact can be substantial for both patients and caregivers

HRQoL=health-related quality of life.Levy AR, et al. Health Qual Life Outcomes. 2008, 6: 73.

Patients suffering hypoglycemic episodes are more

prone to anxiety and panic attacks.

In order to avoid hypoglycemic events, some patients

alter treatment and others may engage in behaviors like

overeating

Hypoglycemia facilitates clinical inertia: "the failure to

initiate or intensify therapy in a defined time among

patients who haven't attained clinical goals and whom

intensification is likely to benefit."

TZDs4–6

Metformin + TZD5,6,9

Metformin + SU1–3

Meglitinides4,7,8

SUs1–4

Metformin1–3

Weight Change (kg)OAD Agents

OAD=oral antidiabetic agent; SU=sulfonylurea; TZD=thiazolidinedione.1Glucophage [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 2Glucovance [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 3Metaglip [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2002. 4Malone M. Ann Pharmacother. 2005; 39: 2046–2055. 5Actos [package insert]. Indianapolis, Ind: Eli Lilly and Company, 2004. 6Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005. 7Starlix [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2004. 8Prandin [package insert]. Princeton, NJ: Novo Nordisk, Inc, 2004. 9Avandamet [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005.

Weight gain is a common side effect of treatments with SU

−5 −4 −3 −2 −1 0 1 2 3 4 5

-3.8–0.5

-0.4–1.7

0.9–4.6

0.3–3.0

-0.3–1.9

0.8–2.1

13

0

2

4

6

8

10

12

14

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= metforminMatthews 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 (%)

0

4

8

12

16

20

2.3

18.2

0

100

200

300

400

500

600

700

800

900

59

838

0

2

4

6

8

10

12

14

16

0

15

Inc

ide

nc

e (

%)

Nu

mb

er

of

ev

en

ts

Nu

mb

er

of

ev

en

ts

This hypoglycemic profile was maintained in patients > 65 years

Discontinuation due to

hypoglycemia

0

Nu

mb

er

of

ev

en

ts

No

. o

f ev

en

ts

Duration: 104 weeks, add-on to metformin: vildagliptin vs glimepiride Hypoglycaemia 2

1) Per protocol population. 2) Safety population. 3) Intent-to-treat population. a) any episode requiring the assistance of another party *p <0.001. BL=baseline; EP = week 104 endpoint; Met= metformin; hypo = hypoglycemia; HbA1c= glycosylated hemoglobin. Matthews DR et al. Diab Obes Metab 2010; 12: 780–789.

Vildagliptin was as effective as glimepiride when added to metformin at 104 weeks with no weight gain and low incidence of hypoglycemia

No

. o

f ev

en

ts

Inci

de

nce

(%

)

18.2

Patients with > 1 hypo (%) Discontinuations due to hyposNumber of severe events aNumber of hypo events

1553 1546N =

Glimepiride up to 6 mg qd +met

Vildagliptin 50 mg bid + met

No

. o

f ev

en

ts

59

1553 1546N = 1553 1546N = 1553 1546N =

Mean HbA1c 1

Adjusted mean change in HbA1c was comparable between vildagliptin and glimepiride treatment: −0.1% (0.0%) for both

Primary objective of non-inferiority was met: 97.5% CI= (-0.00, 0.17); upper limit 0.3%

0

13

02468

10121416

0

15

0

2

4

6

8

10

12

14

16

-0.3 -1.5

1.2

-2.0

-1.0

0.0

1.0

2.0A

dju

ste

d m

ean

ch

an

ge

in

bo

dy

we

igh

t (k

g) 1539n = 1520

*

Change in body weight 3

Change from BL to EP(BL Mean ~89kg)

Between-treatment Difference

51

-0.3

-1.5

1.2

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

Change from BL to EP(BL Mean ~ 89 kg)

Between-treatment difference

Vildagliptin: weight loss vs. glimepiride as add on to metformin at 2 years

Intention-to-treat (ITT) population; *P <0.001.BL=baseline; EP=week 104 end point; glim=glimiperide; met=metformin; vilda=vildagliptin.Matthews DR et al Diab Obes Metab. 2010; 12:780-789

Ad

just

ed M

ean

Ch

ang

e in

B

od

y w

eig

ht

(kg

)

1539 1520N=

*

Glim up to 6 mg once daily + metVilda 50 mg twice daily + met

Weight gain is a common side effect of diabetes treatments

Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 DiabetesOlivia J. Phung; Jennifer M. Scholle; Mehak Talwar; Coleman, CI. JAMA. 2010;303(14):1410-1418

AGIS

4.4) Use of TZDs is associated with weight gain, edema, cardiovascular risk and bone fractures

Totipotent Stem cell

Hematopoietic Stem cell

Osteoblast

Mesenchymalstem cell

Bone formation

Preadipocyte

PPARɣ Adipocyte

Preosteoblast

+

Myeloid Precursors

Lymphoid Precursors

Erythroid lineageMyeloid, Monocyte, Granulocyte lineages

T, NK, B cell lineages

Preosteoclast Osteoclast

TZDs increase conversion from preadipocytes into adipocytes in fat tissue as well as in the bone marrow, consequently decreasing other pathways leading to osteoblasts, erythrocytes or lymphocytes

Adapted from Rosen et al. Nat Clin Pract Rheumatol 2006, 2:35-43 and Payne et al Medical Hypothesis 2007, 69:778-786.

*PPARγ agonists determine MSC lineage commitment towards adipocytes instead of osteoblasts or erythrocytes

TZDs

PROactive: incidence of edema, and magnitude of weight gain with pioglitazone

21.6

13.0

0

5

10

15

20

25 3.6

-0.4-1

0

1

2

3

4

% of Edema without HF Weight Gain (kg)

Placebo Pioglitazone <45 mg daily

HF=heart failure.Adapted from Dormandy JA, et al. Lancet. 2005; 366: 1279–1289.

P <0.0001

Weight gain is a common side effect of diabetes treatments

Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 DiabetesOlivia J. Phung; Jennifer M. Scholle; Mehak Talwar; Coleman, CI. JAMA. 2010;303(14):1410-1418

AGIS

Edema is common with TZDs (pioglitazone)

TZDs=thiazolidinediones.1Actos [prescribing information]. Indianapolis, IN: Eli Lilly and Company, 2004.

4.8

7.26.0

15.3

1.22.1 2.5

7.0

0

2

4

6

8

10

12

14

16

18

Monotherapy Combinationwith SU

Combinationwith

metformin

Combinationwith insulin

Pro

po

rtio

n o

f P

atie

nts

(%

) Pioglitazone1

Placebo or combination

Use of TZDs is associated with increased incidence of congestive heart failure

Nu

mb

er o

f C

HF

Eve

nts P=0.01

CHF=congestive heart failure; TZDs=thiazolidinediones.Adapted from DREAM Trial Investigators, et al. Lancet. 2006; 368: 1096–1105.

HF=heart failureAdapted from Dormandy JA, et al. Lancet. 2005; 366: 1279–1289.

P <0.000114

2

0

5

10

15

20

11

8

0

5

10

15

Rosiglitazone

Placebo

Pat

ien

ts w

ith

HF

(%

)

Placebo

Pioglitazone ≤45 mg daily

DREAM Study PROactive Study

Risk of myocardial infarction and death from cardiovascular causes with rosiglitazone

CI=confidence interval; CV=cardiovascular.Adapted from Nissen SE, Wolski K. N Engl J Med. 2007; 356: 2457–2471.

Myocardial infarction

Small trials combined

DREAM

ADOPT

Overall

Death from CV causes

Small trials combined

DREAM

ADOPT

Overall

2.0 4.01.0

Log Odds Ratio (95% CI)

0.5

1.43 (1.03–1.98) P=0.03

1.45; P=0.15

1.65; P=0.22

1.33; P=0.27

2.40; P=0.02

1.20; P=0.67

0.80; P=0.78

1.64 (0.98–2.74) P=0.06

RECORD study results: secondary endpoints – cardiovascular

All cause

Heart failure*

Hazard Ratio (95% CI)

0.86 (0.68, 1.08); P=0.19

0.84 (0.59, 1.18); P=0.32

0.72 (0.49, 1.06); P=0.10

0.93 (0.74, 1.15); P=0.50

2.10 (1.35, 3.27); P=0.001

MI

Stroke

CV death, MI or stroke

*Fatal and non-fatal. CI=confidence interval; CV=cardiovascular; MI=myocardial infarction.Home PD et al. Lancet. 2009; 373: 2125–2135.

Rosiglitazone (n=2220)

Control(n=2227)

46

64

154

63

2961

165

56 1.14 (0.80, 1.63); P=0.47

Hazard ratio (95% CI)

0.5 1.0 2.0 3.0 4.0

Death

CV

136

60

157

71

Rosiglitazone: EMA / FDA decision 23rd September 2010

23rd of September 2010:

• FDA notified healthcare professionals and patients that it will significantly restrict the use of the diabetes drug Avandia (rosiglitazone) to patients with Type 2 diabetes who cannot control their diabetes on other medications.

• These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with Avandia

• EMA (European Medicines Agency) recommended the suspension of the marketing authorisations for the rosiglitazone-containing anti-diabetes medicines Avandia, Avandamet and Avaglim.

• Data from clinical trials, observational studies and meta-analyses of existing studies that have become available over the last three years have suggested a possibly increased risk of ischaemic heart disease associated with the use of rosiglitazone.

• GBA has decided to withdraw reimbursment of rosiglitazone*

* GBA= Gemeinsame Bundesausschuss (The German Health Care System and the Federal Joint Committee) http://www.g-ba.de/institution/sys/english/

ADOPT Study: proportion of female patients with limb fractures was almost twice as high with rosiglitazone compared to metformin-treated patients

*P <0.01; **P <0.05 vs rosiglitazone (unadjusted, contingency 2 test).Kahn SE, et al. N Engl J Med. 2006; 355: 2427–2443.

9.3

5.6

3.4

5.1

3.1

1.7

3.5

1.3 1.5

0

2

4

6

8

10

Overall Lower limb Upper limb

Pat

ien

ts (

%)

*

*

Rosiglitazone (n=1456)

Glyburide (n=1441)Metformin (n=1454)

* **

**

RECORD study results: increased limb fractures in patients with rosiglitazone

*P <0.0001 Rosiglitazone vs controlHome PD, et al. Lancet. 2009; 373: 2125–2135.

Women Men

1241078

681075

471078

631078

361075

161075

611142

231142

501152

191152

231142

111152

Rosiglitazone

Active control

All Distal lower limb

Upper limb

All Distal lower limb

Upper limb

Pat

ien

ts (

%)

n (events)N (patients)

Overall incidence of bone fractures higher with rosiglitazone (p<0.0001*)

Pioglitazone has a similar risk of fractures as rosiglitazone

77% increased risk of peripheral fracture in women2

Aubert RE, et al. Diabetes Obes Metab. 2010;12(8):716-721

Colin R. Arch Intern Med. 2009;169(15):1395-1402.

1-year number need to harm range from 21 - 55

Loke YK, Singh S. Furberg C. Long-term use of thiazolidinediones and fractures in type 2diabetes: a meta-analysis CMAJ Jan 6 2009 180 (1)

*mean age 56 years; diabetes diagnosed within 3 years before study; no previous use of oral hypoglycemic agent

Number needed to harm via excess fractures with TZDs ranges from 21 to 55

Population Baseline risk of fractures

per 1000Patent-years

Odds ratio of fracture (95% CI)

from meta-analysis

1-year number needed to

harm* (95% CI)

Excess fractures with TZD use per 100 patient-years

(95% CI)

Women in the metformin arm of the ADOPT study:*

15.4 2.23 (1.65-3.01) 55 (34-103) 18 (10-29)

Elderly postmenopausal women in Women’s Health Initiative Observational Study; mean age 65 years

28.6 2.23 (1.65-3.01) 31 (19-57) 32 (18-53)

Older cohort of women with diabetes not using insulin; mean age 72 years 43.5 2.23 (1.65-3.01) 21 (14-39) 48 (26-71)

Note: ADOPT- A Diabetes Outcome and Progression Trial. * Number of patients with type 2 diabetes who must be treated with a thiazolidinedione, rather than another intervetnion, for 1 additional patient to have a fracture.

In patients failing on metformin vildagliptin is the only DPP-4 inhibitor showing similar efficacy to pioglitazone at 1 year without weight gain

HbA1c=hemoglobin A1c, NI=non-inferiority, * P<0.001 pio vs BLIntention-to-treat population. Vildagliptin (n=295); pioglitazone (n=281).Bolli G, et al. Diabetes Obes Metab. 2009; 11: 589–595.

Vildagliptin 50 mg bid + metformin

Pioglitazone 30 mg od + metformin

24-week analysis

Vilda NI established

−4 0 4 12 16 24 32 40 52

Time (Weeks)

7.0

7.5

8.0

8.5

9.0

Mea

n H

bA

1c (

%)

Duration: 52 weeks add-on to metformin: vildagliptin vs pioglitazone

n=277n=293

Un

ad

jus

ted

Me

an

Ch

an

ge

in

Bo

dy

We

igh

t (k

g)

*

Change in Body Weight(Mean BL Body Weight ~91 kg)

*P <0.001 change from baseline

Change in HbA1c

0.30.1

1.9

2.6

0.0

0.5

1.0

1.5

2.0

2.5

3.0

All PatientsMean BL ~91.8 kg

n =

Pioglitazone added greater body weight burden to obese patients (BMI >35 kg/m2)

BL=baseline; BMI=body mass index; met=metformin; pio=pioglitazone; vilda=vildagliptin. *P <0.001 vs pioglitazone. Per protocol population. Adjusted mean change derived from analysis of covariance model.Bolli G, et al. Diabetes Obes Metab. 2008; 10: 82–90.

Ad

jus

ted

Mea

n C

han

ge

inB

od

y W

eig

ht

(kg

) to

Wee

k 24

BMI >35 kg/m2

Mean BL ~110.4 kg

264 246 7073

Pio 30 mg once daily + metVilda 50 mg twice daily + met

*

*

Duration: 24 weeksAdd-on to met:vilda vs pio

Vildagliptin demonstrated to be likely more cost-effective than pioglitazone - even without considering the recent evidence on the increased risk of fractures in men an women

Costs QALYs Net benefit

ICER

Vildagliptin Pioglitazone Diff % Vildagliptin Pioglitazone Diff %

£20,222 £20,245 -£23 -0.1% 9.4541 9.45270.001

40.01%

£50 Vildagliptin dominates

QALY: quality adjusted life year; ICER: incremental cost-effectiveness ratio; net benefit: (payer acceptability threshold £20l x ΔQALYs) – Δ costs Pricing assumption: Vildagliptin at £1.20 for 100mg dailyEfficacy data based on study LAF237A2354

· Long-term HbA1c trend is assumed to be similar to vildagliptin – this is mainly explained by the weight gain beyond the first year of treatment, which is a significant disadvantage of the glitazones

· Cost of liver function testing was shown to have little impact on the cost-effectiveness of vildagliptin in the first year of treatment

Source: http://www.ispor.org/congresses/Greece1108/Posters2.aspxESTIMATING THE COST EFFECTIVENESS IN THE UK OF VILDAGLIPTIN COMPARED TO PIOGLITAZONE AS ADD-ON THERAPY TO METFORMIN USING THE SHEFFIELD TYPE 2 DIABETES MODEL Brennan A, Gillett M, Duenas A , University of Sheffield, Sheffield, United Kingdom

Vildagliptin vs pioglitazone as add-on to metformin

4.5) Bone fractures cause significant healthcare cost

Fractures cause a significant direct economic burden

Unit cost of a fragility fracture (Stevenson et al 2006)

Fracture siteProportion of

fractures hospitalized

Length of stay per hospitalization (days)

Total cost per fracture

Hip 100% 26.0 £10,760

Vertebrae 35% 15.0 £1,706

Proximal humerus

32% 10.6 £1,112

Wrist 25% 5.4 £527

Data for the cost of fracture were taken from a publication by Stevenson et al (2006), which calculates the average unit cost of a fragility fracture in the UK. Unit costs are reported for fractures at the hip, spine, proximal humerus and humeral shaft, and forearm.

Stevenson M, Davis S, Kanis J. The hospitalisation costs and out-patient costs of fragility fractures. Women's Health Med 2006;3:149–151.

Fractures have significant health related quality of life impact in elderly women

Mayo Clin Proc. 2010; 85: 806-13. Epub 2010 Jul 15. Impact of prevalent fractures on quality of life: baseline results from the global longitudinal study of osteoporosis in women. Adachi JD, Adami S, Gehlbach S, Anderson FA Jr,

Reductions in health-related quality of life (EQ-5D, for women with previous fractures compared with women without fracture history or medical condition, adjusted for all listed conditions plus age and study site

EQ-5D (N=51,165)

Reduction 95% CI

P value

Comparison condition

Arthritis (n=22,331)

0.12 0.11-0.12 <0.001

Type 1 diabetes (n=1950) 0.09 0.08-0.09 <0.001

Lung disease (n=8659) 0.06 0.05-0.06 <0.001

Previous fracture location

Ankle (n=3123) 0.04 0.03-0.04 <0.001

Wrist (n=4250) 0.01 0.001-0.01 <0.05

a EQ-5D= European Quality of Life 5 Dimensions Index; CI= Confidence Interval; b Reduction in score between comparison groups (eg, with vs without diabetes);

4.6) GLP-1 analogs are associated with gastrointestinal adverse events

Gastrointestinal adverse events are common during treatment with exenatide

*In three 30-week placebo-controlled trials.Adapted from Byetta [prescribing information]. San Diego, CA: Amylin Pharmaceuticals Inc, 2005.

18%

4%6%

44%

13% 13%

0

5

10

15

20

25

30

35

40

45

50

Nausea Vomiting Diarrhea

Pro

po

rtio

n o

f P

atie

nts

(%

) Placebo (n=483)Exenatide (n=963)

bid=twice daily; GLP-1=glucagon-like peptide-1; SU=sulfonylurea.*In three 30-week placebo-controlled trials; exenatide and placebo were administered before the morning and evening meals.Adapted from Byetta [prescribing information]. San Diego, CA: Amylin Pharmaceuticals Inc, 2005.

Incidence of hypoglycemia during treatment with exenatide

5.3%3.3%

12.6%

4.5%

14.4%

19.2%

5.3%

35.7%

27.8%

0

5

10

15

20

25

30

35

40

Combinationwith metformin

Combinationwith SU

Combination withmetformin + SU

Pro

po

rtio

n o

f P

atie

nts

(%

)

Placebo

Exenatide 5 mcg bid

Exenatide 10 mcg bid

4.7) Hypoglycemia has clinical, social and economic consequences

Mechanisms by which hypoglycemia may affect cardiovascular events

Desouza CV et al. Hypoglycemia, Diabetes, and Cardiovascular Events. Diabetes Care 2010; 33: 1389-1394.

IL6: interleukin 6CRP: C-reactive proteinVEGF: vascular endothelial growth factor

Hypoglycemia consequences

1: Whitmer RA et al JAMA 2009, 301:1565-15722: Zammitt NN et al Diabetes Care 2005, 28:2948-29613 Canadian Diabetes Association’s Clinical Practice Guidelines for Diabetes and Private and Commercial Driving. Canadian Journal Of Diabetes. 2003;27(2):128-140. 4:Jönsson L et al. Cost of Hypoglycemia in Patients with Type 2 Diabetes in Sweden. Value In Health. 2006; 9: 193-1985: Barnett AH, CMRO 26, 1333-1342, 20106. Foley J & Jordan J, Vascular Health Risk Management, 2010 6:541-548

Hypoglycemia

CV complications5

Weight gain by defensive eating6

Coma5

Car accident3

Hospitalization costs4

Dizzy turn unconsciousness5

Seizures5

Death2

Increased risk of dementia1

*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 deathLower 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 12Hazard Ratio

Short-term consequences: unpleasant symptoms (and potential risky situations) related with the actual episode

Long-term consequences: pattern of “fear of hypoglycemia” with negative impact on patients´ HRQOL”

Hypoglycemia and QoL:The impact can be substantial for both patients and caregivers

HRQoL=health-related quality of life.Levy AR, et al. Health Qual Life Outcomes. 2008, 6: 73.

Patients suffering hypoglycemic episodes are more

prone to anxiety and panic attacks.

In order to avoid hypoglycemic events, some patients

alter treatment and others may engage in behaviors like

overeating

Hypoglycemia facilitates clinical inertia: "the failure to

initiate or intensify therapy in a defined time among

patients who haven't attained clinical goals and whom

intensification is likely to benefit."

Hypoglycemia increases costly hospital admissions

UK 2007-08 Admitted Patient Care Mandatory Tariff

Cc = comorbidity or complication; HRG = Healthcare resource group

HRG NameHealthcare Resource Group

Non-elective spell tariff (£)

% applied in calculation of reduced short stay emergency tariff

Reduced short stay emergency tariff (£)

Weighted Average (£)

Diabetes with Hypoglycaemic Emergency >69 years or with cc

2,171 20% 434 1,824

Diabetes with Hypoglycaemic Emergency <70 years without cc

776 50% 388 582

Gillette M, Fitzgerald P, Brennan A. Analysis of the economic impact of hypos – comparison of vildagliptin versus sulphonylurea. Modelling phase report. University of Sheffield, School of Health and Related Research. October 2009. (Prepared for Novartis)

Costs Of Hypoglycaemia Per NHS Reference Costs

UK Payer Perspective

5) Incretin hormones and DPP-4 inhibitors

5.1) Incretins restore the physiological balance between glucagon and insulin in a glucose-dependent manner

The incretins

Y A E GT

FI S D Y

SI

A M D KI

HQ

QDFVNWLLAQKGKKNDW

KH N QTI

GIP: Glucose-dependent Insulinotropic Peptide

H A E GT F T S D V

SS Y L E G

Q AA

KEFIAWLVKGRG

GLP-1: Glucagon-like Peptide-1

Amino acids shown in orange are homologous with the structure of glucagon.

L-cell(ileum)

Proglucagon

GLP-1 [7–37]

GLP-1 [7–36 NH2]

K-cell(jejunum)

ProGIP

GIP [1–42]

GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1. Adapted from Drucker DJ. Diabetes Care. 2003; 26: 2929–2940.

GLP-1 and GIP are synthesized and secreted from the gut in response to food Intake

Food intake

a cells

b cells

Insulin secretion

Insulin biosynthesis

b cell proliferation

b cell survival

Glucose sensing

Glucagon secretion

Intestinal secretion of GLP1 (7-36) amide+ GIP (1-42)

DPP4

Action on b cells and a cells

GLP-1 (9-36) amideAnd GIP (3-42)

DPP4 inhibitors

Adapted from L Baggio and DJ Drucker Gastroenterology 2007 132:2131-2157And DJ Drucker The J Clin Invest 2007, 117:24-32

Incretin hormones are the body’s natural way to maintain glycemic control

Intestine

Pancreas

Blood Glucose level

85

IV=intravenous.Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986; 63: 492–498.

Oral Glucose Tolerance Test and Matched IV Infusion

Pla

sma

Glu

cose

(m

g/d

L)

0

50

100

150

200

–30 0 30 60 90 120 150 180 210

Time (min)

Pla

sma

Insu

lin

(p

mo

l/L

)

0

100

200

300

400

–30 0 30 60 90 120 150 180 210

Time (min)

Proof of a gastrointestinal ‘incretin effect’: different responses to oral vs i.v. glucose

Oral IV

50 g Glucose

N=6

GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus. *P <0.05. †GLP-1(7–36 amide) infused at 1.2 pmol/kg/min for 240 minutes.Adapted from Nauck MA, et al. Diabetologia. 1993; 36: 741–744.

GLP-1 restores insulin and glucagon responses ina glucose-sensitive manner in patients with T2DM

0

50

100

150

200

250

300

*

*

*

**

**

–30 0 30 60 90 120 150 180 210 240

Time (min)

GLP-1 infusion

Glucose (mg/dL)

N=10

0.0

0.5

1.0

1.5

2.0

2.5

3.0

**

*

**

*

*

*

–30 0 30 60 90 120 150 180 210 240

Time (min)

GLP-1 infusion

C-peptide (nmol/L)

–30 0 30 60 90 120 150 180 210 240

Time (min)

0

5

10

15

20

25

30

*

** *

GLP-1 infusion

Glucagon (pmol/L)

GLP-1†

Placebo

5.2) Oral DPP-4 inhibitors enhance the physiological effects of incretin hormones such as GLP-1 and GIP

Inhibition of DPP-4 increases active GLP-1

GLP-1inactive

(>80% of pool)

ActiveGLP-1

Meal

DPP-4

IntestinalGLP-1 release

GLP-1 t½=1–2 min

DPP-4inhibitor

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR.Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131.

Acute effects of vildagliptin on insulin, glucose and glucagon levels in patients with T2DM

OGTT 30 min after Single Oral Dose of Vildagliptin (100 mg)

OGTT=oral glucose tolerance test. *P <0.01. He YL, et al. J Clin Pharmacol. 2007; 47: 633–641. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd,

7.5

12.5

17.5

22.5

Glu

co

se

(m

mo

l/L

)

0

60

80

100

120

40

20

Ins

uli

n

(pm

ol/

L)

60

80

100

120

140

Glu

ca

go

n(n

g/L

)

−90 −60 −30 0 30

60

90

120

150

180

210

240

270

300

−90 −60 −30 0 30

60

90

120

150

180

210

240

270

300

−90 −60 −30 0 30

60

90

120

150

180

210

240

270

300Time

Vildagliptin 100 mg (n=15)Placebo (n=16)

75 g Glucose

Dose

Meal

*

*

*

*

*

** * *

**

*

Vildagliptin 100 mg (n=16)

Placebo (n=16)

Acute effects of vildagliptin on GLP-1 levels in patients with T2DM: increased GLP-1 levels that persist beyond the post-meal period

GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus.*P <0.05.Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd,

0.0

4.0

8.0

12.0

16.0

17:00 20:00 23:00 02:00 05:00 08:00

Time

Acti

ve G

LP

-1 (

pm

ol/

L)

*

91

Effects of vildagliptin and vildagliptin plus metformin on fasting GLP-1 levels

0

2

4

6

8

10

12

14

*

In

tact

GL

P-1

(p

M)

Fasting Levels of Intact GLP-1 at Baseline and at 3 Months

BL=baseline; GLP-1=glucagon-like peptide-1; met=metformin; PBO=placebo; vilda=vildagliptin.*P <0.05 vildagliptin 3 months vs baseline; **P <0.05 vildagliptin add-on metformin significantly improved at 3 months vs baseline.†Contains patients on vildagliptin alone and those on vildagliptin plus metformin.D’Alessio DA, et al. J Clin Endocrinol Metab. 2009; 94: 81-88.

Vilda group† Placebo

BL BL3 months 3 months

n = 20 20 19 19

In

tact

GL

P-1

(p

M)

**

02

468

10

1214

Vilda only

Fasting Levels of Intact GLP-1 in Vildagliptin Subgroups at 3 Months

Vilda + met

7 13

Vildagliptin: 50 mg bid

5.3) Mode of action evidence supports potential intra-class differentiation of vildagliptin vs. sitagliptin

Vildagliptin vs Sitagliptin: what do we know so far? Chemical structures of DPP-4 inhibitors

1Januvia Prescribing Information. http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf. Accessed January 2010.2Burkey BF, et al. Poster 0788 presented at EASD 2006.3Neumiller JJ. J Am Pharm Assoc. 2009; 49: S16–S29.4Onglyza Prescribing Information. http://packageinserts.bms.com/pi/pi_onglyza.pdf. Accessed January 2010.Ahren B et al, Diab Obes Metab 2011 "Accepted Article"; doi: 10.1111/j.1463-1326.2010.01321.x

N N

O

H3C

O N

CN

NH3+ PhCO2

-

Alogliptin3

Non-covalent

F

F

FO

N

NH2

NN

N

CF3

Sitagliptin1

Non-covalent

Vildagliptin2

HO

NH

O

N

NC

Covalent (cyanopyrrolidine)

Competitive inhibitors Substrates acting as inhibitors

Saxagliptin4

N

O

HH

NCHO

NH2

Covalent (cyanopyrrolidine)

Different binding kinetics within DPP-4 class

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.

Inhibitor: DPP-4 complex

Inhibitor

+DPP-4

K-1

K1Competitive

inhibitor:(sitagliptin, alogliptin) Fast dissociation

Substrate acting as inhibitor:(vildagliptin, saxagliptin) DPP-4Substrate-like

enzyme blocker

+DPP-4

K-1

K1

Substrate-like enzyme blocker: DPP-4 complex

K2

Slow(~ 1 h)

Inactivesubstrate-like

enzyme blocker

+Slow dissociation

Natural substrate:

(GLP-1)

GLP-1

+DPP-4

K-1

K1

GLP-1: DPP-4complex

K2

Fast(~1 sec)

DPP-4InactiveGLP-1

+

Comparison of plasma GLP-1 levels following 3 Months’ treatment with vildagliptin or sitagliptin

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.Marfella R, et al. J Diabetes Complications. 24: 79-83, 2010..

30

25

20

15

10

5

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

Breakfast Lunch Dinner

Inta

ct G

LP

-1 (

pm

ol/

L)

Sitagliptin 100 mg once daily + metformin (N=20)

Vildagliptin 50 mg twice daily + metformin (N=18)

Retrospective analysis of patients on sitagliptin (N=20) or vildagliptin (N=18)

-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

ang

e i

n H

bA

1c (%

)

Add-on Treatment to Insulin

140

**

149 42 41n =

*

Duration: 24 weeksAdd-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

10N

o.

of

Sev

ere

Ev

ents

113

185

0

6

*

**

No

. o

f E

ven

ts

Vilsbøll T, et al. Diabetes Obes Metab 2010;12:167–177

8.6

8.1

7.8

7.9

8.0

8.1

8.2

8.3

8.4

8.5

8.6

8.7

Placebo Sitagliptin

Hb

A1

c (

%)

8

16

0

2

4

6

8

10

12

14

16

18

Placebo Sitagliptin

Pa

tie

nts

(%

)

HbA1c (%) Symptomatic hypoglycaemia

Sitagliptin

Placebo

* **

1 severe hypo in placebo2 severe hypos with Sitagliptin

Sitagliptin in add-on to insulin setting

Mean insulin dose ~50 U/day

98

Meal

*

*

*

*

*

** * *

**

*

Vildagliptin 100 mg (n=16)

Placebo (n=16)

Acute effects of vildagliptin on GLP-1 levels in patients with T2DM: increased GLP-1 levels that persist beyond the post-meal period

GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus.*P <0.05.Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd,

0.0

4.0

8.0

12.0

16.0

17:00 20:00 23:00 02:00 05:00 08:00

Time

Acti

ve G

LP

-1 (

pm

ol/

L)

*

99

Acute effects of vildagliptin on glucagon levels in patients with T2DM: decreased glucagon levels persist beyond the post-meal period

Meal

*

* **

*

*

*

*

*P <0.05 vs placebo.Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd,

−60

−50

−40

−30

−20

−10

0

10

20

17:00Time

Delt

a G

lucag

on

(n

g/L

)

20:00 23:00 02:00 05:00 08:00

Placebo (n=16)Vildagliptin 100 mg (n=16)

*

100

Acute effects of vildagliptin on endogenous glucose production (EGP) levels in patients with T2DM: decreased EGP levels persist beyond post-meal period

EGP=endogenous glucose production.*P <0.05 vs placebo.Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd,

0

−0.3

−0.6

−0.9

−1.2

−1.5

Del

ta E

GP

(m

g/k

g/m

in)

17:00 20:00 23:00 02:00 05:00 08:00

Time

**********

*

*

****************Placebo (n=16)Vildagliptin 100 mg (n=16)

Meal

6) Vildagliptin in monotherapy settings

6.1) Vildagliptin demonstrates favorable efficacy and tolerability profile in monotherapy settings

Vildagliptin comprehensive phase III clinical development program

Early Type 2Diabetes

Glucoseintolerance

Advanced Type 2 Diabetes

Diabetic Complications

in IFG

In IGT

Efficacy/safety in mono settings vs. PBO (2)

Mono vs PBO, Japan

Mono long-term safety, Japan

H2H vs TZD (rosiglitazone)

H2H vs met (2)- General population- Elderly

H2H vs SU (glicl.)

H2H vs α-GI (acarbose), China

H2H vs α-GI (voglibose), Japan

Add-on to metformin:vs. PBO- Genaral population- Chinese population

vs TZD (pioglitazone)

vs SU (glim. or glicl.)- Low BLHbA1c - High BL HbA1c

vs up-titration of met

Initial combination met

Add-on to TZD (p incl Japanio):- PBO controlled- Initial combo

Add-on to SU (glim)Add-on to SU (glim), JapanAdd-on insulin

In mild hyperglycemia

Moderate and severe renal impairment(ongoing)

CHF (ongoing)

Asian studies

FPG=fasting plasma glucose; IGT=impaired glucose tolerance; OGTT=oral glucose tolerance test.Rosenstock J, et al. Diabetes Care. 2008; 31: 30–35.

Objective: to assess the effects of vildagliptin on prandial glucose control, incretin hormone levels, and islet function

Target population: drug-naïve patients with IGT documented by OGTT (FPG <7.0 mmol/L and 2-h glucose >7.8 and <11.1 mmol/L)

Study Design Study Design Study Design Study Design

n=89: Placebo

12 weeks4 weeks

N=179

n=90: Vildagliptin 50 mg once daily

IGT patients diagnosed by OGTT

Vildagliptin monotherapy in IGT :study design and objective

Vildagliptin’s effect on GLP-1 and glucagon is fully evident in IGT population

12.0

8.0

4.0

0.0

GL

P-1

(p

mo

l/L)

–30 0 30 60 90 120Time (min)

Meal

Vildagliptin 50 mg once daily (n=89)

Placebo (n=89)9.0

8.0

7.0

6.0

Glu

cose

(m

mo

l/L)

–30 0 30 60 90 120Time (min)

Meal

26

22

20

18

Glu

cag

on

(p

mo

l/L)

–30 0 30 60 90 120Time (min)

24

Meal

Insulin secretion relative to glucose

8.0

6.0

4.0

2.0

0.0

–2.0

–4.0

Vildagliptin 50 mg once daily (n=89)

Placebo (n=89)*

a b

c d

Intention-to-treat population. *P=0.002 vs placebo. Rosenstock J, et al. Diabetes Care. 2008: 31: 30–35.

ISR

AU

C0-

2h /

Glu

cose

AU

C0-

2h

(pm

ol/L

•min

-1•m

-2•m

M)

GLP-1

β-cell Function

Glucose

Glucagon

Objective: to assess the long-term efficacy and safety of vildagliptin in patients with T2DM and mild hyperglycemia during 108 weeks of treatment

Target population: drug-naïve patients with T2DM (HbA1c 6.2-7.2%); completed 52-week core; HbA1c <8% at Week 52 core

52 weeks2 weeks

N=306*

n=156: Vilda 50 mg once daily

n=150: Placebo

Washout Washout

52 weeks4 weeks 4 weeks

n=63: Placebo

n=68: Vilda 50 mg once daily

Core Extension**

*Randomized population; **Extension population.HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus; vilda=vildagliptin.Scherbaum WA, et al. Diabetes Obes Metab. 2008; 10: 1114–1124.

Vildagliptin in T2DM patients with mild hyperglycemia: study design and objective

0.1

-0.4

0.5

-0.5-0.4-0.3-0.2-0.10.00.10.20.30.40.50.6

Change from BL to EP(BL Mean ~6.64%)

Mea

n C

ha

ng

e in

Hb

A1c

(%

)

Mean Difference vs Placebo

n = 67 63

PlaceboVildagliptin 50 mg once daily

*

Vildagliptin therapeutic effects are fully manifested in patients with mild hyperglycemia : change from baseline in HbA1c

Extension intention-to-treat population. *P <0.001 vs core baseline.BL=core baseline; EP=study end point (Week 108); HbA1c=hemoglobin A1c.Scherbaum WA, et al. Diabetes Obes Metab. 2008; 10: 1114–1124.

Duration: 2 yearsVildagliptinvs placebo

Vildagliptin 50 mg once daily

Placebo

Mea

n H

bA

1c (

%)

Time (Weeks)Extension intention-to-treat population. HbA1c=hemoglobin A1c.--- = washout period (52-56 weeks, 108-112 weeks);vildagliptin (n=67 at Week 0, 56 at Week 108, 51 at Week 112);placebo (n=63 at Week 0, 47 at Week 108, 44 at Week 112).Scherbaum WA, et al. Diabetes Obes Metab. 2008; 10: 1114–1124.

Treatment period Wk 0–52 Treatment period Wk 56–108Washout Washout

Vildagliptin efficacy in mild hyperglycemia: mean HbA1c over 112 weeks

Duration: 2 yearsVildagliptinvs placebo

0.1

-0.3

0.4

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

Change from BL to Week 112 (BL Mean ~6.64)

Mean Difference vs Placebo

Mea

n C

ha

ng

e in

Hb

A1c

(%

)

57 50n =

PlaceboVildagliptin 50 mg once daily

*

Vildagliptin efficacy in mild hyperglycemia: maintenance of effects after washout

Extension intention-to-treat population.BL=core baseline; HbA1c=hemoglobin A1c.*P <0.001 from core baseline.Scherbaum WA, et al. Diabetes Obes Metab. 2008; 10: 1114–1124.

Duration: 2 yearsVildagliptinvs placebo

Vildagliptin dose-ranging study: study design and objective

HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus.Pi-Sunyer FX, et al. Diabetes Res Clin Pract. 2007; 76: 132–138.

Drug-naïve

24 weeks2 weeks

N=354

n=88: Vildagliptin 50 mg once daily

n=83: Vildagliptin 50 mg twice daily

n=91: Vildagliptin 100 mg once daily*

n=92: Placebo

Design: a 24-week, double-blind, randomized, placebo-controlled,parallel-group study

Objective: to demonstrate superior HbA1c reduction of vildagliptin versus placebo

Target population: drug-naïve patients with T2DM; HbA1c 7.5–10%

*100 mg once daily is NOT an approved dose

100 mg once daily is NOT an approved dose

Vildagliptin 100 mg once daily (n=89)

Vildagliptin 50 mg twice daily (n=79)

Vildagliptin 50 mg once daily (n=84)

Placebo (n=88)

Pi-Sunyer FX, et al. Diabetes Res Clin Pract. 2007; 76: 132–138.

Vildagliptin dose-ranging study: efficacy over 24 weeks without weight gain

-0.6

-1.3 -1.3-1.6

-1.2

-0.8

-0.4

0.0

0.4

Ch

ang

e in

FP

G (

mm

ol/L

)

**

Change in FPG from BL vs Placebo Mean BL ~10.5 mmol/L

**

HbA1c

7.0

7.4

7.8

8.2

8.6

9.0

-4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24

Me

an

Hb

A1

c (

%)

*****

HbA1c=hemoglobin A1c.BL=baseline; FPG=fasting plasma glucose.Primary intention-to-treat population.

* p=0.01**p <0.001 vs placebo.

Time (Weeks)

n=238 n=179: Rosiglitazone 8 mg once dailyDrug-naïve

N=697*

n=459 n=354: Vildagliptin 50 mg twice daily

80 weeks2 weeks

HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus.*Patient number refers to primary intention-to-treat population. Drug-naïve patients: defined as patients who had had no treatment with oral antidiabetic agents for at least 12 weeks prior to study entry (visit 1) and no treatment with oral antidiabetic agents >3 consecutive months at any time in the past. For this study, 8 mg given as a single daily dose was selected because usage data indicate that in clinical practice 80% of patients treated with 8 mg daily take it as a single dose.aRosenstock J, et al. Diabetes Care. 2007; 30: 217–223; bRosenstock J, et al. Diabetes Obes Metab. 2009; 11: 571–578.

Objective: to assess the long-term efficacy (HbA1c reduction) and safety of vildagliptin compared with rosiglitazone

Target population: drug-naïve patients with T2DM; HbA1c 7.5–11%

24 weeks

Vildagliptin vs rosiglitazone: study design and objective

Core studya Extension studyb

Vildagliptin provides HbA1c reductions that are sustained over two years of treatment

*Not non-inferior; **Statistically significant larger increase in body weight from baseline to end point was seen in the rosiglitazone group than in the vildagliptin group; ** P <0.001.aHead-to-head vildagliptin vs rosiglitazone comparison: 80-week extension to 24-week core study; extension intention-to-treat population; bVildagliptin n=354, rosiglitazone n=179; observations censored at rescue med; error bars represent standard error values; cPitting edema, peripheral edema, and other edema.Rosenstock J, et al. Diabetes Obes Metab. 2009; 11: 571–578. Data on file, Novartis Pharmaceuticals. LAF237A2354.

Vildagliptin vs rosiglitazone: 104 weeksa (including 80-week extension to the 24-week core study)

Not NI*

Change in HbA1c Change in Body Weight

−4.7kg P<0.001**

Rosiglitazone 8 mg qdVildagliptin 50 mg bid

Ad

jus

ted

me

an

% c

ha

ng

e

−8−6−4−2

02468

101214 TG TC LDL-C HDL-C

** **

Vildagliptin vs metformin: study design and objective

HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus.*Patient number refers to randomized population. aRefers to the extension intention-to-treat population. Drug-naïve patients: defined as patients who had had no treatment with oral antidiabetic agents for at least 12 weeks prior to study entry (visit 1) and no treatment with oral antidiabetic agents>3 consecutive months at any time in the past. Metformin was uptitrated: 1000 mg daily for 1 week; 1500 mg daily for 2 weeks; 2000 mg daily thereafter.†Schweizer A, et al. Diabet Med. 2007; 24: 955–961; ††Göke B, et al. Horm Metab Res. 2008; 40: 892–895.

Objective: to demonstrate that HbA1c reduction with vildagliptin is not inferior to metformin

Target population: drug-naïve patients with T2DM; HbA1c 7.5–11%

Drug-naïve

N=780*

52 weeks2 weeks

n=254: Metformin 1000 mg n=158a

twice daily

n=526: Vildagliptin 50 mg n=300a

twice daily

52 weeks

Core study† Extension study††

Vildagliptin vs metformin monotherapy : HbA1c efficacy and tolerability at 2 years

6.5

7.0

7.5

8.5

9.5

−2 0 4 8 24 32 40 52 76 104

9.0

8.0

886412 16

AE=adverse event; HbA1c=hemoglobin A1c*Not non-inferior; **P <0.001 vs metformin (Fisher’s exact test). Göke B, et al. Horm Metab Res. 2008; 40: 892–895.

Metformin 1000 mg twice dailyVildagliptin 50 mg twice daily

Mean HbA1c (%)

0

10

20

30

40

50

25.0

45.6

Gastrointestinal AE Incidence (%)

**

Time (Weeks)

Duration: 104 weeks (including 52-week extension to the 52-week core study)Vildagliptin vs metformin

Not NI*

Study purpose: to demonstrate the efficacy and safety of vildagliptin compared to metformin in elderly treatment-naïve patients with T2DM

Target population: Drug-naïve elderly patients (age ≥ 65 years) with T2DM (baseline HbA1c 7-9%)

n=166 Met up to 1500 mg daily**

N* = 335

n=169 Vilda 100 mg qd

2 weeks 24 weeks

*Randomized population (original target before amendment: N = 850) ** Metformin dosing: 2 x 500 mg in the morning and 1 x 500 mg in the evening; titrated over 3 weeks T2DM= Type 2 diabetes mellitus; Met= metformin; Vilda= vildagliptin; HbA1c= glycosylated hemoglobin.Schweizer et al Diabetes, Obesity and Metabolism 2009, 11:804-812.

Vildagliptin compared to metformin in elderly treatment-naïve patients: study design and objective

Vildagliptin in elderly patients:similar HbA1c reductions compared to metformin

159

Change from BL to EPMean BL ~ 7.7%

161N=

Between-treatment difference

-0.64

0.11

-0.75

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

Ad

juste

d M

ean

Ch

an

ge

in H

bA

1c (

%)

Intention-to-treat population.BL=baseline; EP=end point; HbA1c=glycosylated hemoglobin.*95% CI (–0.08, 0.29), P=0.258; pre-specified non-inferiority margin = 0.4% and 0.3%.Schweizer A, et al. Diabetes Obes Metab. 2009; 11: 804–812.

Vildagliptin 100 mg once daily

Metformin 1500 mg once daily

Non-inferior* Vildagliptin 100 mg qd is not approved.

117

Vildagliptin has a good safety profile and a better GI tolerability than metformin in elderly patients: AEs with incidence ≥3% in any group

AE preferred term, % patientsVilda 100 mg qd

N=167Met 1500 mg/daily

N=165

Any preferred term 44.3 50.3

Nasopharyngitis 4.8 5.5

Dizziness 4.2 2.4

Headache 3.6 1.8

Hypertension 3.6 4.2

Abdominal pain 3.0 3.0

Cataract 3.0 0

Constipation 3.0 0.6

Diarrhea 3.0 13.3

Nausea 3.0 5.5

Osteoarthritis 3.0 1.2

Cough 1.2 3.0Safety populationVilda= vildagliptin; Met= metformin; AE= adverse eventsA patient with multiple occurrences of an AE under 1 treatment is counted only once in the AE categoryData on file, Novartis Pharmaceuticals, LAF237A2398.Schweizer A, et al. Diabetes Obes Metab. 2009; 11: 804–812.

Study purpose: To compare efficacy and safety of long-term vildagliptin vs. gliclazide monotherapy in drug naïve patients with T2DM in a two-year randomized, double-blind multicenter study

Target population: Drug naïve patients with T2DM (baseline HbA1c = 7.5%-11%)

n=546 Gliclazide up to 320 mg daily

N* = 1092

n=546 Vildagliptin 50 mg bid

2 weeks 104 weeks

*Randomized population T2DM= Type 2 diabetes mellitus; HbA1c= glycosylated hemoglobin.J Foley & S Sreenan, Horm Metabo Res 2009.41:905-909. erratum in Horm Metab Res 2009 41:909

Long term efficacy and safety of vildagliptin vs SU: study design and objective

Vildagliptin vs gliclazide in monotherapy setting: less weight gain and less hypoglycemia despite the unmet non inferiority

Per protocol population; ANCOVA results for change in HbA1c (%) or in body weight (kg) from baseline to endpoint† The associated 95% CI for the difference in mean change was (-0.06%, 0.33%) thus the study failed to meet the non-inferiority criterion of an upper limit of the CI of 0.3%, Adjusted mean change from BL to EP and between-treatment difference were from an ANCOVA model containing terms for treatment, baseline and pooled centers* p=0.004 between-treatment difference; 95% CI (-1.42,-0.27)Vilda= vildagliptin; Glic= gliclazide; HbA1c= glycosylated hemoglobin; BL= baseline; EP= end point; BL= baselineJ Foley & S Sreenan, Horm Metabo Res 2009.41:905-909. erratum in Horm Metab Res 2009 41:909

Glic up to 320 mg dailyVilda 50 mg bid

Ad

juste

d M

ean

C

han

ge

in

Hb

A1c (

%)

HbA1c Change(a)

from BL to EP

† Mean

Ch

an

ge in

B

od

y w

eig

ht

(kg

)

Body weight Change(a)

from BL to EPHypoglycemia(b)

% p

ati

en

ts w

ith

m

ild

hyp

og

lycem

ia

a: per protocolepopulation; b: safety population

120

Vildagliptin vs acarbose in Chinese population: study design and objective

* Randomized population.HbA1c=glycosylated hemoglobin; T2DM=type 2 diabetes mellitusPan C. et al. Diabeteic Medicine. 2008. 25:435-441

Objective: To assess the efficacy and safety of vildagliptin compared with acarbose in patients with T2DM during 24 weeks of treatment

Target Population: Drug-naïve T2DM patients; HbA1c 7.5%–11%

n=220 Acarbose ≤100 mg tid Drug naïve

N=661*

n=441 Vildagliptin 50 mg bid

24 weeks2 weeks

Vildagliptin is as effective as acarbose but with half the incidence of gastrointestinal side effects

Change in HbA1c is expressed for ITT population. Gastrointestinal adverse events reports from the safety population; ***p<0.001 vs acarboseBL=core baseline; CI=confidence interval; EP=study end point; HbA1c=glycosylated hemoglobinNI: Non-inferiority of vildagliptin as compared to acarbose demonstrated; 95% CI (-0.32, -0.10); statistical significance for non-inferiority margin defined by CI upper limit of 0.4%.Pan C. et al. Diabeteic Medicine. 2008. 25:435-441

Change from BL to EP*(BL Mean ~8.6)

Vildagliptin 50 mg bidAcarbose ≤100 mg tid

Mea

n C

ha

ng

e in

Hb

A1c

(%)

12.3

25.5

0

5

10

15

20

25

30

(% p

ati

en

ts r

ep

ort

ing

GI

ad

ve

rse

ev

en

ts)

Gastrointestinal adverse events

n= 440 220n= 441 220

***

NI

Series1

-1.5

-1

-0.5

0

-1.4-1.3

Vildagliptin monotherapy vs voglibose in Japanese population: study design and objective

n=188 Vildagliptin 50 mg BID

12 weeks

Objective: To compare the efficacy and tolerability of vildagliptin vs voglibose, an α-glucosidase inhibitor, in a Japanese population with T2DM.

Design: Randomized, double-blind, active-controlled, parallel-arm 12 weeks study.

N=380

n=192 Voglibose 0.2 mg TID

T2DM=type 2 diabetes mellitus.Vildagliptin monotherapy is not approved in EU, please refer to your local label (SmPC).Vildagliptin monotherapy is approved in Japan (Japan label).

2 weeks

Drug-naïve

Iwamoto Y et al. Diab Obes Metab 2010, 12:700-708.

Ad

just

ed M

ean

Ch

ang

e in

H

bA

1c (

%)

188 192n=

Vildagliptin monotherapy is superior to voglibose monotherapy in Japanese population

Change from BL to Wk 12 Mean BL ~ 7.5 %

Voglibose 0.2 mg tidVildagliptin 50 mg bid

• p< 0.001 vs voglibose

Iwamoto Y et al. Diab Obes Metab 2010, 12:700-708.

At 12 weeks treatment

Vildagliptin monotherapy is not approved in EU, please refer to your local label (SmPC).Vildagliptin monotherapy is approved in Japan (Japan label).

Target HbA1c ≤6.5%

Reduction≥ 1.0%

% p

atie

nts

rea

chin

g t

arg

et

n 65 65 71 72

Series1

-1

-0.8

-0.6

-0.4

-0.2

0

-0.95 *

-0.380000000000002

% patientsVildagliptin 50 md BID

(n=188)Voglibose 0.2 mg TID

(n=192)

Any AE 61.2 71.4

Serious AE 0.0 2.1

Suspected drug-related AE 25.0 40.6

DC due to AE 2.1 2.1

Hypoglycemia 0.0 0.5

Gastrointestinal AE 18.6** 32.8

Specific AEs occurring in >4% of either group

Nasopharyngitis 18.1 16.7

Constipation 6.9 6.8

Flatulence 3.2 12.0

Abdominal distension 2.1 7.3

Diarrhoea 1.6 5.7

↑ Alanine aminotransferase 1.6 5.7

Better GI tolerability with vildagliptin monotherapy vs voglibose monotherapy in Japanese population

**P=0.002 vs voglibose.AE=adverse event; DC=discontinuation.

Iwamoto Y et al. Diab Obes Metab 2010, 12:700-708.

Vildagliptin monotherapy is not approved in EU, please refer to your local label (SmPC).Vildagliptin monotherapy is approved in Japan (Japan label).

7) Vildagliptin in combination therapy settings

7.1) Vildagliptin on top of metformin demonstrates favorable efficacy and tolerability profile

Effects of vildagliptin and vildagliptin plus metformin on fasting GLP-1 levels

0

2

4

6

8

10

12

14

*

In

tact

GL

P-1

(p

M)

Fasting Levels of Intact GLP-1 at Baseline and at 3 Months

BL=baseline; GLP-1=glucagon-like peptide-1; met=metformin; PBO=placebo; vilda=vildagliptin.*P <0.05 vildagliptin 3 months vs baseline; **P <0.05 vildagliptin add-on metformin significantly improved at 3 months vs baseline.†Contains patients on vildagliptin alone and those on vildagliptin plus metformin.

D’Alessio DA, et al. J Clin Endocrinol Metab. 2009; 94: 81-88.

Vilda group† Placebo

BL BL3 months 3 months

n = 20 20 19 19

In

tact

GL

P-1

(p

M)

**

02

468

10

1214

Vilda only

Fasting Levels of Intact GLP-1 in Vildagliptin Subgroups at 3 Months

Vilda + met

7 13

Vildagliptin dosing: 50 mg bid

Vildagliptin add-on to metformin: significantly lowers HbA1c over 52 weeks

6.8

7.2

7.6

8.0

8.4

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

Week

Vilda 50 mg daily + met (extension, ITT n=42)

PBO + met (extension, ITT n=29)

Vilda 50 mg daily + met (core, ITT n=56)

PBO + met (core, ITT n=51)

Hb

A1c

(%

)

P <0.0001

P <0.0001 –1.1 ± 0.2%

n refers to ITT population.HbA1c=hemoglobin A1c; ITT=intention-to-treat; met=metformin; PBO=placebo; vilda=vildagliptin.Adapted from Ahrén B, et al. Diabetes Care. 2004; 27: 2874–2880.

Duration: 52 weeksVilda add-on to met

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*

Vildagliptin produces clinically meaningful, dose related decreases in A1C and 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)

Mea

n H

bA

1c (

%)

−0.7% vs placebo

−1.1% vs placebo

*

*

Duration: 24 weeksVildagliptin add-onto metformin

Time (Weeks)

Mea

n F

PG

(m

mo

l/L)

−4 0 4 8 12 16 20 24

8

9

10

11

−0.8 vs placebo

−1.7 vs placebo

**

***

Duration: 24 weeksVildagliptin add-onto metformin

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

Reduction in HbA1c Reduction in FPG

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. Diabetes Care. 2007; 30: 890–895.

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

β-cell Function

Placebo-adjusted values

Ad

jus

ted

Mea

n C

han

ge

in I

SR

AU

C /

Glu

co

se A

UC

* *

5.25.7

0.0

2.0

4.0

6.0

8.0

10.0

Ad

jus

ted

Mea

n C

han

ge

in 2

-h P

PG

(m

mo

l/L

)

*

*

-1.9

-2.3

-3.0

-2.0

-1.0

0.0

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

Duration: 24 weeksVilda add-on to met

2-h PPG

Placebo-adjusted values

Vildagliptin: efficacious in elderly and obese patients and those with poorly controlled T2DM

BL=baseline; BMI=body mass index; HbA1c=hemoglobin A1c;met=metformin; PBO=placebo; T2DM=type 2 diabetes mellitus; vilda=vildagliptin.Primary intention-to-treat population.Data on file, Novartis Pharmaceuticals, LAF237A2303.

>65 yearsMean BL ~8.3%

BL BMI >30 kg/m2

Mean BL ~8.3%

Vilda 50 mg twice daily + met

PBO + met

Ch

ang

e f

rom

BL

in

Hb

A1c

(%)

n= 20 22 103 86 29 29

BL HbA1c>9%

Duration: 24 weeksVilda add-on to met Add-on Treatment to Metformin (2.1 g Mean Daily)

Primary objective: To compare efficacy and safety of vildagliptin as add-on to metformin

Target population: Chinese T2DM patients not controlled (HbA1c 6.4-10.8%) on a stable metformin monotherapy

n=144 Placebo + Metformin ‡

N = 438 n= 146 Vildagliptin 50 mg bid + Metformin‡

2 weeks 24 weeks

Metformin

n= 148 Vildagliptin 50 mg qd + Metformin‡ n= 148 Vildagliptin 50 mg qd + Metformin‡

‡ metformin dose >= 1500 mg daily

Vildagliptin add on to metformin in Chinese patients : Study design and objective

Data on file LAF237A23140

Vildagliptin add on to metformin in Chinese patients : significant improvement in HbA1c, FPP and PPG

Note: 50 qd data for HbA1c change vs baseline were secondary endpointData on file LAF237A23140 Table s 11-4, 11-5, 11.7, 11-8, Figure 11.1

Change in FPG (mmol/L) from baseline to endpoint

Change in 2h prandial glucose from baseline to end point

Vilda 50 mg qd

Vilda 50 mg bid

placebo

* P<0.001 vs. Placebo** P=0.001 vs. Placebo*** P<0.05 vs Placebo

***

Ad

juste

d m

ean

ch

an

ge

******

Ad

juste

d c

han

ge in

2-h

r p

ran

dia

l

glu

cose (

mm

ol/

L)

N=40 N=46 N=44

N=147 N=145 N=144

*

**

HbA1c reductionBL 8.768.788.72

BL 13.1313.4912.29

Vildagliptin increases number of patients reaching targets in Chinese patients not controlled with metformin

Reduction HbA1c <7.0% at end point Reduction HbA1c <= 6.5% at end point

*p =0.018 vs placebo; ** p=0.002 vs placebo; *** p=0.222 vs placebo; ****p=0.061

Data on file LAF237A23140, Table 11-6

48.9

26.2

53.7

29.734.8

20.1

0

10

20

30

40

50

60

70

vilda 50 qd + met vilda 50 mg bid + met Placebo

n / N = 67/147 73 / 145 48/144 38/147 43/145 29/144

**

***

*

****

% p

atie

nts

rea

chin

g t

arg

et

Preferred term Vilda 50 mg qd*

Vilda 50 mg bid

Placebo

Diarrhea 3.4 4.1 2.1

Papitations 2.7 2.7 1.4

Urinary tract infection 2.7 0.7 0.0

Dizziness 2.7 2.7 2.1

Diabetic nephropathy 2.7 0.7 2.8

Nasopharyngitis 2.0 0.7 2.8

Nausea 1.4 0.7 3.5

Hyperhidrosis 0.7 3.4 2.1

Abdominal disconfort 0.0 0.7 2.8

Vildagliptin add on to metformin in Chinese patients :% patients reporting AEs (≥ 2.5% in any group)

Safety population**Vildagliptin 100 mg once daily is not a therapeutic dose according to the Basic Prescribing Information documentData on file LAF237A23140 Table 12-3

Vildagliptin vs pioglitazone as add-on to metformin: study design and objective

Primary objective: to compare efficacy and safety of vildagliptin 50 mg twice daily vs pioglitazone 30 mg once daily both as add-on to metformin during 52 (with interim analysis at 24 weeks)

Target population: patients with T2DM inadequately controlled with metformin monotherapy (baseline HbA1c 7.5–11%)

n=281: Pioglitazone 30 mg once daily + metformin

N=576*

n=295: Vildagliptin 50 mg twice daily + metformin

24 weeks4 weeks 28 weeksInterim analysis

Double-blind1 Single-blind2

Metformin≥1500 mg

HbA1c=haemoglobin A1c; T2DM=type 2 diabetes mellitus.1Bolli G, et al. Diabetes Obes Metab. 2008; 10: 82–90; 2 Bolli G, et al. Diabetes Obes Metab. 2009; 11: 589–595.

-1.0

-1.5-1.5

-0.9

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

In patients uncontrolled with metformin vildaglipitn achieves similar HbA1c drop compared with pioglitazone

OverallMean BL ~8.4%

BL=baseline; HbA1c=hemoglobin A1c; met=metformin; pio=pioglitazone; vilda=vildagliptin.Per protocol population. *Non-inferiority of vildagliptin to pioglitazone established at both 0.4% and 0.3% margins,95% confidence interval=(-0.05, 0.26). Adjusted mean change derived from analysis of covariance model.Bolli G, et al. Diabetes Obes Metab. 2008; 10: 82–90.

Ad

jus

ted

Mea

n C

han

ge

in

Hb

A1c

(%

)

HbA1c >9%Mean BL ~9.7%

n = 264 246

Pio 30 mg once daily + metVilda 50 mg twice daily + met

63 58

Non-inferior*

Duration: 24 weeksAdd-on to met:vilda vs pio

Add-on Treatment to Metformin (2.0 g Mean Daily)

In patients uncontrolled with metformin vildagliptin is the only DPP-4 inhibitor showing similar efficacy to pioglitazone at 1 year without weight gain

HbA1c=hemoglobin A1c, NI=non-inferiority, * P<0.001 pio vs BLIntention-to-treat population. Vildagliptin (n=295); pioglitazone (n=281).Bolli G, et al. Diabetes Obes Metab. 2009; 11: 589–595.

Vildagliptin 50 mg bid + metformin

Pioglitazone 30 mg od + metformin

24-week analysis

Vilda NI established

−4 0 4 12 16 24 32 40 52

Time (Weeks)

7.0

7.5

8.0

8.5

9.0

Mea

n H

bA

1c (

%)

Duration: 52 weeks add-on to metformin: vildagliptin vs pioglitazone

n=277n=293U

na

dju

ste

d M

ea

nC

ha

ng

e i

n B

od

y W

eig

ht

(kg

) *

Change in Body Weight(Mean BL Body Weight ~91 kg)

*P <0.001 change from baseline

Change in HbA1c

0.2

2.6

0.0

0.5

1.0

1.5

2.0

2.5

3.0

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

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 with1 hypos (%)

Number of severe hypoglycaemic

events c

Inci

de

nce

(%

)

1389 1383 1389 1383 1389 1383n =

No

. o

f ev

en

ts

No

. o

f ev

en

ts

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 intervalNI=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

A1c

(%

)

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

just

ed m

ean

ch

ang

e in

b

od

y w

eig

ht

(kg

) fr

om

BL

(BL mean ~88.8kg)

1117n = 1071

Change in body weight a

*

No

. o

f ev

en

ts

Duration: 104 weeks, add-on to metformin: vildagliptin vs glimepiride Hypoglycaemia 2

1) Per protocol population. 2) Safety population. 3) Intent-to-treat population. a) any episode requiring the assistance of another party *p <0.001. BL=baseline; EP = week 104 endpoint; Met= metformin; hypo = hypoglycemia; HbA1c= glycosylated hemoglobin. Matthews DR et al. Diab Obes Metab 2010; 12: 780–789.

Vildagliptin was as effective as glimepiride when added to metformin at 104 weeks with no weight gain and low incidence of hypoglycemia

No

. o

f ev

en

ts

Inci

de

nce

(%

)

18.2

Patients with > 1 hypo (%) Discontinuations due to hyposNumber of severe events aNumber of hypo events

1553 1546N =

Glimepiride up to 6 mg qd +met

Vildagliptin 50 mg bid + met

No

. o

f ev

en

ts

59

1553 1546N = 1553 1546N = 1553 1546N =

Mean HbA1c 1

Adjusted mean change in HbA1c was comparable between vildagliptin and glimepiride treatment: −0.1% (0.0%) for both

Primary objective of non-inferiority was met: 97.5% CI= (-0.00, 0.17); upper limit 0.3%

0

13

02468

10121416

0

15

0

2

4

6

8

10

12

14

16

-0.3 -1.5

1.2

-2.0

-1.0

0.0

1.0

2.0A

dju

ste

d m

ean

ch

an

ge

in

bo

dy

we

igh

t (k

g) 1539n = 1520

*

Change in body weight 3

Change from BL to EP(BL Mean ~89kg)

Between-treatment Difference

AE preferred term, % patients

Vilda 50 mg bid + met

n=1553

Glim up to 6 mg + met

n=1546

Any AE 83.1 86.4

Nasopharyngitis 14.7 13.6

Headache 9.6 9.2

Back pain 9.4 9.5

Bronchitis 9.1 7.3

Dizziness 8.2 16.0

Arthralgia 7.8 6.3

Influenza 7.6 6.4

Diarrhoea 7.4 7.3

Hypertension 6.7 8.1

Upper respiratory tract infection

6.6 5.2

Vildagliptin vs. glimepiride as add-on to metformin: AEs with incidence 5% in any group

AE preferred term, % patients

Vilda 50 mg bid +

met n=1553

Glim up to 6 mg +

metn=1546

Cough 6.2 5.4

Pain in extremity 5.7 6.3

Fatigue 5.4 8.0

Osteoarthritis 5.2 4.3

Asthenia 5.0 11.7

Nausea 4.9 6.0

Tremor 4.8 21.7

Hyperhidrosis 4.5 18.7

Oedema peripheral

2.9 5.0

Hypoglycaemia 2.3 18.2

Hunger 0.9 5.2

Safety population; orange highlighted: hypoglycaemia and symptoms suggestive of hypoglycaemia.AE=adverse event; bid=twice daily; glim=glimiperide; met=metformin; vilda=vildagliptin.

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

Study purpose: to compare the effect of 52 weeks treatment with Vidagliptin 50 mg bid to gliclazide up to 320 mg daily as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy

Target population: T2DM patients inadequately controlled on a stable metformin monotherapy (baseline HbA1c 7.5-11%)

n=494 Gliclazide up to 320 mg# + Met‡

N** = 1007

n=513 Vildagliptin 50 mg bid + Met‡

4 weeks 52 weeks

Metformin‡

Filozof and Gautier. Diabetes Medicine. 2010; 27: 318-326.

Vildagliptin vs. gliclazide as add on to metformin:study design and objective

**Randomized population; ‡ met minimum dose 1500 mg/d; #Gliclazide was titrated from 80 mg initial dose to a maximum daily dose of 320 mg; Patients on gliclazide were titrated to the next dose level at weeks 4 (to 160 mg), 8 (to 240 mg), and 12 (to 320 mg), if the fasting plasma glucose was > 7 mmol/L (126 mg/dL) or fasting blood glucose was > 6.3 mmol/L (113 mg/dL) and titration was not contraindicated in the investigator’s opinion due to the risk of hypoglycemia T2DM= Type 2 diabetes mellitus; Met= metformin; HbA1c= glycosylated hemoglobin.

Filozof and Gautier. Diabetes Medicine. 2010; 27: 318-326.

Change Body weightb from BL to week 52

Glic up to 320 mg + MetVilda 50 mg bid + Met

5 / 510 5 / 493 n/N=

Number of hypoglycemic events#

Patients with one or more hypos (%)

Inc

ide

nc

e (

%)

Nu

mb

er

of

ev

en

ts

510 493 N=

Mean BL ~ 85 kg

Glic= gliclazide; Met= metformin; Vilda= vildagliptin; BL= baseline; EP= end point; * p<0.001 Vilda vs Glic, 95% CI (-1.77, -0.79), adjusted mean change from BL to EP; b) per protocol population; c) safety population;

# All hypoglycemic events: grade 1

Mean HbA1c

EP

Hypoglycemic eventsc

Mean difference of adjusted values: 0.04% 95%CI: -0.11, 0.20

Vildagliptin provides similar HbA1c reduction as gliclazide but with a better tolerability profile

-0.81% vilda + met-0.84 glic +met Non-inferior

Me

an

Hb

A1

c (

%)

7

7.5

8

8.5

9

-4 0 4 12 16 24 32 40 52 56

Time (Week)

Ad

jus

ted

Me

an

Ch

an

ge

in

b

od

y w

eig

ht

(kg

)

386 393N=

0.08

1.36

0.0

0.4

0.8

1.2

*

Vildagliptin vs. gliclazide as add on to metformin:AEs with incidence in ≥4% in any group

Safety population; orange highlighted: hypoglycaemia and symptoms suggestive of hypoglycaemia AEs= adverse events; Vilda= vildagliptin; Glic= gliclazide; Met= metforminFilozof and Gautier. Diabetes Medicine. 2010; 27: 318-326.

AE preferred term, % patientsVilda 50 mg bid + Met

N=510% (n)

Glic up to 320 mg + MetN=493

Any AE 61.8 (315) 61.3 (302)

Nasopharyngitis 6.3 (32) 5.7 (28)

Hypertension 5.7 (29) 6.3 (31)

Diarrhea 5.1 (26) 5.5 (27)

Headache 3.1 (16) 5.7 (28)

Pain in extremity 2.7 (14) 4.5 (22)

Asthenia 2.2 (11) 4.9 (24)

Bronchitis 2.0 (10) 4.1 (20)

Fatigue 2.0 (10) 4.1 (20)

Tremor 1.8 (9) 4.9 (24)

Hyperhidrosis 1.4 (7) 5.3 (26)

Initial combination of vildagliptin and metformin:study design and objectives

Primary objective: to demonstrate efficacy of single-pill combination therapy of vildagliptin and metformin compared with individual monotherapy in drug-naïve patients with T2DM in a multicenter, randomized, double-blind, active-controlled study

Target population: drug-naïve patients with T2DM (HbA1c 7.5–11%)

*Randomized population. HbA1c=hemoglobin A1c; met=metformin; T2DM=type 2 diabetes mellitus; vilda=vildagliptin.Bosi E, et al Diabe Obes Metab. 2009; 11: 506–515.

Met 500 mg qd Met 500 mg bidMet 1000 mg AMMet 500 mg PM

Metformin 1000 mg bid

Vilda 50 mg qdVildagliptin 50 mg bidn=300

n=294

Vilda / met 50/500 mg qdLow dose: vilda / met 50/500 mg bidn=290

50/1000 mg AM 50/500 mg PM

High dose: vilda / met 50/1000 mg bidn=29550/500 mg bid

Screening Titration Maintenance

N=1179*

2 weeks 2 weeks 2 weeks 2 weeks 18 weeks

24 weeks

Vilda/met 50/500 qd

Initial combination of vildagliptin + metformin provides significantly more HbA1c reductions than the monotherapies

Mea

n C

ha

ng

e in

Hb

A1c

(%

)

Intention-to-treat population.HbA1c=hemoglobin A1c; HD=high dose; LD=low dose; met=metformin; vilda=vildagliptin.Bosi E, et al. Diab Obes Metab. 2009; 11: 506–515.

n = 287 277

Change from Baseline to End Point

Mean Baseline HbA1c ~8.6%

285 285

P <0.001

P=0.004

P <0.001

P <0.001

Vilda + HD met (50/1000 mg bid)

Vilda + LD met (50/500 mg bid)Met 1000 mg bid

Vilda 50 mg bid

Duration: 24 weeksVilda + met vs mono

Initial combination of vildagliptin + metformin:robust change in FPG

Mea

n C

ha

ng

e in

FP

G (

mm

ol/

L)

P <0.001

P=0.999*

P <0.001

P <0.001

Vilda + HD met (50/1000 mg bid)

Vilda + LD met (50/500 mg bid)

Met 1000 mg bid

Vilda 50 mg bid

Change from Baseline to End PointMean baseline FPG ~10.4 mmol/L

287 277285 285n =

Duration: 24 weeksvilda + met vs mono

Intention-to-treat population.FPG=fasting plasma glucose; HD=high dose; LD=low dose; met=metformin; vilda=vildagliptin.Bosi E, et al. Diabetes Obes Metab. 2009; 11: 506–515; *Data on file, Novartis Pharmaceuticals, LMF237A2302.

Initial combination of vildagliptin and metformin:effective across the hyperglycemia spectrum (data from corestudy and open-label sub-study)

~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 daily** + met 2000 mg daily open-label sub-study (P <0.001vs BL)d

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

BL mean=

n =

>11%

~12. 1%

86

*

Duration: 24 weeksVilda + met vs mono

As with traditional OADs, vildagliptin as add-on to metformin substantially reduces HbA1c in patients with high baseline levels

7.2) Vildagliptin significantly reduces HbA1c in patients uncontrolled with only SU or TZD

Vildagliptin add-on to maximum-dose pioglitazone: study design and objective

4 weeks 24 weeks

Pioglitazone45 mg daily

N=398*

n=138: Placebo + pioglitazone 45 mg daily

n=136: Vildagliptin 50 mg twice daily + pioglitazone 45 mg daily

n=124: Vildagliptin 50 mg once daily + pioglitazone 45 mg daily

Objective: to demonstrate that HbA1c reduction with vildagliptin(50 mg once daily or 50 mg twice daily) is superior to that with placebo after 24 weeks of treatment as add-on to pioglitazone therapy

Target population: patients with T2DM inadequately controlled with prior thiazolidinedione monotherapy (HbA1c 7.5–11%)

HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus.*Patient number refers to primary intention-to-treat population.Garber A et al. Diabetes Obes Metab. 2007; 9: 166–174.

Vildagliptin as add-on to pioglitazone effectively decreased HbA1c levels in patients inadequately controlled with a maximum dose of TZD monotherapy

HbA1c=hemoglobin A1c; PBO=placebo; pio=pioglitazone; vilda=vildagliptin.*P ≤0.001 vs PBO. Primary intention-to-treat population.Garber A et al. Diabetes Obes Metab. 2007; 9: 166–174.

PBO + pio 45 mg daily (n=138)

Vilda 50 mg once daily + pio (n=124)

Vilda 50 mg twice daily + pio (n=136)

Time (Weeks)

Mea

n H

bA

1c (

%)

7.4

7.6

7.8

8.0

8.2

8.4

8.6

8.8

9.0

−4 0 4 8 12 16 20 24

*

*

–0.5% vs PBO

–0.7% vs PBO

Duration: 24 weeksAdd-on to pio:vilda vs PBO

Add-on Treatment to Pioglitazone 45 mg Daily

Vildagliptin add-on to glimepiride: study design and objective

HbA1c=hemoglobin A1c; SU=sulfonylurea; T2DM=type 2 diabetes mellitus.*Patient number refers to primary intention-to-treat population.Garber A et al. Diabetes Obes Metab. 2008; 10: 1047–1056.

4 weeks

Glimepiride4 mg daily

N=408*

n=144: Placebo + glimepiride 4 mg once daily

n=132: Vildagliptin 50 mg twice daily + glimepiride 4 mg once daily

n=132: Vildagliptin 50 mg once daily + glimepiride 4 mg once daily

24 weeks

Objective: to demonstrate superior HbA1c reduction with vildagliptin + glimepiride vs placebo + glimepiride

Target population: patients with T2DM not adequately controlled with an SU; HbA1c 7.5–11%

HbA1c=hemoglobin A1c; PBO=placebo; SU=sulfonylurea; vilda=vildagliptin.*P <0.001 vs PBO. Primary intention-to-treat population.Garber A et al. Diabetes Obes Metab. 2008; 10: 1047–1056.

Vildagliptin as add-on to glimepiride produces clinically meaningful reductions in HbA1c levels in patients with T2DM not adequately treated with a sulfonylurea

−0.6% vs PBO

−0.7% vs PBO

Time (Weeks)

7.6

7.8

8.0

8.2

8.4

8.6

8.8

9.0

−4 0 4 8 12 16 20 24

Mea

n H

bA

1c (

%)

PBO + glimepiride (n=144)

Vilda 50 mg once daily + glimepiride (n=132)Vilda 50 mg twice daily + glimepiride (n=132)

*

*

Duration: 24 weeksAdd-on to SU:vilda vs PBO

Add-on Treatment to an SU (Glimepiride 4 mg Once Daily)

Objective: To demonstrate the efficacy of add-on therapy with vildagliptin to glimepiride in patients with type 2 diabetes inadequately controlled with prior glimepiride monotherapy

Design: Randomized, double-blind, placebo-controlled, parallel-arm study

Study population: patients with T2DM inadequately controlled on a stable glimepiride monotherapy (dose≥1mg/d, baseline HbA1c 7.0–10.0%)

n=102 Vildagliptin 50 mg BID + Glimepiride (up to 1mg OD)

12 weeks

N=202

n=100 Placebo + Glimepiride (up to 1mg OD)Glimepiride

Efficacy and tolerability of vildagliptin as add-on to glimepiride in Japanese patients with Type 2 Diabetes

T2DM=type 2 diabetes mellitus.Kikuchi M et al. Diab Res Clin Pract. 2010; 89:216-223.

Vildagliptin 50 mg qd as add on to SU is approved in EU (SmPC).Vildagliptin as add on to SU 50 mg qd or bid is approved in Japan (Japan label).

Mea

n H

bA

1c (

%)

6.5

7.5

8.5

-2 0 2 4 8 12

Vilda+Glim

Placebo+Glim

8.0

7.0

6.0

Time (week)

Vildagliptin as add-on to glimepiride in Japanese patients: significant HbA1c drop

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Vilda+Glim(N=102)

Placebo+Glim (N=100)

- 1.00

- 0.06

LS

Mea

n c

han

ge

in H

bA

1c (

%)

p ＜0.001

Mean HbA1C±SD; Full Analysis Set (FAS) population

Kikuchi M et al. Diab Res Clin Pract. 2010; 89:216-223.

LS (Least square) mean change ±SD;FAS population; P-value, ANCOVA

Vildagliptin 50 mg qd as add on to SU is approved in EU (SmPC).Vildagliptin as add on to SU 50 mg qd or bid is approved in Japan (Japan label).

Higher responder rates with vildagliptin as add-on to glimepiride vs placebo in Japanese patients

FAS population; p-value, chi-square test;

1) Subjects with HbA1c ≤ 6.5% at endpoint / subjects with HbA1c > 6.5% at baseline (%)

2) N’ is the number of subjects with observations at both baseline and endpoint. %: percentages based on N’

Achieved HbA1c≤6.5%1,2

≥1.0% decreasing in HbA1c2

Vilda+Glim(N=102)

Placebo+Glim(N=100)

Vilda+Glim(N=102)

Placebo+Glim(N=100)

45.0

3.0

54.9

5.0

0

20

40

60

80(%)

0

20

40

60

80(%)

p ＜ 0.001p ＜ 0.001

Kikuchi M, et al. Diab Res Clin Pract 2010 89:216-223.

Vildagliptin 50 mg qd as add on to SU is approved in EU (SmPC).Vildagliptin as add on to SU 50 mg qd or bid is approved in Japan (Japan label).

8) Vildagliptin: the power of mechanistic evidence

8.1) Vildagliptin enhances islet function by improving α- and β-cell sensitivity to glucose restoring the physiological balance between glucagon and insulin

Acute effects of vildagliptin on insulin, glucose and glucagon levels in patients with T2DM

OGTT 30 min after Single Oral Dose of Vildagliptin (100 mg qd**)

OGTT=oral glucose tolerance test. *P <0.01. ** 100 mg qd is NOT an approved dose.He YL, et al. J Clin Pharmacol. 2007; 47: 633–641. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea.

7.5

12.5

17.5

22.5

Glu

co

se

(m

mo

l/L

)

0

60

80

100

120

40

20

Ins

uli

n

(pm

ol/

L)

60

80

100

120

140

Glu

ca

go

n(n

g/L

)

−90 −60 −30 0 30

60

90

120

150

180

210

240

270

300

−90 −60 −30 0 30

60

90

120

150

180

210

240

270

300

−90 −60 −30 0 30

60

90

120

150

180

210

240

270

300Time

Vildagliptin 100 mg** (n=15)Placebo (n=16)

75 g Glucose

Dose

Meal

*

*

*

*

*

** * *

**

*

Vildagliptin 100 mg (n=16)

Placebo (n=16)

Acute effects of vildagliptin on GLP-1 levels in patients with T2DM: increased GLP-1 levels that persist beyond the post-meal period

GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus.*P <0.05.Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd,

0.0

4.0

8.0

12.0

16.0

17:00 20:00 23:00 02:00 05:00 08:00

Time

Acti

ve G

LP

-1 (

pm

ol/

L)

*

161

Acute effects of vildagliptin on glucagon levels in patients with T2DM: decreased glucagon levels persist beyond the post-meal period

Meal

*

* **

*

*

*

*

*P <0.05 vs placebo.Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd,

−60

−50

−40

−30

−20

−10

0

10

20

17:00Time

Delt

a G

lucag

on

(n

g/L

)

20:00 23:00 02:00 05:00 08:00

Placebo (n=16)Vildagliptin 100 mg (n=16)

*

162

Acute effects of vildagliptin on endogenous glucose production (EGP) levels in patients with T2DM: decreased EGP levels persist beyond post-meal period

EGP=endogenous glucose production.*P <0.05 vs placebo.Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255. Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea. Galvus is NOT approved for 100 mg qd,

0

−0.3

−0.6

−0.9

−1.2

−1.5

Del

ta E

GP

(m

g/k

g/m

in)

17:00 20:00 23:00 02:00 05:00 08:00

Time

**********

*

*

****************Placebo (n=16)Vildagliptin 100 mg (n=16)

Meal

Acute effects of vildagliptin on insulin secretion rates in patients with T2DM: increased rate persists beyond the post-meal period

AUC=area under the curve; ISR=insulin secretion rate.*P <0.05.** 100 mg qd is NOT an approved dose. Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255.Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily incombination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea.

ISR

(A

UC

) /

glu

cose

(A

UC

) 1

00 (

pm

ol•

kg-1•m

in-1)/

(mg

/dL

)

0

2

4

6

8

18:00

* **

**** * * * * * * * * * * * * * *

Time

20:00 23:00 02:00 05:00 08:00

Placebo (n=16)

Vildagliptin 100 mg qd** (n=16)

**

Meal

Comparison of plasma GLP-1 levels following 3 Months’ treatment with vildagliptin or sitagliptin

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.Marfella R, et al. J Diabetes Complications. 24: 79-83, 2010..

30

25

20

15

10

5

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

Breakfast Lunch Dinner

Inta

ct G

LP

-1 (

pm

ol/

L)

Sitagliptin 100 mg once daily + metformin (N=20)

Vildagliptin 50 mg twice daily + metformin (N=18)

Retrospective analysis of patients on sitagliptin (N=20) or vildagliptin (N=18)

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

sma

Glu

cag

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 30 60 90 120 180 240 300 min

Retrospective analysis of patients on sitagliptin (N=20) or vildagliptin (N=18)

Vildagliptin improves β-cell sensitivity to glucose

Vildagliptin 50 mg once daily

Placebo

Mari A, et al. J Clin Endocrinol Metab. 2008; 93: 103–109.

Sec

reti

on

at

7 m

M g

luco

se(p

mo

l/min

/m2)

180

200

220

240

260

−4 0 4 8 12 16202428323640444852

Time (weeks)

Basal Secretory Tone

45

50

55

60

65

70

75

−4 0 4 8 12 1620 24 2832 36 40 4448 52Time (weeks)

Glu

cose

Sen

siti

vity

(pm

ol/m

in/m

2/m

M)

Glucose Sensitivity

Ahrén B, et al. J Clin Endocrinol Metab. 2009;94(4):1236–1243.Vildagliptin 100 mg once daily is NOT an approved dose.

Effects of vildagliptin treatment on the sensitivity of the α-cell to glucose

Time (min)

−30 0 30 60 90 120 165 210 255 28590

110

130

150

170

Dose

Meal

Glu

cag

on

(n

g/L

)

7.5 mM 5.0 mM 2.5 mM

Placebo

Vildagliptin 100 mg once daily

8.2) Vildagliptin reduces insulin resistance

Vildagliptin treatment improves insulin sensitivity

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Duration: 6 weeksVildagliptin vsplacebo

Glu

cose

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

* * *

0 12 24 52

Time (Week)

* * †

0 12 24 52

Time (Week)

pm

ol/

L 3

0 m

in/(

mm

ol/

L)

0 12 24 52

Time (Week)

* *

mL

· m

in-1 ·

m -2

0.050

0.040

0.045

0.025

0.030

0.035

300

250

275

200

225

14

10

12

6

8

InsulinSecretio

n

Insulin Sensitivit

y

Adaptation

Index

Effects of vildagliptin treatment on -cell function and insulin sensitivity over 52 Weeks

Patients on Stable Metformin Therapy

*P <0.05 vs placebo; †P <0.01 vs placebo.Adapted from Ahrén B, et al. Diabetes Care. 2005; 28: 1936–1940.

Vildagliptin 50 mg daily / metformin

Placebo / metformin

nm

ol C

-pe

pti

de ·

mm

ol g

luc

os

e-1 ·

m

L-1 ·

m-2

8.3) Vildagliptin reduces postprandial lipids

Vildagliptin improves postprandial lipid and lipoprotein metabolism

TG=triglyceride; Vilda=vildagliptin.Matikainen N, et al. Diabetologia. 2006; 49: 2049–2057.

Before vilda, Week 0 (n=13)Vilda 50 mg twice daily,Week 4 (n=15)

0.8

0.6

0.4

0.2

0.0−1 0 1 2 3 4 5 6 7 8

0.08

0.06

0.04

0.02

0.00−1 0 1 2 3 4 5 6 7 8

Time (h)

0.50

0.40

0.30

0.20

0.10

0.00−1 0 1 2 3 4 5 6 7 8

Time (h)

4.0

3.5

3.0

2.5

2.0

1.5

1.0−1 0 1 2 3 4 5 6 7 8

Plasma TG Chylomicron TG

Chylomicron apo B-48 Chylomicron cholesterol

mm

ol/

L

mm

ol/

Lm

mo

l/L

mg

/L

8.4) Vildagliptin has the potential for disease prevention and modification

Replication

-c

ell

Ma

ss

(m

g)

Vehicle Vildagliptin

P <0.05

0.000.020.040.060.080.100.120.14

VehicleBrd

U-p

os

itiv

e C

ell

s (

%)

P <0.001

0

20

40

60

80

100

120

Vildagliptin

Ap

op

Tag

-po

sit

ive

Ce

lls

(%

)

Vehicle Vildagliptin

P <0.05

0.0

0.5

1.0

1.5

2.0

2.5

Apoptosis -cell Mass

Vildagliptin60 mg/kg21 days

Vehicle

Insulin

Day 7 Day 21

Duttaroy A, et al. Diabetes. 2005; 54 (Suppl 1): A141. Abstract 572-P and poster presented at ADA.

Effect of vildagliptin on β-cell mass in a neonatal rat pancreatic growth model

Vildagliptin increases pancreatic beta cell mass in neonatal rats

Duttaroy A. et al. European J Pharmacol. 2011; 650: 703–707

Control Vildagliptin

Day 7BrdU+ cells

Day 7Apoptag+ cells

Day 21Insulin+ cells

*p<0.05; **p<0.01

Replication

Apoptosis

-cell Mass

ISR/G=insulin-secretory rate relative to glucose concentration.Scherbaum WA, et al. Diabetes Obes Metab. 2008; 10: 1114–1124.

Durability of β-cell function over 2 yearsM

ean

IS

R/G

(p

mo

l/m

in/m

2/m

M)

Time (Weeks)

Treatment period Wk 0–52 Treatment period Wk 56–108Washout Washout

Placebo (n=40)

Vildagliptin 50 mg once daily (n=49)

30−8 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112

35

40

45

50

* * *

0 12 24 52

Time (Week)

* * †

0 12 24 52

Time (Week)

pm

ol/

L 3

0 m

in/(

mm

ol/

L)

0 12 24 52

Time (Week)

* *

mL

· m

in-1 ·

m -2

0.050

0.040

0.045

0.025

0.030

0.035

300

250

275

200

225

14

10

12

6

8

InsulinSecretio

n

Insulin Sensitivit

y

Adaptation

Index

Effects of vildagliptin treatment on -cell function and insulin sensitivity over 52 weeks

Patients on Stable Metformin Therapy

*P <0.05 vs placebo; †P <0.01 vs placebo.Adapted from Ahrén B, et al. Diabetes Care. 2005; 28: 1936–1940.

Vildagliptin 50 mg daily / metformin

Placebo / metformin

nm

ol C

-pe

pti

de ·

mm

ol g

luc

os

e-1 ·

m

L-1 ·

m-2

9) Vildagliptin shows a favorable safety and tolerability profile

9.1) Pooled analysis demonstrates that overall incidence of adverse events is similar for vildagliptin vs. comparators

Pooled analysis: most common AEs by preferred term (occurring in >3% of patients in either group)

AEs=adverse events; bid=twice daily; comp=all comparators; PBO=placebo; All-study safety (excluding open-label) population. Schweizer A. et al, Vasc Health Risk Manag 2011(accepted version)

Preferred term, n (%) Vildagliptin 50 mg bidN= 6116

Total compN=6210

Nasopharyngitis 577 (9.4) 528 (8.5)

Headache 431 (7.0) 371 (6.0)

Dizziness 390 (6.4) 460 (7.4)

Back pain 356 (5.8) 321 (5.2)

Upper respiratory tract infection 317 (5.2) 254 (4.1)

Bronchitis 297 (4.9) 278 (4.5)

Diarrhea 345 (5.6) 418 (6.7)

Hypertension 297 (4.9) 315 (5.1)

Influenza 290 (4.7) 282 (4.5)

Arthralgia 289 (4.7) 236 (3.8)

Nausea 247 (4.0) 268 (4.3)

Pain in extremity 217 (3.5) 238 (3.8)

Fatigue 210 (3.4) 253 (4.1)

Cough 206 (3.4) 210 (3.4)

Urinary tract infection 204 (3.3) 185 (3.0)

Asthenia 198 (3.2) 306 (4.9)

Tremor 184 (3.0) 471 (7.6)

Oedema peripheral 180 (2.9) 219 (3.5)

Hyperhidrosis 169 (2.8) 422 (6.8)

Hypoglycemia 1.7 5.8

Similar incidence of SAEs, discontinuations due to AEs, or death for vildagliptin and comparators

n (%)Vilda

50 mg bidN=6116

Total comparators

N=6210

Any AE 4225 (69.1) 4228 (69.0)

Drug-related AEs 961 (15.7) 1349 (21.7)

SAEs 545 (8.9) 557 (9.0)

Discontinuation of study drug due to AEs 347 (5.7) 400 (6.4)

Deaths 24 (0.4) 23 (0.4)

AEs=adverse events; bid=twice daily; PBO=placebo; SAEs= serious adverse events; vilda=vildagliptin.All-study safety (excluding open-label) population.Schweizer A. et al, Vasc Health Risk Manag 2011(accepted version)

No increased risk for hepatic AEs and SAEs vs comparators

AEs=adverse events; bid=twice daily; CI=confidence interval; qd=once daily; SAEs=serious adverse events; vilda=vildagliptin. *Vs comparators (all non-vildagliptin treatment groups). All-study safety (excluding open-label) population.

Vildagliptin better Vildagliptin worse

Vildagliptin Reference Peto odds ratio

n / N (%) n / N (%) (95% CI)

Hepatic AEs

Vilda 50 mg qd* 15 / 1502 (1.00) 14 / 1662 (0.84) 1.29 (0.61–2.70)

Vilda 50 mg bid* 83 / 6116 (1.36) 84 / 4872 (1.72) 0.87 (0.64–1.19)

Hepatic SAEs

Vilda 50 mg qd* 2 / 1502 (0.13) 2 / 1662 (0.12) 1.08 (0.15–7.76)

Vilda 50 mg bid* 6 / 6116 (0.10) 5 / 4872 (0.10) 1.13 (0.35–3.67)

Odds Ratio

0.01 0.1 1 10 100

According to the Prescribing information, vildagliptin should not be used in patients with hepatic impairment, including patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x the upper limit of normal (ULN). Liver function tests should be performed prior to the initiation of treatment with vildagliptin in order to know the patient’s baseline value. Liver function should be monitored during treatment with vildagliptin at 3-month intervals during the first year and periodically thereafter.Ligueros-Saylan M, et al. Diab Obes Metab 2010 12:495-509

No increased risk of liver enzyme (ALT / AST) elevations vs. comparators

Vildagliptin better Vildagliptin worse

Vildagliptin Reference Peto odds ratio n / N (%) n / N (%) (95% CI)

ALT / AST >3 × ULN

Vilda 50 mg qd* 6 / 1406 (0.43) 4 / 1574 (0.25) 1.60 (0.46–5.49)

Vilda 50 mg bid* 51 / 5874 (0.87) 32 / 4597 (0.70) 1.24 (0.80–1.93)

ALT / AST >3 × ULN and bilirubin >ULN    

Vilda 50 mg qd* 0 / 1400 (0.00) 1 / 1571 (0.06) 0.21 (<0.01–6.54)

Vilda 50 mg bid* 5 / 5863 (0.09) 3 / 4588 (0.07) 1.19 (0.29–4.90)

Odds Ratio

ALT=alanine aminotransferase; AST=aspartate aminotransferase; bid=twice daily; CI=confidence interval; qd=once daily; ULN=upper limit of normal; vilda=vildagliptin. *Vs comparators (all non-vildagliptin treatment groups). All-study safety (including open-label) population. ‡Persistent elevations are those which met the criterion at consecutive on-treatment measurements or at last on-treatment visit.

0.01 0.1 1 10 100

According to the Prescribing information, vildagliptin should not be used in patients with hepatic impairment, including patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x the upper limit of normal (ULN). Liver function tests should be performed prior to the initiation of treatment with vildagliptin in order to know the patient’s baseline value. Liver function should be monitored during treatment with vildagliptin at 3-month intervals during the first year and periodically thereafter.Ligueros-Saylan M, et al. Diab Obes Metab 2010 12:495-509

Low incidence of persistent markedly elevated hepatic enzymes across treatment groups

Vildagliptin

50 mg qd 50 mg bid Total comp

AST or ALT N= 2091 N= 5917 N=6695

≥10 x ULN n (%) 0 1 (0.0) 2 (0.0)

≥20 x ULN n(%) 0 0 0

ALT or AST and bilirubin N= 2085 N= 5906 N= 6595

ALT or AST ≥3 xULN and bilirubin ≥2 xULN n(%) 0 3 (0.1) 3 (0.0)

ALT= alanine aminotransferase; AST= aspartate aminotransferase; bid= twise a day, qd: once a day; total comp: all comparators.ULN= upper limit of normal; *Persistent elevations are defined as those not present at any pretreatment visit and meeting the criterion at consecutive on-treatment measurements or at last on-treatment visitLigueros-Saylan M, et al. Diab Obes Metab 2010 12:495-509

Number (%) of patients with treatment-emergent, Persistent* on-treatment hepatic enzyme elevations

Summary of hepatic safety profile of vildagliptin

• There was no evidence of increased risk for hepatic AEs and SAEs with vildagliptin treatment.

• There was no significant difference in ALT / AST >3x of vildagliptin vs. comparators

• The incidences of markedly elevated persistent hepatic enzyme elevations (ALT/AST ≥10× or ≥20× ULN) were very low across all treatment groups and similar in the vildagliptin 50 mg bid group (1/5917 patients for ALT/AST ≥10× ULN and 0/5917 patients for ALT/AST ≥20× ULN), and the all comparators group.

AEs= adverse events; ALT= alanine aminotransferase; AST= aspartate aminotransferaseSAEs= serious adverse events; ULN= upper limit of normal

According to the Prescribing information, vildagliptin should not be used in patients with hepatic impairment, including patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST)>3x ULN. Liver function should be performed prior to the initiation of treatment with vildagliptin in order to know the patient‘s baseline value. Liver function should be monitored during treatment with vildagliptin at three-month intervals during the first year and periodically thereafter.

Ligueros-Saylan M, et al. Diab Obes Metab 2010 12:495-509

Galvus labelling recommendations regarding liver monitoring

• LFTs should be performed prior to the initiation of treatment with Galvus. Galvus is not recommended in patients with a pre-treatment ALT or AST >2.5X the upper limit of normal according to the BPI or above 3X according to European SmPC

• LFTs should be monitored during Galvus treatment at three-month intervals during the first year and periodically thereafter

• Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality (ies) return to normal

• Should an increase in AST or ALT of 3x upper limit of normal or greater persist, withdrawal of therapy with Galvus is recommended. Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue Galvus and contact their physician immediately

• Following withdrawal of treatment with Galvus and LFT normaisation, vildagliptin treament should not be reinitiated.

LFT: liver function test; AST= aspartate aminotransferase; ALT= alanine aminotransferaseBPI: Basic prescribing informationSmPC= European Summary of Product Characteristics

No increased risk for adjudicated CCV events, relative to all comparators*

AEs=adverse events; bid=twice daily; CI=confidence interval; CV=cardiovascular; M-H RR=Mantel-Haenszel risk ratio; qd=once daily; vilda=vildagliptin.

*Vs comparators (all non-vildagliptin treatment groups). All-study safety population.‡Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), December 2008.Schweizer A, et al. Diab Obes Metab .2010 ;12:485-494.

Vildagliptin All comparators M-H RR

n / N (%) n / N (%) (95% CI)

Vilda 50 mg qd# 10 / 1393 (0.72) 14 / 1555 (0.90) 0.88 (0.37–2.11)

Vilda 50 mg bid# 81 / 6116 (1.32) 80 / 4872 (1.64) 0.84 (0.62–1.14)

Risk Ratio

Incidences and Odds Ratios for Adjudicated CV Events by Treatment

Vildagliptin better Vildagliptin worse0.1 1 10

#Meta-analysis of vildagliptin 50 mg bid data vs all comparators according to the methodology set by the US Food and Drug Administration‡ [50 mg bid odds ratio = 0.84 (95% CI 0.62–1.14)].

The incidence of SYE-adjusted* adjudicated CCV events was similar with vildagliptin relative to comparators

SY

E-a

dju

sted

In

cid

ence

*

ACS=acute coronary syndrome; CCV=cardiovascular and cerebrovascular; SYE=subject-year exposure; TIA=transient ischemic attack; vilda=vildagliptin.*SYE-adjusted rates calculated as number of patients having events per 100 subject-years of exposure.Schweizer A, et al. Diab Obes Metab .2010;12:485-494

Vildagliptin not associated with increased risk for infections

Vildagliptin All Peto odds ratio comparators

n / N (%) n / N (%) (95% CI)

Infections / infestations

Vilda 50 mg qd* 356 / 1502 (23.07) 432 / 1662 (26.0) 0.88 (0.75–1.04)

Vilda 50 mg bid* 2099 / 6116 (34.3) 1697 / 4872 (34.8) 1.04 (0.96–1.13)

Vildagliptin better Vildagliptin worse

Odds Ratio

bid=twice daily; CI=confidence interval; qd=once daily; vilda=vildagliptin.*Vs comparators (all non-vildagliptin treatment groups). All-study safety (excluding open-label) population.Ligueros-Saylan M, et al. Diab Obes Metab 2010 ;12:495-509

0.1 1 10

No increased risk for pancreatitis-related AEs

Vildagliptin All comparators Peto odds ratio

n / N (%) n / N (%) (95% CI)

Pancreatitis events

Vilda 50 mg qd* 2 / 1502 (0.13) 4 / 1662 (0.24) 0.76 (0.15–3.89)

Vilda 50 mg bid* 7 / 6116 (0.11) 9 / 4872 (0.18) 0.70 (0.26–1.88)

Odds Ratio

Vildagliptin better Vildagliptin worse

AEs=adverse events; bid=twice daily; CI=confidence interval; qd=once daily; vilda=vildagliptin.*Vs comparators (all non-vildagliptin treatment groups). All-study safety (excluding open-label) population.Ligueros-Saylan M, et al. Diab Obes Metab 2010 ;12:495-509

0.01 0.1 1 10 100

Vildagliptin All Comparators Peto odds ratio n / N (%) n / N (%) (95% CI)

Selected Skin-related AEs

Vilda 50 mg qd 19/1502 (1.26) 11/1662 (0.66) 1.93 (0.93-3.99)

Vilda 50 mg bid 89/6116 (1.47) 71/4872 (1.46) 1.10 (0.80–1.51)

Selected Skin-related SAEs    

Vilda 50 mg qd 0/1502 (0.00) 1/1662 (0.06) 0.23 (<0.01–7.11)

Vilda 50 mg bid 6/6116 (0.10) 7/4872 (0.14) 0.84 (0.29–2.49)

0.01 100

Vildagliptin worse

Odds Ratio

Vildagliptin better

0.1 1 10

No increased risk of skin-related AEs and SAEs with vildagliptin vs all comparators

Odds ratios for selected skin and vascular- related AEs and SAEs in the all controlled studies (excluding open-label) safety population. (Vilda= vildagliptin; All comparators= all non-Vilda treatment groups, that is placebo and active comparators. n = number of patients experiencing an AE, N = total number of patients). Test for heterogeneity of selected skin- and/ or vascular – related AEs: Q = 9.58, p = 0.653 and I2 = 0.00 (vildagliptin 50 mg qd); Q= 10.79, p= 0.702 and I2 = 0.00 (vildagliptin 50 mg bid). Test for heterogeneity of selected skin- and/ or vascular – related SAEs: Q = 0.20, p = 0.999 and I2 = 0.00 (vildagliptin 50 mg qd); Q= 10.31, p= 0.739and I2 = 0.00 (vildagliptin 50 mg bid).Ligueros-Saylan M, et al. Diab Obes Metab 2010 ;12:495-509

9.2) Mild renal impairment does not affect vildagliptin’s safety compared to patients with normal renal function

50 mg qd1338

50 mg bid4232

comparators4217

65.6

8.1

68.4

7.5

70.3

11.6

68.7

7.9

70.1

11.24.2

58.7

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0

Normal renal Function

% o

f A

E o

r S

AE

Mild renal Function

n =

Vildagliptin 50 mg qd

All comparators

Vildagliptin 50 mg bid

Ligueros-Saylan M, et al. Diab Obes Metab 2010 12:495-509

Normal Renal function: GFR (MDRD) > 80 (ml/min) x (1.73 m2)Mild renal impairment: GFR (MDRD) ≥ 50 but ≤ 80 (ml/min) x (1.73 m2)

Any AE Any SAE Any AE Any SAE

50 mg qd665

50 mg bid1802

comparators1918

all studies [excluding open-label] safety population

Mild renal impairment does not adversely affect the safety of vildagliptin relative to patients with normal renal function

Pooled safety data

9.3) Overall incidence of edema is similar to all comparators

The incidence and odds ratios of selected edema-related AEs were similar with vildagliptin relative to comparators

Vildagliptin Comparators Peto OR

n / N (%) n / N (%) (95% CI)

Vilda 50 mg bid 189 / 6116 (3.09) 211/ 4872 (4.33) 0.72 (0.59–0.88)

Risk Ratio

Incidences and odds ratios for selected edema-related events by treatment

Vildagliptin better Vildagliptin worse0.1 1 10

All studies [excluding open-label] safety populationSchweizer A. et al, Vasc Health Risk Manag 2011(accepted version)

Pooled safety data

9.4) No change in bone markers has been observed with vildagliptin treatment

Vildagliptin does not increase fasting parameters of bone metabolism and calcium homeostasis

Diamant M, et al. Poster Presentation 0706-P. Presented at: 70th Scientific Sessions of the American Diabetes Association 2010.

Baseline Endpoint LSM Change

Between-group

difference P-value

Calcium (mmol/L)

Placebo 2.32 ± 0.07 2.32 ± 0.08 –0.004 ± 0.012

0.000 ± 0.017 0.981 Vildagliptin 2.33 ± 0.07 2.33 ± 0.07 –0.005 ± 0.011

Phosphate (mmol/L)

Placebo 0.97 ± 0.16 1.01 ± 0.19 0.037 ± 0.024

0.010 ± 0.033 0.762 Vildagliptin 1.00 ± 0.15 1.04 ± 0.15 0.047 ± 0.023

Alkaline phosphatase (IU/L)

Placebo 7.04 ± 15.5 66.8 ± 14.2 –3.31 ± 5.24

7.14 ± 7.20 0.327 Vildagliptin 66.5 ± 18.6 70.6 ± 36.3 3.83 ± 4.91

Since nutrient intake plays an important role in maintaining bone health, mediated by ensuing pancreatic islet and incretin response, this study explored effects of vildagliptin on (postprandial) markers of bone metabolism in patients with T2D and mild hyperglycemia

9.5) Hypoglycemia risk is consistently low with vildagliptin

0.6 0.8 0.3

9.2

00

2

4

6

8

10

12

14

Inci

den

ce (

%)

n = 2 23 1 189 0N= 340 3021 354 2045 280

Low risk of hypoglycemic events in add-on metformin trials in vildagliptin treated patients

Vildagliptin 50 mg qd + met

Vildagliptin 50 mg bid + met

Placebo + met

SU + met

Pioglitazone* + met

Hypoglycemia Incidence in Add-on Metformin

bid=twice daily; glim=glimepiride; met=metformin; pio=pioglitazone; qd=once daily.Up to 24-week add-on to metformin population. SU: glimepiride and gliclazide. *Pioglitazone 30 mg once daily. Data on file, Novartis Pharmaceuticals.

Vildagliptin resulted in a significantly lower incidence of hypoglycaemia than glimepiride at 52 weeks (interim analysis)

Number of Hypoglycaemic

Events

Severe Events(Grade 2 and

Suspected Grade 2)

Patients with>1 Hypos (%)

1389

Glimepiride up to 6 mg once daily + metforminVildagliptin 50 mg twice daily + metformin

1383 1389 1383 1389 1383n =

Duration: 52 weeksAdd-on to met:vilda vs glim

Inci

den

ce

(%)

No

. o

f E

ven

ts

No

. o

f E

ven

ts

glim=glimepiride; met=metformin; vilda=vildagliptin.Safety population.Ferrannini E, et al. Diabetes Obes Metab. 2009; 11: 157–166.

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= metforminMatthews 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 (%)

2.3

18.2

0

4

8

12

16

20

59

838

0

100

200

300

400

500

600

700

800

900

0

2

4

6

8

10

12

14

16

0

15

Incid

en

ce (

%)

Nu

mb

er

of

even

ts

Nu

mb

er

of

even

ts

This hypoglycemic profile was maintained in patients > 65 years

Discontinuation due to

hypoglycemia

13

0

2

4

6

8

10

12

14

0Nu

mb

er

of

even

ts

Fewer hypoglycemic events in vildagliptin add-on to insulin compared with insulin alone

Add-on Treatment to InsulinDuration: 24 weeksAdd-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.

0 0

No. of Events No. of Severe Events

40

80

120

160

200

2

4

6

8

10

No

. o

f S

eve

re E

ven

ts

113

185

0

6

*

**

No

. o

f E

ven

ts

9.6) Overall vildagliptin causes no weight gain and shows greater benefits on weight in obese patients

-0.3

-1.1

1.6 1.7

-2

-1

0

1

2

Weight loss relative to rosiglitazone

BL=baseline; BMI=body mass index.*P <0.001 vs rosiglitazone. Primary intention-to-treat population.Rosenstock J, et al. Diabetes Care. 2007; 20: 217–223.

*

Overall BMI >35 kg/m2

n = 459 238 132 76

BL (kg)= 91 93 111 112

Wei

gh

t ch

ang

e fr

om

BL

(kg

)

*

+2.8 kg difference

Duration: 24 weeksVildagliptinvs rosiglitazonemonotherapy

Rosiglitazone 8 mg once dailyVildagliptin 50 mg twice daily

Vildagliptin: similar effect on weight as metformin

Intention-to-treat population.Schweizer A, et al. Diabet Med. 2007; 24: 955–961.

Vildagliptin 50 mg twice daily (n=511)Metformin 1000 mg twice daily (n=249)

Duration: 52 weeks; Vildagliptin vs metformin monotherapy

80

85

90

95

100

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

Time (Weeks)

Mea

n B

od

y W

eig

ht

(kg

)

Initial combination of vildagliptin + metformin:change in body weight

276 258271 275n =

Mea

n C

ha

ng

e in

Bo

dy

We

igh

t (k

g)

Change from Baseline to End PointMean Baseline Body Weight ~88.3 kg

Duration: 24 weeksVilda + met vs mono

Vilda + HD met (50/1000 mg bid)

Vilda + LD met (50/500 mg bid)

Met 1000 mg bid

Vilda 50 mg bid

Intention-to-treat population.HD=high dose; LD=low dose; met=metformin; vilda=vildagliptin.Bosi E, et al. Diabetes Obes Metab. 2009; 11: 506–515.

Vildagliptin: weight loss compared to glimepiride in add-on to metformin at 52 weeks

Time (Weeks)

−1.8 kgdifference

Vildagliptin 50 mg twice daily + metformin

Glimepiride up to 6 mg once daily + metformin

Duration: 52 weeksAdd-on to met:vilda vs glim

Add-on Treatment to Metformin (~1.9 g Mean Daily)

Bo

dy

Wei

gh

t (k

g)

glim=glimepiride; met=metformin; vilda=vildagliptin.Vildagliptin (n=1396); glimepiride (n=1393).Ferrannini E, et al. Diabetes Obes Metab. 2009; 11: 157–166.Data on file, Novartis Pharmaceuticals, LAF237A2308.

-0.3

-1.5

1.2

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

Change from BL to EP(BL Mean ~ 89kg)

Between-treatment difference

Vildagliptin: weight loss compared to glimepiride in add-on to metformin at 2 years

Intent to treat (ITT) population; * p=<0.001BL= baseline; Vilda= vildagliptin; Glim= glimiperide; Met= metformin; EP= week 104 endpointMatthews DR et al Diabetes Obes Metab 2010; 12: 780–789

Ad

just

ed M

ean

Ch

ang

e in

B

od

y w

eig

ht

(kg

)

1539 1520N=

*

Glim up to 6 mg qd + MetVilda 50 mg bid + Met

Duration: 2 yearsAdd-on to met:vilda vs glim

Ad

just

ed M

ean

Ch

ang

e in

b

od

y w

eig

ht

(kg

)

386

Change from BL to Wk 52 Mean BL ~ 85 kg

Glic up to 320 mg + MetVilda 50 mg bid + Met

393N=

Between-treatment difference

Per protocol (PP) population; * p<0.001 Vilda vs Glic, 95% CI (-1.77, -0.79)Glic= gliclazide; Met= metformin; Vilda= vildagliptin; BL= baseline; EP= end pointAdjusted mean change from BL to EP and p-value were from an ANCOVA model containing terms for treatment, baseline and pooled center.Filozof et al Diabetes Medicine 2010 (27) 318-326.

*

0.08

-1.28

1.36

-1.6

-1.2

-0.8

-0.4

0.0

0.4

0.8

1.2

Vildagliptin: weight loss compared to gliclazide in add-on to metformin at 52 weeks

Duration: 52 weeksAdd-on to met:vilda vs glic

10) Special Populations

10.1) Vildagliptin demonstrates significant efficacy and favorable safety in elderly patients

Elderly: Background information

Fast growing segment of patients with T2DM

Management of T2DM in the elderly is particularly challenging :

High prevalence of CV risk factors and comorbidities as CHF, geriatric syndromes (e.g. frailty, cognitive disorders), as well as social isolation and depression.

Polypharmacy can be high with potential increased risk of drug interactions.

Very heterogeneous population (e.g. diabetes duration, coexisting disorders and treatments ) 

Therapeutic goals are unclear due to lack of data with specific focus in this population mainly in very elderly

211

Hypoglycemia in the elderly

- More common among elderly patients

- Generally unrecognized, symptoms (disorientation, confusion or other neuroglycopenic symptoms) can be confused with concomitant medical conditions

- Unawareness of hypoglycemia increase the risk of future severe events

- It is often more severe and can precipitate serious events such as falls and hip fractures.

- Among older people hypoglycemia is associated with higher risk of dementia

Very elderly (≥ 75years) data from pooled analysis

Efficacy data were collected from randomized, double-blind, controlled, parallel group studies with duration ≥ 24 weeks

Only studies with the approved vildagliptin dose of 50 mg bid. It included 7 monotherapy and 3 add-on to metformin studies

Safety profile was oserved from a pool of 38 PhII and III studies which include monotherapy and add-on therapy

AEs, SAEs, discontinuation due to AE, hepatic- related AEs , the analysis was performed only in double-blind studies

Safety on persistent treatment-emergent transaminase elevations was analysed including open-label studies (no bias expected)

Schweizer A. et al, Diabetes, Obesity and Metabolism 13: 55–64, 2011.

Age ≥ 75 yearsVilda 50 mg bid

n=132

Age ≥ 75 yearsComparators

n=169

Age < 75 yearsVilda 50 mg bid

n=5984

Age < 75 years Comparators

n=6041

Age (years) 76.9 77.0 54.9 55.9

Male (%) 42.4 55.0 55.3 54.7

Caucasian (%) 84.8 79.3 72.6 72.5

Mean BMI (kg/m2) 29.4 28.9 31.5 31.3

Mean HbA1c % 8.3 7.9 8.3 8.0

FPG (mmol/L) 9.9 8.8 10.1 9.8

Duration of T2DM (years)

6.3 5.9 4.1 4.5

GFR, # (% pts) normal mild ( ≥50, <80) moderate (≥30, <50) severe (<30)

27.362.1

10.6 0.0

34.958.06.50.6

70.128.71.00.1

68.830.11.00.0

High CV R status* (%) 31.8 36.1 15.0 15.2

* History of prior CCV events in the SMQs ‘ischaemic heart disease, cardiac failure, ischaemic cerebrovascular conditions and/or embolic/thrombotic events arterial‘

Data presented are for patients in “all studies“ (excluding open-label studies) safety population# MDRD = mL/min per 1.73m2

Very elderly patients pooled analysis:Demographics and baseline characteristics

Schweizer A et al. Diab Obes Metab 2010;13(1):55–64

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

-0.9

-1.1

-0.9

Vildagliptin: significant HbA1c drop from baseline in the very elderly

Ch

ang

e i

n H

bA

1c (

%)

fro

m b

asel

ine

Add-on therapy studies

n =

BL (%)=

2303

8.7

62

8.3

910

8.4

25

8.5

*

*

*

*

*<0.05 vs baseline (within group)

Age < 75 y ≥ 75 y

≥ 75 y

Age < 75 y-1.2

Monotherapy studies

Schweizer A et al. Diab Obes Metab 2010;13(1):55–64

Efficacy pool: All randomized, double-blind, controlled, parallel group studies with duration ≥ 24 and with patients ≥ 75years. Only studies with the approved dose of 50 mg bid. It included 7 monotherapy and 3 add-on to metformin studies.

Pooled analysis at 24 weeks 50 mg bid

215

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

-0.9

-0.2

-0.0

Vildagliptin: no clinically significant body weight changeC

han

ge

in

bo

dy

wei

gh

t (%

) fr

om

b

asel

ine

Add-on therapy studies

n =

BL (kg)=

2299

86.1

62

74.9

914

89.0

25

82.8

*

*

*<0.05 vs baseline (within group)

At 24 weeks treatment 50 mg bid

Age < 75 y

≥ 75 y

≥ 75 y

Age < 75 y

-0.4

Monotherapy studies

Schweizer A et al. Diab Obes Metab 2010;13(1):55–64

216

Vildagliptin: lower AEs, SAEs, and drug-related AEs in the very elderly

Age ≥ 75 yearsVilda 50 mg bid

n=132

Age ≥ 75 yearsComparators

n=169

Age < 75 yearsVilda 50 mg bid

n=5984

Age < 75 years Comparators

n=6041

Any AEs SYE-adj n (%)

133.9 86 (65.2)

200.6 114 (67.5)

147.9 4139 (69.2)

177.3 4174 (69.1)

Drug-related AEs SYE-adj n (%)

14.5 18 (13.6)

21.8 24 (14.2)

14.9 943 (15.8)

26.0 1325 (21.9)

SAEs SYE-adjn (%)

8.8 12 (9.1)

16.5 19 (11.2)

7.8 533 (8.9)

8.9 538 (8.9)

Discontinuation due to AEs SYE-adjn (%)

7.2 10 (7.6)

7.5 9 (5.3)

4.7 337 (5.6)

6.1 391 (6.5)

Deaths SYE-adjn (%)

0.0 0 (0.0)

1.7 2 (1.2)

0.3 24 (0.4)

0.3 21 (0.3)

SYE-adj: SYE-adjusted

Safety pool: A pool of 38 PhII and III studies (monotherapy and add-on therapy)

Comparators group includes active comparator or placebo

Schweizer A et al. Diab Obes Metab 2010;13(1):55–64

Monotherapy studies pool

Add on therapy studies pool

n =

BL

62

8.3

25

8.5

Ch

ang

e i

n H

bA

1c

(%)

fro

m b

ase

lin

e

Mono > 75 Add on > 75*<0.05 vs baseline (within group)

*

Body Weight: At 24 weeks treatment

n =

BL

62

74.925

82.8

**

Monotherapy studies pool

Add on therapy studies pool

Ch

ang

e i

n B

od

y W

eig

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Very elderly patients pooled analysis: change in HbA1c and body weight at 24 weeks treatment, and hypoglycemic events

HbA1c Reduction: At 24 weeks treatment

Hypoglycemic events Monotherapy studies pool Add on therapy studies pool

Any events 0.0 0.0

Severe events 0.0 0.0

OR No hypoglycemic events, including severe events was reported in elderly patients with monotherapy and add-on therapy

Schweizer A. et al, Diabetes, Obesity and Metabolism 13: 55–64, 2011.

Pooled analysis at 24 weeks; 50 mg bid

Vildagliptin (Galvus) in Taiwan

適應症 : 第二型糖尿病 用法、用量 :

宜用於已使用 metformin 或 SU 或 TZD 且血糖控制不佳者 與 metformin 、 TZD 合併使用 ---- 50 mg BID 與 SU 合併使用 ---- 50 mg QD

特殊族群 : 1. 輕度腎功能不全 ( 肌酸酐清除率 > 50 ml/min) 無需調整劑量 中度或重度腎功能不全以及必須接受洗腎之末期腎臟疾病 (ESRD) 患者而言 ，不建議使用 Galvus 。 2. 不建議使用於肝功能不全的患者，包括治療前 ALT 或 AST >2.5 X ULN者在 使用 Galvus 治療的第一年內，建議每三個月需進行一次肝功能測試，直至 一年，之後建議定期監測，且當病人有噁心、嘔吐、倦怠、上腹不適、黃 疸等可能為肝傷害之症狀或證後發生時，宜檢測肝生化值 (ALT) 。患者的 肝臟轉胺酶濃度若增加，則應進行第二次肝功能監測加以確認，並應持續 進行肝功能測試追蹤，直至恢復正常為止。若病患之 AST 或 ALT 值持續超 過 2.5 x ULN 或更高， 則建議病患退出 Galvus 治療。患者若出現黃疸或其 他肝功能異常徵兆，應停止使用 Galvus 。在退出 Galvus 治療與肝功能回復 正常值之後， 不應再度使用 Galvus 。