Galvus Introduction: Legacy Effect and Islet Dysfunction

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.

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
Adjustedincidence
per1000personyears(%)
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=0.04
1W. 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 coronary
disease, 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
Probabilityofsurvival
Years
Standard
therapy
Intensive
therapy
892
899
774
770
707
693
No. at risk
Intensive
Standard
639
637
582
570
510
471
252
240
62
55
0
0
VADT
Primary 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 complications
HbA1c(%)
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.
MedianHbA1c(%)
0
6
7
8
9
UKPDS 1998
Conventional
Metformin
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*
+
Glucose

Pancreatic islet dysfunction leads to hyperglycemia
in T2DM
↑ Glucose
Fewer
-cells
-cells
Hypertrophy
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 resistance
Insulinsecretion
Insulin resistance
T2DM
IGT
NGT
Nonprogressors (n=23)
Progressors (n=11)
NGT
NGT
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)
Glucose(mg/dL)
500
400
300
200
100
0
Time (min)
Insulin(pmol/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 8–10
Diet 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
0
0 2 4 6
HOMA%B
Years from Diagnosis
β-cell Function
80
40
20
0
0 2 4 6HOMA%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

Glucagon
25
30
35
40
45
pmol/L
Time (min)
-60 0 60 120 180 240 300
NGT
IGT
0
Insulin
200
400
600
pmol/L
Glucose
Glucose
50
100
150
200
250
mg/dL
NGT
IGT
NGT
IGT
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
NGT
T2DM
-60
Time (min)
0 60 120 180 240
Glucose100
200
300
400
mg/dL
0
Insulin
50
100
150
μU/mL
NGT
T2DM
Glucagon
75
100
125
150
pg/mL NGT
T2DM

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
EndogenousGlucose
(µmol/min/kg)
NGT (n=12)
T2DM (n=18)

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

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.
FastingPlasmaInsulin(µU/mL)
Fasting Plasma Glucose (mg/dL)
N=149
0
25
20
15
10
5
0
60 100 140 180 220 260 260

β-cell function continues to decline regardless of
intervention in T2DM
*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-cellFunction(%)*
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
pmol/L
Time (min)
-60 0 60 120 180 240 300
NGT
IGT
0
Insulin
200
400
600
pmol/L
Glucose
Glucose
50
100
150
200
250
mg/dL
NGT
IGT
NGT
IGT
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
NGT
T2DM
-60
Time (min)
0 60 120 180 240
Glucose100
200
300
400
mg/dL
0
Insulin
50
100
150
μU/mL
NGT
T2DM
Glucagon
75
100
125
150
pg/mL NGT
T2DM

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
Spendingonpeoplewithdiabetes
(US$billion)
Non-Medicare population Medicare-eligible population
US 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
CostImpactFactor
Costs were assessed retrospectively for 6 months
Incremental cost due to complications Base 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%
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
JapanChinaGermanyFranceUKUS
198
3'125
115
3'751
4'141
3'574
7'383
JapanChinaGermanyFranceUKUS
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
HbA1c(%)
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=0.002
Rosiglitazone 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%
%patientsreachingtarget
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 in
the treatment of T2DM
-glucosidase inhibitors
Delay intestinal carbohydrate
absorption
Thiazolidinediones
Decrease lipolysis in
adipose tissue, increase
glucose uptake in skeletal
muscle and decrease
glucose production in liver
Sulfonylureas
Increase insulin secretion
from pancreatic -cells
GLP-1 analogs
Improve pancreatic islet glucose sensing,
slow gastric emptying, improve satiety
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.
Glinides
Increase insulin secretion
from pancreatic -cells
DPP-4 inhibitors
Prolong 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  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
Gliclazide
0.85
Glipizide
8.70
Glimepiride
0.86
Tolbutamide
3.50
Chlorpropamide
16.00
Glyburide
16.00
Severe hypoglycemia*
n/1000 person years =
RelativeRisk(%)

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= metformin
Matthews DR et al Diab Obes Metab. 2010; 12:780-789
Glim up to 6 mg qd + Met (n=1546)
Vilda 50 mg bid + Met (n=1553)
Number of
hypoglycemic
events
Number of
Severe hypo
events*
Patients with one
or more
hypoglycemic
events (%)
2.3
18.2
0
4
8
12
16
20
59
838
0
100
200
300
400
500
600
700
800
900
0
15
0
2
4
6
8
10
12
14
16
Incidence(%)
Numberofevents
Numberofevents
This hypoglycemic profile was maintained in patients > 65 years
Discontinuation
due to
hypoglycemia
0
Numberofevents

No.ofevents
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.ofevents
Incidence(%)
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.ofevents
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
0
2
4
6
8
10
12
14
16
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
2.0Adjustedmeanchange
inbodyweight(kg)
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
(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
AdjustedMeanChangein
Bodyweight(kg)
1539 1520N=
*
Glim up to 6 mg once daily + met
Vilda 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 Diabetes
Olivia 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
Mesenchymal
stem cell
Bone formation
Preadipocyte
PPARɣ Adipocyte
Preosteoblast
+
Myeloid Precursors
Lymphoid Precursors
Erythroid lineage
Myeloid, 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

Edema is common with TZDs (pioglitazone)
TZDs=thiazolidinediones.
1Actos [prescribing information]. Indianapolis, IN: Eli Lilly and Company, 2004.
4.8
7.2
6.0
15.3
1.2
2.1 2.5
7.0
0
2
4
6
8
10
12
14
16
18
Monotherapy Combination
with SU
Combination
with
metformin
Combination
with insulin
ProportionofPatients(%)
Pioglitazone1
Placebo or combination

Use of TZDs is associated with increased incidence of
congestive heart failure
NumberofCHFEvents
P=0.01
CHF=congestive heart failure; TZDs=thiazolidinediones.
Adapted from DREAM Trial Investigators, et al. Lancet. 2006; 368: 1096–1105.
HF=heart failure
Adapted from Dormandy JA, et al. Lancet. 2005; 366: 1279–1289.
P <0.0001
14
2
0
5
10
15
20
11
8
0
5
10
15
Rosiglitazone
Placebo
PatientswithHF(%)
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
Patients(%)
*
*
Rosiglitazone (n=1456)
Glyburide (n=1441)
Metformin (n=1454)
* **
**

RECORD study results: increased limb fractures in
patients with rosiglitazone
*P <0.0001 Rosiglitazone vs control
Home PD, et al. Lancet. 2009; 373: 2125–2135.
Women Men
124
1078
68
1075
47
1078
63
1078
36
1075
16
1075
61
1142
23
1142
50
1152
19
1152
23
1142
11
1152
Rosiglitazone
Active control
All Distal lower
limb
Upper
limb
All Distal lower
limb
Upper
limb
Patients(%)
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 2
diabetes: 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 1000
Patent-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 BL
Intention-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
MeanHbA1c(%)
Duration: 52 weeks add-on to metformin: vildagliptin vs pioglitazone
n=277n=293
UnadjustedMean
ChangeinBodyWeight(kg)
*
Change in Body Weight
(Mean BL Body Weight ~91 kg)
*P <0.001 change from baseline
Change in HbA1c

0.3
0.1
1.9
2.6
0.0
0.5
1.0
1.5
2.0
2.5
3.0
All Patients
Mean 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.
BodyWeight(kg)toWeek24
BMI >35 kg/m2
Mean BL ~110.4 kg
264 246 7073
Pio 30 mg once daily + met
*
*
Duration: 24 weeks
Add-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 9.4527
0.001
4
0.01
%
£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 daily
Efficacy 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.aspx
ESTIMATING 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 site
Proportion 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
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
Combination
with metformin
Combination
with SU
Combination with
metformin + SU
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 6
CRP: C-reactive protein
VEGF: vascular endothelial growth factor

Hypoglycemia consequences
1: Whitmer RA et al JAMA 2009, 301:1565-1572
2: Zammitt NN et al Diabetes Care 2005, 28:2948-2961
3 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: 193-198
5: Barnett AH, CMRO 26, 1333-1342, 2010
6. 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 death
Lower Higher
Hypoglycemia
HbA1c
HDL-C
Age
Prior event
4.042 (1.449, 11.276)*
1.213 (1.038, 1.417)**
0.699 (0.536, 0.910)*
2.090 (1.518, 2.877)***
3.116 (1.744, 5.567)***
Hypoglycemia was a strong predictor of CV death in
VADT study
0 2 4 6 8 10 12
Hazard Ratio

Hypoglycemia increases costly hospital admissions
UK 2007-08 Admitted Patient Care Mandatory Tariff
Cc = comorbidity or complication; HRG = Healthcare resource group
HRG Name
Healthcare
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 G
T
F
I
S
D Y
S
I
A
M
D K
I
H
Q
Q
DFVN
WLLA
QKGKKNDW
K
H N QTI
GIP: Glucose-dependent Insulinotropic Peptide
H A E G
T
F
T S D V
S
S
Y L E G
Q
A
A
K
EFIAWLVKGRG
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
 cells
 cells
Insulin secretion
Insulin biosynthesis
cell proliferation
cell survival
Glucose sensing
Glucagon secretion
Intestinal secretion of
GLP1 (7-36) amide
+ GIP (1-42)
DPP4
Action on  cells
and  cells
GLP-1 (9-36) amide
And GIP (3-42)
DPP4 inhibitors
Adapted from L Baggio and DJ Drucker Gastroenterology 2007 132:2131-2157
And 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
PlasmaGlucose(mg/dL)
0
50
100
150
200
–30 0 30 60 90 120 150 180 210
Time (min)
PlasmaInsulin(pmol/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 in
a 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-1
inactive
(>80% of pool)
Active
GLP-1
Meal
DPP-4
Intestinal
GLP-1
release
GLP-1 t½=1–2 min
DPP-4
inhibitor
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
Glucose
(mmol/L)
0
60
80
100
120
40
20
Insulin
(pmol/L)
60
80
100
120
140
Glucagon
(ng/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 90 120 150 180 210 240 270 300
Time
Vildagliptin 100 mg (n=15)
Placebo (n=16)
75 g Glucose
Dose

Meal
*
*
*
*
*
*
* * *
*
*
*
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
*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
ActiveGLP-1(pmol/L)
*
91

Effects of vildagliptin and vildagliptin plus metformin
on fasting GLP-1 levels
0
2
4
6
8
10
12
14
*
IntactGLP-1(pM)
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
IntactGLP-1(pM)
**
0
2
4
6
8
10
12
14
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
F
O
N
NH2
N
N
N
CF3
Sitagliptin1
Non-
covalent
Vildagliptin2
HO
N
H
O
N
NC
Covalent
(cyanopyrrolidine)
Competitive inhibitors Substrates acting as inhibitors
Saxagliptin4
N
O
H
H
NC
HO
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
K1
Competitive
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)
Inactive
substrate-like
enzyme blocker
+
Slow dissociation
Natural
substrate:
(GLP-1)
GLP-1
+
DPP-4
K-1
K1
GLP-1: DPP-4
complex
K2
Fast
(~1 sec)
DPP-4
Inactive
GLP-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 3060 90 120 180 240 300 min
Breakfast Lunch Dinner
IntactGLP-1(pmol/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%
ChangeinHbA1c(%)
Add-on Treatment to Insulin
140
**
149 42 41n =
*
Duration: 24 weeks
Add-on to insulin:
vilda vs PBO
PBO + insulin
Vilda 50 mg twice daily
+ insulin
PBO=placebo; vilda=vildagliptin; *P <0.001; **P <0.05 between groups.
Fonseca V, et al. Diabetologia. 2007; 50: 1148–1155.
No. of Hypoglycemic Events No. of Severe Hypoglycemic Events
0
40
80
120
160
200
0
2
4
6
8
10
No.ofSevereEvents
113
185
0
6
*
**
No.ofEvents

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
HbA1c(%)
8
16
0
2
4
6
8
10
12
14
16
18
Placebo Sitagliptin
Patients(%)
HbA1c (%) Symptomatic hypoglycaemia
Sitagliptin
Placebo
* **
1 severe hypo in placebo
2 severe hypos with Sitagliptin
Sitagliptin in add-on to insulin setting
Mean insulin dose ~50 U/day
98

Meal
*
*
*
*
*
*
* * *
*
*
*
Placebo (n=16)
*P <0.05.
0.0
4.0
8.0
12.0
16.0
17:00 20:00 23:00 02:00 05:00 08:00
Time
ActiveGLP-1(pmol/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.
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
17:00
Time
DeltaGlucagon(ng/L)
20:00 23:00 02:00 05:00 08:00
Placebo (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.
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
DeltaEGP(mg/kg/min)
17:00 20:00 23:00 02:00 05:00 08:00
Time
*********
*
*
*
**************** Placebo (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 2
Diabetes
Glucose
intolerance
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),
Japan
Add-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 DesignStudy 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
GLP-1(pmol/L)
–30 0 30 60 90 120
Time (min)
Meal
Vildagliptin 50 mg once daily (n=89)
Placebo (n=89)
9.0
8.0
7.0
6.0
Glucose(mmol/L)
–30 0 30 60 90 120
Time (min)
Meal
26
22
20
18
Glucagon(pmol/L)
–30 0 30 60 90 120
Time (min)
24
Meal
Insulin secretion relative to glucose
8.0
6.0
4.0
2.0
0.0
–2.0
–4.0
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.
ISRAUC0-2h/GlucoseAUC0-2h
(pmol/L•min-1•m-2•mM)
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:

0.1
-0.4
0.5
-0.5
-0.4
-0.3
-0.2
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
(BL Mean ~6.64%)
MeanChangeinHbA1c(%)
Mean Difference vs Placebo
n = 67 63
Placebo
Vildagliptin 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.
Duration: 2 years
Vildagliptin
vs placebo

Placebo
MeanHbA1c(%)
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).
Treatment period Wk 0–52 Treatment period Wk 56–108Washout Washout
Vildagliptin efficacy in mild hyperglycemia:
mean HbA1c over 112 weeks
Duration: 2 years
Vildagliptin
vs 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
57 50n =
Placebo
*
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.
Duration: 2 years
Vildagliptin
vs placebo

Vildagliptin dose-ranging study:
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 50 mg twice daily (n=79)
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
ChangeinFPG(mmol/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
MeanHbA1c(%)
*
**
**
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
*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
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 qd
Vildagliptin 50 mg bid
Adjustedmean%change
−8
−6
−4
−2
0
2
4
6
8
10
12
14 TG TC LDL-C HDL-C
** **

Vildagliptin vs metformin: study design and objective
*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
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 daily
Vildagliptin 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
Mean 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
AdjustedMeanChange
inHbA1c(%)
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.
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, % patients
Vilda 100 mg qd
N=167
Met 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 3.0
Safety population
Vilda= vildagliptin; Met= metformin; AE= adverse events
A patient with multiple occurrences of an AE under 1 treatment is counted only once in the AE category
Data 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:

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= baseline
J Foley & S Sreenan, Horm Metabo Res 2009.41:905-909. erratum in Horm Metab Res 2009 41:909
Glic up to 320 mg daily
Vilda 50 mg bid
AdjustedMeanChange
inHbA1c(%)
HbA1c Change(a)
from BL to EP
†
MeanChangeinBody
weight(kg)
Body weight Change(a)
from BL to EP
Hypoglycemia(b)
%patientswithmild
hypoglycemia
a: per protocolepopulation; b: safety population
120

Vildagliptin vs acarbose in Chinese population:
* Randomized population.
HbA1c=glycosylated hemoglobin; T2DM=type 2 diabetes mellitus
Pan 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 tidDrug 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 acarbose
BL=core baseline; CI=confidence interval; EP=study end point; HbA1c=glycosylated hemoglobin
NI: 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)
Acarbose ≤100 mg tid
12.3
25.5
0
5
10
15
20
25
30
(%patientsreporting
GIadverseevents)
Gastrointestinal adverse events
n= 440 220n= 441 220
***
NI
-1.4 -1.3
-1.5
-1
-0.5
0

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
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.

HbA1c(%)
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 tid
•p< 0.001 vs voglibose
At 12 weeks treatment
Target HbA1c
≤6.5%
Reduction
≥ 1.0%
n 65 65 71 72
-0.95 *
-0.38
-1
-0.8
-0.6
-0.4
-0.2
0

% patients
Vildagliptin 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
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.

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
*
IntactGLP-1(pM)
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
IntactGLP-1(pM)
**
0
2
4
6
8
10
12
14
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)
HbA1c(%)
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 weeks
Vilda add-on to met

Vildagliptin add-on to metformin:
Objective: to demonstrate superior HbA1c reduction with vildagliptin
+ metformin vs metformin monotherapy
Target population: T2DM on maximal dose of metformin;
HbA1c 7.5–11%
*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.
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)
MeanHbA1c(%)
−0.7% vs placebo
−1.1% vs
placebo
*
*
Duration: 24 weeks
Vildagliptin add-on
to metformin
Time (Weeks)
MeanFPG(mmol/L)
−4 0 4 8 12 16 20 24
8
9
10
11
−0.8 vs placebo
−1.7 vs
placebo
**
***
Duration: 24 weeks
Vildagliptin add-on
to 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.
Vilda 50 mg twice daily + met (n=57)
β-cell Function
Placebo-adjusted
values
ISRAUC/GlucoseAUC
* *
5.2
5.7
0.0
2.0
4.0
6.0
8.0
10.0
2-hPPG(mmol/L)
*
*
-1.9
-2.3
-3.0
-2.0
-1.0
0.0
Vilda 50 mg once daily + met (n=53)
Duration: 24 weeks
Vilda add-on to met
2-h PPG
Placebo-adjusted
values

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.
Data on file, Novartis Pharmaceuticals, LAF237A2303.
>65 years
Mean BL ~8.3%
BL BMI >30 kg/m2
Mean BL ~8.3%
PBO + met
ChangefromBLinHbA1c(%)
n= 20 22 103 86 29 29
BL HbA1c
>9%
Duration: 24 weeks
Vilda 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‡
‡ metformin dose >= 1500 mg daily
Vildagliptin add on to metformin in Chinese patients :
Study design and objective
Data on file LAF237A23140

significant improvement in HbA1c, FPP and PPG
Note: 50 qd data for HbA1c change vs baseline were secondary endpoint
Data 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
**
*
Adjustedmeanchange
***
***
Adjustedchangein2-hrprandial
glucose(mmol/L)
N=40 N=46 N=44
N=147 N=145 N=144
*
**
HbA1c reduction
BL 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
29.7
34.8
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
**
***
*
****

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
% 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 document
Data on file LAF237A23140 Table 12-3

Vildagliptin vs pioglitazone as add-on to metformin:
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*
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
Overall
Mean 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.
AdjustedMean
ChangeinHbA1c(%)
HbA1c >9%
Mean BL ~9.7%
n = 264 246
Pio 30 mg once daily + met
63 58
Non-inferior*
Duration: 24 weeks
Add-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 BL
Intention-to-treat population. Vildagliptin (n=295); pioglitazone (n=281).
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
MeanHbA1c(%)
Duration: 52 weeks add-on to metformin: vildagliptin vs pioglitazone
n=277n=293
UnadjustedMean
ChangeinBodyWeight(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 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
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 with
1 hypos (%)
Number of severe
hypoglycaemic
events c
Incidence(%)
1389 1383 1389 1383 1389 1383n =
No.ofevents
No.ofevents
16.2
1.7 39
554
Duration: 52 weeks, add-on to metformin: vildagliptin vs glimepiride
Mean HbA1c reduction a
Incidence of hypoglycaemia b
BL=baseline; CI=confidence interval
NI=non-inferiority; aPer protocol population ; bSafety population.
cGrade 2 or suspected grade 2 events.
*P <0.001; adjusted mean change from BL to Week 52,
between-treatment difference and P value were from
an ANCOVA model containing terms for treatment,
baseline and pooled centre.
Ferrannini E et al. Diab Obes Metab 2009; 11: 157–166.
MeanHbA1c(%)
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)
Adjustedmeanchangein
bodyweight(kg)fromBL
(BL mean ~88.8kg)
1117n = 1071
Change in body weight a

No.ofevents
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.
Vildagliptin was as effective as glimepiride when added to metformin at 104
weeks with no weight gain and low incidence of hypoglycemia
No.ofevents
Incidence(%)
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.ofevents
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
0
2
4
6
8
10
12
14
16
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
2.0Adjustedmeanchange
inbodyweight(kg)
1539n = 1520
*
Change in body weight 3
(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
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 +
met
n=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.

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:
**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.

Change Body weightb from BL to week 52
Glic up to 320 mg + Met
Vilda 50 mg bid + Met
5 / 510 5 / 493n/N=
Number of
hypoglycemic events#
Patients with one
or more hypos (%)
Incidence(%)
Numberofevents
510 493N=
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
MeanHbA1c(%)
7
7.5
8
8.5
9
-4 0 4 12 16 24 32 40 52 56
Time (Week)
AdjustedMeanChange
inbodyweight(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= metformin
AE preferred term, % patients
Vilda 50 mg bid + Met
N=510
% (n)
Glic up to 320 mg + Met
N=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 bid
Met 1000 mg AM
Met 500 mg PM
Metformin 1000 mg bid
Vilda 50 mg qd
Vildagliptin 50 mg bidn=300
n=294
Vilda / met 50/500 mg qd
Low dose: vilda / met 50/500 mg bidn=290
50/1000 mg AM
50/500 mg PM
High dose: vilda / met 50/1000 mg bidn=295
50/500 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
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 weeks
Vilda + met vs mono

Initial combination of vildagliptin + metformin:
robust change in FPGMeanChangeinFPG(mmol/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 Point
Mean baseline FPG ~10.4 mmol/L
287 277285 285n =
Duration: 24 weeks
vilda + met vs mono
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 core
study and open-label sub-study)
~9.9%
96
~8.7%
285
Overall*
>9%
High BL Open-label
Sub-studyb
≥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 <0.001
vs BL)d
High-dose vilda + met (50/1000 mg twice daily)c
BL mean=
n =
>11%
~12. 1%
86
*
Duration: 24 weeks
Vilda + met vs mono
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:
4 weeks 24 weeks
Pioglitazone
45 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%)
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.
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)
MeanHbA1c(%)
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 weeks
Add-on to pio:
vilda vs PBO
Add-on Treatment to Pioglitazone 45 mg Daily

Vildagliptin add-on to glimepiride:
HbA1c=hemoglobin A1c; SU=sulfonylurea; T2DM=type 2 diabetes mellitus.
4 weeks
Glimepiride
4 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.
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
MeanHbA1c(%)
PBO + glimepiride (n=144)
Vilda 50 mg once daily + glimepiride (n=132)
Vilda 50 mg twice daily + glimepiride (n=132)
*
*
Duration: 24 weeks
Add-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
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).

MeanHbA1c(%)
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
LSMeanchangeinHbA1c(%)
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

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＜0.001
p＜0.001
Kikuchi M, et al. Diab Res Clin Pract 2010 89:216-223.

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.
7.5
12.5
17.5
22.5
Glucose
(mmol/L)
0
60
80
100
120
40
20
Insulin
(pmol/L)
60
80
100
120
140
Glucagon
(ng/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 90 120 150 180 210 240 270 300
Time
Vildagliptin 100 mg** (n=15)
Placebo (n=16)
75 g Glucose
Dose

Meal
*
*
*
*
*
*
* * *
*
*
*
Placebo (n=16)
*P <0.05.
0.0
4.0
8.0
12.0
16.0
17:00 20:00 23:00 02:00 05:00 08:00
Time
ActiveGLP-1(pmol/L)
*
161

Acute effects of vildagliptin on glucagon levels in patients with T2DM:
decreased glucagon levels persist beyond the post-meal period
Meal
*
* **
*
*
*
*
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
17:00
Time
DeltaGlucagon(ng/L)
20:00 23:00 02:00 05:00 08:00
Placebo (n=16)
*
162

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.
ISR(AUC)/glucose(AUC)
100(pmol•kg-1•min-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

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