Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared...

OR I G I N A L A R T I C L E doi: 10.1111/j.1463-1326.2006.00698.x

Efficacy and tolerability of initial combination therapy with

vildagliptin and pioglitazone compared with component

monotherapy in patients with type 2 diabetes

J. Rosenstock,1 S. W. Kim,2 M. A. Baron,3 R.-P. Camisasca,4 F. Cressier,4

A. Couturier3 and S. Dejager3

1Dallas Diabetes and Endocrine Center, Dallas, TX, USA2Division of Endrocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital,

Sungkyunkwan University School of Medicine, Seoul, Korea3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA4Novartis Pharma AG, Basel, Switzerland

Aim: The aim of this study was to compare efficacy and tolerability of initial combination therapy with vildagliptin/

pioglitazone to component monotherapy.

Methods: This 24-week, multicentre, randomized, double-blind, active-controlled study assessed the effects of the

dipeptidyl peptidase-4 inhibitor vildagliptin (100 mg q.d.), pioglitazone (30 mg q.d.) and vildagliptin combined with

pioglitazone (100/30 mg q.d. or 50/15 mg q.d.) in 607 drug-naive patients with type 2 diabetes (T2DM). The primary

outcome measure was change from baseline in HbA1c in patients receiving initial combination therapy compared

with pioglitazone monotherapy.

Results: After 24-week treatment, adjusted mean changes in HbA1c from baseline (approximately 8.7%) in patients

receiving pioglitazone monotherapy, 50/15 mg combination, 100/30 mg combination and vildagliptin monotherapy

were �1.4 � 0.1%, �1.7 � 0.1%, �1.9 � 0.1% and �1.1 � 0.1% respectively. Both low-dose and high-dose combi-

nations were significantly more efficacious than pioglitazone alone (p ¼ 0.039 and p < 0.001 respectively).

Adjusted mean changes in fasting plasma glucose were �1.9 � 0.2, �2.4 � 0.2, �2.8 � 0.2 and �1.3 � 0.2 mmol/l

respectively, and both combination groups were significantly more effective than pioglitazone monotherapy (p ¼0.022 and p < 0.001 respectively). The overall incidence of adverse events ranged from 45.8% in the low-dose com-

bination to 51.6% in the pioglitazone monotherapy group. The incidence of peripheral oedema was highest in

patients receiving pioglitazone monotherapy (9.3%) and lowest in those receiving low-dose combination (3.5%).

One mild hypoglycaemic event was reported by one patient receiving high-dose combination and one patient

receiving vildagliptin monotherapy.

Conclusions: First-line treatment with vildagliptin/pioglitazone combination in patients with T2DM provides better

glycaemic control than either monotherapy component yet has minimal risk of hypoglycaemia and a tolerability profile

comparable with component monotherapy.

Keywords: dipeptidyl peptidase-4, HbA1c, incretin hormones, pioglitazone

Received 7 November 2006; returned for revision 17 November 2006; revised version accepted 23 November 2006

Correspondence:

Sylvie Dejager, MD, PhD, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA.

E-mail:

[email protected]

# 2007 Novartis

Journal Compilation # 2007 Blackwell Publishing LtdDiabetes, Obesity and Metabolism, 9, 2007, 175–185 j 175

Introduction

The clinical benefits of good glycaemic control are well

established [1]. However, the traditional stepwise

approach beginning with diet and exercise and sequen-

tially adding and titrating does not address the multifac-

torial nature of T2DM and the critical value of early

intervention to avoid progressive beta-cell failure [2].

The most recent modification of the American Diabetes

Association (ADA) recommendations goes beyond the

evidence-based target HbA1c of less than 7% for diabe-

tes populations at large and calls for individualized

goals for patients to attempt to achieve a HbA1c target as

close to normal as possible without significant hypo-

glycaemia and/or unwanted adverse events (AEs) [3].

This recommendation implies that patients with T2DM

will require multiple pharmacological combinations

much earlier to accomplish these goals, with careful

therapy selection to avoid AEs and hypoglycaemia.

Indeed, most recent guidelines for the pharmacological

management of T2DM have become more aggressive,

with specific recommendations on the progressive use of

combination strategies if HbA1c remains more than 7%

in an attempt to attain and sustain the increasingly strin-

gent glycaemic targets [4].

However, clinical inertia with failure to advance therapy

despite persistently elevated HbA1c levels above target has

been a major problem [5,6], but perhaps the increasing

use of combination therapy as a first-line intervention in

T2DM may facilitate resolution of this compliance issue.

Initial combination therapy using two Oral Antidiabetic

Drug (OAD) with complementary mechanisms of action is

an alternative approach that may provide better or more

sustainedglycaemiccontrol,orallowtheuseof lowerdoses

of the component OADs to minimize any dose-related AEs.

Vildagliptin is a selective dipeptidyl peptidase (DPP)-4

inhibitor that improves glycaemic control in patients with

T2DM by increasing both a- and b-cell responsiveness to

glucose [7,8]. Vildagliptin has been shown to decrease

HbA1c when given as monotherapy [9,10] or in combina-

tion with metformin [11], but its effects in combination

with a thiazolidinedione (TZD) remain to be determined.

The present study compared the efficacy and tolerabil-

ity of initial combination therapy with vildagliptin,

which improves islet function, and the TZD pioglitazone,

which enhances insulin sensitivity, to the monotherapy

components. For the monotherapy arms, doses of 100 mg

q.d. for vildagliptin and 30 mg q.d. for pioglitazone were

chosen and compared with the combination of vildaglip-

tin/pioglitazone (100/30 mg q.d.) and to a low-dose com-

bination of 50/15 mg q.d.

Methods

Study Design

This was a 24-week, double-blind, randomized, active-

controlled, parallel-group study conducted at 145 centres

in eight countries, including the United States, four coun-

tries in Europe and three in Asia. Eligible patients were

randomized to receive vildagliptin 100 mg q.d. (n ¼ 154),

pioglitazone 30 mg q.d. (n ¼ 161), or a vildagliptin/pio-

glitazone combination of 100/30 mg q.d. (‘high dose’, n ¼148) or 50/15 mg q.d. (‘low dose’, n ¼ 144). The doses of

pioglitazone used were selected based on those recom-

mended (for either monotherapy or combination with

a sulfonylurea or metformin) in the prescribing informa-

tion. Treatment blinding was maintained with a double-

dummy technique.

Study Population

The study enrolled patients diagnosed with T2DM and

who had HbA1c between 7.5 and 11.0% at screening

while receiving no pharmacological treatment for at

least 12 weeks prior to screening and no OAD for more

than three consecutive months at any time in the past.

Male and female patients aged 18–80 years, body mass

index (BMI) range of 22–45 kg/m2 and with FPG <15

mmol/l were eligible to participate.

Patients were excluded if they had a history of type 1 or

secondary forms of diabetes, acute metabolic diabetic

complications, myocardial infarction, unstable angina

or coronary artery bypass surgery within the previous 6

months, congestive heart failure, liver disease such as

cirrhosis or chronic active hepatitis, or any contraindica-

tions and warnings according to the country-specific

label for pioglitazone. Patients with any of the following

laboratory abnormalities were also excluded: alanine

aminotransferase or aspartate aminotransferase >2.5

times the upper limit of normal (ULN); direct bilirubin

>1.3 times the ULN; serum creatinine levels >220

mmol/l, clinically significant abnormal TSH or fasting tri-

glycerides (TGs) >7.9 mmol/l.

Study Assessments

HbA1c, fasting plasma glucose (FPG), body weight and

vital signs were measured at each study visit. Standard

haematology and biochemistry laboratory assessments

were made at each visit except week 16. Fasting lipid

profiles and free fatty acids (FFA) were measured, and

ECGs were performed at screening (week �2) and at

OA j Vildagliptin/TZD initial combination J. Rosenstock et al.

176 j Diabetes, Obesity and Metabolism, 9, 2007, 175–185# 2007 Novartis

Journal Compilation # 2007 Blackwell Publishing Ltd

weeks 0, 12 and 24. Standard breakfast meal tests (500

kcal; 60% CHO, 30% fat and 10% protein) were per-

formed at week 0 and week 24 or study endpoint for

assessment of prandial glucose control and b-cell func-

tion in patients agreeing to participate (approximately

19% of randomized patients). Insulin secretory rate

(ISR) was calculated by deconvolution of plasma C-pep-

tide levels [12]. The 2-h area under the curve (AUC) for

ISR and glucose were calculated with the trapezoidal

method, and the ratio of ISR AUC to glucose AUC was

used as a measure of b-cell function.

All AEs were recorded. Patients were provided with glu-

cose monitoring devices and supplies and instructed on

their use. Hypoglycaemia was defined as symptoms sug-

gestive of low blood glucose confirmed by self-monitored

blood glucose (SMBG) measurement <3.1 mmol/l plasma

glucose equivalent. Severe hypoglycaemia was defined as

any episode requiring the assistance of another party.

All laboratory assessments were made by a central lab-

oratory (Covance-US, Indianapolis, IN, USA) with stan-

dardized and validated procedures according to Good

Laboratory Practice. HbA1c was measured using ion

exchange high-performance liquid chromatography.

Data Analysis

The primary efficacy variable was the change from base-

line in HbA1c at study endpoint in the intention-to-treat

(ITT) population using last observation carried forward

for patients who discontinued early. The ITT pop-

ulation comprises all patients who received at least one

dose of study medication and for whom a baseline and

at least one postbaseline efficacy assessment was avail-

able. Secondary efficacy parameters included changes

in FPG, fasting plasma lipids and body weight. Changes

from baseline in primary and secondary endpoints were

analysed using an analysis of variance (ANCOVA) model,

with treatment and pooled centre as the classification

variables and baseline value as the covariate. The pri-

mary comparisons were made to test for superiority of

the vildagliptin/pioglitazone combination (100/30 mg

q.d.) to pioglitazone monotherapy. Secondary compar-

isons were made to test for superiority of the vilda-

gliptin/pioglitazone combination (100/30 mg q.d.) to

vildagliptin monotherapy and for superiority of the low-

dose combination (50/15 mg q.d.) to pioglitazone (30 mg

q.d.) monotherapy. Chi-square tests were performed to

compare the percentage of patients achieving ADA tar-

get HbA1c level at endpoint. Repeated measures ANCO-

VAs were performed to determine the significance of the

between-group differences in HbA1c. Comparability of

baseline characteristics across treatment groups was

assessed by F test for continuous variables and by

Cochran–Mantel–Haenszel chi-square test for categori-

cal variables.

Ethics and Good Clinical Practice

All the participants provided written informed consent.

The protocol was approved by the independent ethics

committee/institutional review board at each study site,

and the study was conducted in accordance with the Dec-

laration of Helsinki, using Good Clinical Practice.

Results

Patients Studied

A total of 607 patients were randomized, and 592 com-

prised the ITT population. Table 1 reports the demo-

graphic and baseline metabolic characteristics of the

randomized population and figure 1 summarizes dispo-

sition of patients from screening through study endpoint.

The groups were well balanced, with HbA1c averaging

8.7% and FPG averaging 10.7 mmol/l, with a mean age

of 51.5 years and disease duration of 2.1 years in the

combined cohort. More than two-third of the patients

(70.2%) presented with an HbA1c above 8% and 35%,

with an HbA1c above 9%. Reflecting the location of

study centres, participants were predominantly Asian

(45%) or Caucasian (approximately 40%). Patients were

on average overweight, with a mean BMI of 29.2 kg/m2,

and a mean waist circumference of approximately 97 cm.

The study was completed by �80% of patients in each

treatment group (figure 1).

Efficacy

Figure 2 depicts the time course of the mean HbA1c dur-

ing 24-week treatment (panel A), and the percentage of

patients achieving ADA-recommended target level of

HbA1c (<7.0%) at study endpoint (panel B). Mean

HbA1c decreased progressively during the first 16 weeks

of treatment then tended to remain stable from week 16

to week 24 in each treatment group. The adjusted mean

reduction in HbA1c from baseline to endpoint was signifi-

cantly greater in patients receiving either the 100/30 mg

combination (�1.9 � 0.1%, p < 0.001) or the 50/15 mg

combination (�1.7 � 0.1%, p ¼ 0.039) than in patients

receiving pioglitazone monotherapy (�1.4 � 0.1%). The

adjusted mean change in HbA1c in patients receiving

vildagliptin monotherapy was �1.1 � 0.1% (p < 0.001

vs. 100/30 mg). As illustrated in figure 2b, a signifi-

cantly higher percentage of patients (65.0%) receiving

J. Rosenstock et al. Vildagliptin/TZD initial combination j OA

# 2007 Novartis


the high-dose combination had endpoint HbA1c < 7.0%

than patients receiving monotherapy with either piogli-

tazone (42.9%, p < 0.001) or vildagliptin (42.5%, p <

0.001).

A preplanned subanalysis of the primary endpoint was

also performed based on initial HbA1c level. In patients

with baseline HbA1c > 9.0% receiving the high-dose

combination, the mean change from a baseline HbA1c of

10.0% was �2.8 � 0.2%. In those receiving the low-

dose combination, vildagliptin monotherapy or pioglita-

zone monotherapy the mean changes from baseline

HbA1cs of 9.8, 9.9 and 9.8% respectively, were

�2.3 � 0.2%, �1.5 � 0.2% and �1.8 � 0.2% respec-

tively (figure 3).

Fasting Glucose, Meal Tests, Fasting Lipids and

Body Weight

Figure 4a depicts the time course of the mean FPG during

24-week treatment with the vildagliptin/pioglitazone

combination or component monotherapy. Fasting glu-

cose decreased sharply from baseline to week 4 in each

group of patients. In those receiving vildagliptin mono-

therapy, FPG was stable from week 4 to week 24. In

patients receiving either combination dose strength or

pioglitazone monotherapy, FPG decreased from week 4

to week 12 and remained stable from week 12 to week

24. The adjusted mean change in FPG was �1.9 � 0.2,

�2.4 � 0.2, �2.8 � 0.2 and �1.3 � 0.2 mmol/l in

patients receiving pioglitazone monotherapy, low-dose

combination, high-dose combination and vildagliptin

monotherapy respectively. The decrease with both the

high-dose (p < 0.001) and low-dose combination (p ¼0.022) was significantly greater than with pioglitazone

monotherapy.

A standard breakfast meal challenge was performed at

baseline and endpoint in a subset of patients with base-

line characteristics representative of the ITT population.

The incremental glucose AUC0–4 h at baseline averaged

13.8 � 1.1, 13.9 � 1.2, 13.4 � 1.5 and 14.2 � 1.2 mmol/l

h in patients randomized to pioglitazone monotherapy,

low-dose combination, high-dose combination and vil-

dagliptin monotherapy respectively. Relative to base-

line, this decreased significantly in each treatment

group, and relative to pioglitazone monotherapy, the

decrease was significantly greater with both the low-

dose combination (between-group difference in the

adjusted mean change in incremental glucose AUC0–4 h

Table 1 Baseline characteristics of the randomized population

Mean � s.d. or n (%)

Pioglitazone

30 mg q.d.

Vildagliptin 1 pioglitazone

50/15 mg q.d.


100/30 mg q.d.

Vildagliptin

100 mg q.d. p value*

n 161 144 148 154

Age (years) 52.4 � 10.3 51.0 � 11.0 51.0 � 11.3 51.4 � 10.8 0.6421

Sex 0.5735

Male 103 (64.0) 84 (58.3) 86 (58.1) 98 (63.6)

Female 58 (36.0) 60 (41.7) 62 (41.9) 56 (36.4)

Race 0.6256

Asian 69 (42.9) 68 (47.2) 66 (44.7) 70 (45.5)

Caucasian 71 (44.1) 52 (36.1) 56 (37.8) 60 (39.0)

Hispanic or Latino 14 (8.7) 15 (10.4) 23 (15.5) 17 (11.0)

All other 7 (4.3) 9 (6.3) 3 (2.0) 7 (4.5)

BMI (kg/m2) 28.9 � 5.5 29.0 � 5.4 29.6 � 5.8 29.4 � 5.8 0.6544

HbA1c (%) 8.7 � 1.0 8.8 � 0.9 8.8 � 1.1 8.6 � 1.0 0.5208

HbA1c group

�9.0% 106 (65.8) 93 (64.6) 92 (62.2) 106 (68.8)

>9.0% 55 (34.2) 51 (35.4) 56 (37.8) 48 (31.2)

FPG (mmol/l) 10.5 � 3.1 10.7 � 2.7 10.9 � 2.7 10.6 � 2.7 0.6370

Disease duration (years) 2.2 � 3.3 2.0 � 3.2 2.0 � 3.1 1.9 � 3.1 0.8418

Fasting lipid parameters (mmol/l)

Triglycerides 2.3 � 0.1 2.5 � 0.2 2.4 � 0.1 2.5 � 0.1 0.4485

Total cholesterol 5.3 � 0.1 5.2 � 0.1 5.2 � 0.1 5.4 � 0.1 0.3473

LDL-cholesterol 3.2 � 0.1 3.1 � 0.1 3.1 � 0.1 3.2 � 0.1 0.6136

HDL-cholesterol 1.13 � 0.03 1.10 � 0.03 1.09 � 0.02 1.09 � 0.03 0.6011

Non-HDL-cholesterol 4.1 � 0.1 4.1 � 0.1 4.1 � 0.1 4.3 � 0.1 0.2490

FFA 0.51 � 0.03 0.57 � 0.03 0.62 � 0.03 0.58 � 0.03 0.0229

BMI (body mass index); FPG (fasting plasma glucose), FFA (free fatty acids).

*Comparability of baseline characteristics assessed by F test for continuous variables and by Cochran–Mantel–Haenszel chi-square test for

categorical variables.




¼ �3.8 � 1.6 mmol/l h, p ¼ 0.024) and the high-dose

combination (�5.2 � 1.3 mmol/l h, p < 0.001).

Figure 4 also depicts the adjusted mean changes in

peak prandial glucose excursions (panel B) and the b-cell

function index (insulin secretory rate AUC0–2 h O glu-

cose AUC0–2 h, panel C) during the standard meal tests.

The peak prandial glucose excursion was significantly

decreased relative to baseline in each treatment group,

and relative to pioglitazone monotherapy, the peak

prandial glucose excursion was significantly decreased

in patients receiving low-dose (�1.1 � 0.5 mmol/l, p ¼0.017) or high-dose (�2.0 � 0.4 mmol/l, p < 0.001) com-

bination treatment. Beta-cell function improved relative

to baseline in patients receiving vildagliptin mono-

therapy and both combination treatment groups. Rela-

tive to pioglitazone monotherapy, b-cell function was

significantly increased in patients receiving the low-

dose combination (þ8.0 � 3.7 pmol/min/m2/mmol/l,

p ¼ 0.046), but the between-treatment difference (com-

bination – pioglitazone) in the adjusted mean change in

the b-cell function index was not statistically significant

for the 100/30 mg combination treatment group

(5.5 � 4.1 pmol/min/m2/mmol/l, p ¼ 0.196).

Table 2 reports the changes in fasting lipid parameters

observed during 24-week treatment with vildagliptin,

pioglitazone, low-dose and high-dose combination.

Monotherapy with pioglitazone decreased fasting TG

(�13.4%), but increased HDL-cholesterol (þ17.5%) and

LDL-cholesterol (þ9.1%). Monotherapy with vildagliptin

decreased fasting TG (�5.8%) and increased HDL-choles-

terol (þ7.7%). Low-dose combination therapy decreased

TG (�4.8%) and increased HDL-cholesterol (þ10.6%).

All other changes in lipids in these three treatment arms

were minimal (less than 3% change from baseline). The

high-dose combination improved all fasting lipid param-

eters relative to baseline, and relative to pioglitazone

monotherapy, the 100/30 mg combination elicited signif-

icantly greater decreases in total cholesterol (between-

group difference ¼ �5.6 � 1.8%, p < 0.001), LDL

(between-group difference ¼ �10.5 � 4.9%, p ¼ 0.033)

and non-HDL-cholesterol (between-group difference ¼�6.8 � 2.5% p ¼ 0.008). In addition, small decreases in

Assessed for eligibility(n=1284)

Randomized(n=607)

AE (n=9, 5.6%)ALV (n=1,0.5%)UTE (n=4, 2.5%)PV (n=4, 2.5%)PWC (n=5,3.1%)LFU (n=5, 3.1%)Adm(n=0, 0.0%)

AE (n=7, 4.7%)ALV (n=0, 0.0%)UTE (n=2, 1.4%)PV (n=2, 1.4%)PWC (n=5, 3.4%)LFU (n=2, 1.4%)Adm(n=1, 0.7%)



Allocated to :Pio30 mg q.d., n=161Safety population, n=161ITT population, n=157

Allocated to :Vilda/Pio100/30, n=148Safety population, n=148ITT population, n=146

Allocated to :Vilda/Pio50/15, n=144Safety population, n=144ITT population, n=139

Allocated to:Vilda100 mg q.d., n=154Safety population, n=153ITT population, n=150

Completed(n=133, 82.6%)




Excluded (n=677)Did not meetinclusion criteria (n=624)Declined to participate (n=36)Other (n=17)

Abbreviations: AE= adverse event; ALV= abnormal laboratory value; UTE= unsatisfactory therapeutic event; PV= protocol violationPWC= patient withdrew consent; LFU= lost to follow-up; Adm= administrative problems

Fig. 1 Disposition of patients from screening through completion. ITT, intention-to-treat ; AE, adverse event; ALV, abnor-

mal laboratory value; UTE, unsatisfactory therapeutic event; PV, protocol violation; PWC, patient withdrew consent; LFU,

lost to follow up; Adm, administrative problems.


# 2007 Novartis


FFA levels were observed in each treatment group, with

the largest improvements being observed in the high-dose

combination group (�10%) and the pioglitazone mono-

therapy group (�5%).

Body weight did not change from a mean baseline of

82 kg to endpoint in patients receiving vildagliptin mono-

therapy (þ0.2 � 0.3 kg), but increased similarly in patients

receiving pioglitazone monotherapy (þ1.5 � 0.3 kg) and

low-dose combination therapy (þ1.4 � 0.3 kg) from base-

lines of 81 and 80 kg, respectively. The increase from base-

line (82 kg) in body weight in patients receiving the 100/30

mg combination (þ2.1 � 0.3 kg) was also not significantly

different from the pioglitazone monotherapy group

(between-group difference ¼ 0.7 � 0.5 kg).

Tolerability

During the 24-week study, all the treatments appeared to

be well tolerated. Table 3 reports the number and percent-

age of patients experiencing the most common specific

AEs. The most frequently reported AEs in the study were

weight gain, headache and peripheral oedema. The AEs of

weight gain and oedema were less common in patients

receiving the low-dose combination than in those receiv-

ing pioglitazone monotherapy. In addition, these AEs

were less common on vildagliptin monotherapy com-

pared with pioglitazone monotherapy. Further, in a pre-

defined analysis, increases in weight of more than 10%

from baseline were observed in 2.1% of patients in the

low-dose combination group and in 3.7% of patients in

the pioglitazone monotherapy group. The majority of AEs

reported were classified as mild or moderate and unre-

lated to study medication. AEs led to discontinuation in

2.6% of patients receiving vildagliptin monotherapy,

6.8% of patients receiving pioglitazone monotherapy,

and 6.3% and 4.7% of patients receiving the low-dose

and high-dose combination regimens respectively.

Hypoglycaemia was limited to one mild event (SMBG

>2.8 mmol/l) in one patient each (0.7%) receiving high-

dose combination and vildagliptin monotherapy, both

precipitated by a missed meal. In addition, one patient

6.0

7.0

8.0

9.0

–4 0 4 8 12 16 20 24Time (Week)

Mea

n H

bA1c

(%)

Pioglitazone 30mg q.d.Vilda/pio 100/30mg q.d.Vilda/pio 50/15mg q.d.Vildagliptin 100mg q.d.

42.9

65.0

53.6

42.5

20

30

40

50

60

70

80

Per c

ent a

chie

ve ta

rget

Pioglitazone 30mg q.d.Vilda/pio 100/30mg q.d.Vilda/pio 50/15mg q.d.Vildagliptin 100mg q.d.

(b)

(a)

***

***

****** ***

Fig. 2 (a) Mean (�s.e.) HbA1c during 24-week treatment

with vildagliptin (100 mg q.d., open circles, n ¼ 150 at base-

line, 136 at week 24), pioglitazone (30 mg q.d., open squares,

n ¼ 157 at baseline, 135 at week 24) or vildagliptin com-

bined with pioglitazone at doses of 100/30 mg q.d. (closed

triangles, n ¼ 146 at baseline, 128 at week 24) or 50/15 mg

q.d. (closed diamonds, n ¼ 139 at baseline, 114 at week 24)

in drug-naive patients with T2DM. ***p < 0.001 for vilda-

gliptin/pioglitazone (vilda/pio) 100/30 mg q.d. vs. pioglita-

zone monotherapy. p values for vildagliptin/pioglitazone 50/

15 mg q.d. vs. pioglitazone monotherapy at weeks 4, 12, 16

and 24 were 0.039, 0.003, 0.006 and 0.020 respectively. (b)

Percentage of patients achieving endpoint HbA1c < 7.0%.

Pioglitazone monotherapy (30 mg q.d., open bars, n ¼ 157);

high-dose vildagliptin/pioglitazone combination (100/30 mg

q.d., checkered bars, n ¼ 146); low-dose vildagliptin/piogli-

tazone combination (50/15 mg q.d., hatched bars, n ¼ 139);

vildagliptin monotherapy (100 mg q.d., closed bars, n ¼150). ***p < 0.001 combo vs. either monotherapy.

–3.5

–3.0

–2.5

–2.0

–1.5

–1.0

–0.5

0.0

Mea

n ch

ange

in H

bA1c

(%)

Pioglitazone 30mg q.d.Vilda/pio 100/30mg q.d.

Vilda/pio 50/15mg q.d.Vildagliptin 100mg q.d.

***

Fig. 3 Mean change from baseline to endpoint in HbA1c in

patients with baseline HbA1c > 9.0%. Pioglitazone mono-

therapy (30 mg q.d., open bars, n ¼ 54); high-dose vilda-

gliptin/pioglitazone (vilda/pio) combination (100/30 mg

q.d., checkered bars, n ¼ 54); low-dose vildagliptin/piogli-

tazone combination (50/15 mg q.d., hatched bars, n ¼ 49);

vildagliptin monotherapy (100 mg q.d., closed bars, n ¼ 46).

***p < 0.001 combo vs. pioglitazone monotherapy.




in the pioglitazone monotherapy presented an asymp-

tomatic low blood glucose level after strenuous exercise.

Severe AEs were infrequent in all treatment groups,

with no apparent relation to treatment or dose of combi-

nation therapy.

No major changes or consistent trends over time were

observed for any haematological, biochemical, urinalysis

parameter or vital signs, and the frequency of treatment-

emergent ECG abnormalities was low and comparable in

all treatment groups.

7.0

8.0

9.0

10.0

11.0

–4 0 4 8 12 16 20 24

Time (Week)

Mea

n FP

G (m

mol

/l)

Pioglitazone30mg q.d.

Vilda/pio 100/30mg q.d.

Vilda/pio 50/15mg q.d.

Vildagliptin 100mg q.d.

Pioglitazone 30mg q.d.

Vilda/pio 100/30mg q.d.Vilda/pio 50/15mg q.d.

Vildagliptin 100mg q.d.

–4.0

–3.0

–2.0

–1.0

0.0

Adj

uste

d m

ean

chan

ge (m

mol

/l)

(b) (c)

0

3

6

9

12

15

Adj

uste

d m

ean

chan

ge(p

mol

/min

/m2/

mm

ol/l) *

*

***

Peak glucose excursion –cell function

(a)

***

*** *** ***

Fig. 4 (a) Mean (�s.e.) FPG during 24-week treatment with vildagliptin (100 mg q.d., open circles, n ¼ 150 at baseline, 135

at week 24), pioglitazone (30 mg q.d., open squares, n ¼ 157 at baseline, 134 at week 24), or vildagliptin combined with

pioglitazone at doses of 100/30 mg q.d. (closed triangles, n ¼ 146 at baseline, 128 at week 24) or 50/15 mg q.d. (closed dia-

monds, n ¼ 139 at baseline, 116 at week 24) in drug-naive patients with T2DM. ***p < 0.001 for vildagliptin/pioglitazone

(vilda/pio) 100/30 mg q.d. vs. pioglitazone monotherapy. p values for vildagliptin/pioglitazone 50/15 mg q.d. vs. pioglita-

zone monotherapy at weeks 4, 12, 16 and 24 were 0.030, 0.017, 0.040 and 0.036 respectively. (b) Adjusted mean (�s.e.)

change in peak prandial glucose excursion during meal tests after 24-week treatment with pioglitazone monotherapy (30

mg q.d., open bars, n ¼ 26), low-dose vildagliptin/pioglitazone combination (50/15 mg q.d., hatched bars, n ¼ 27), high-dose

vildagliptin/pioglitazone combination (100/30 mg q.d., checkered bars, n ¼ 27) or vildagliptin monotherapy (100 mg q.d.,

closed bars, n ¼ 32). *p < 0.05, ***p < 0.001 combo vs. pioglitazone monotherapy. (c) Adjusted mean (�s.e.) change in b-cell

function index (insulin secretory rate AUC0–120 O glucose AUC0–120) excursion during meal tests after 24-week treatment with

pioglitazone monotherapy (30 mg q.d., open bars, n ¼ 9), low-dose vildagliptin/pioglitazone combination (50/15 mg q.d.,

hatched bars, n ¼ 11), high-dose vildagliptin/pioglitazone combination (100/30 mg q.d., checkered bars, n ¼ 11) or vilda-

gliptin monotherapy (100 mg q.d., closed bars, n ¼ 10). *p < 0.05 vs. pioglitazone monotherapy.


# 2007 Novartis


Discussion

The present study is the first to examine the effects of

initial combination therapy with a DPP-4 inhibitor and

a TZD as first-line therapy in treatment-naive patients

with T2DM. From a theoretical standpoint, combining

vildagliptin, which improves both a- [7] and b-cell func-

tion [8], and pioglitazone, which enhances peripheral

insulin action [13], is an attractive and logical therapeutic

approach. Indeed, preclinical studies in Zucker fatty rats

showed that this combination fully normalized glucose

tolerance when given at doses that were essentially inef-

fective as monotherapy [14]. Thus, the present findings

that first-line treatment with vildagliptin and pioglitazone

Table 2 Fasting lipid parameters

Mean � s.e. n

Adjusted mean

per cent change

Between-group difference

(combination – pioglitazone) p value

Triglycerides

Vildagliptin/pioglitazone 100/30 mg q.d. 144 �18.1 � 2.9 �4.7 � 4.1 0.252

Vilda/Pio 50/15 mg q.d. 136 �4.8 � 3.6 8.9 � 5.0 0.073

Vildagliptin 100 mg q.d. 146 �5.8 � 3.1

Pioglitazone 30 mg q.d. 155 �13.4 � 2.8

Total cholesterol

Vilda/Pio 100/30 mg q.d. 144 �3.1 � 1.3 �5.6 � 1.8 0.001

Vilda/Pio 50/15 mg q.d. 136 1.0 � 1.3 �1.4 � 1.8 0.448


Pioglitazone 30 mg q.d. 155 2.5 � 1.2

LDL-cholesterol

Vilda/Pio 100/30 mg q.d. 129 �1.4 � 3.6 �10.5 � 4.9 0.033

Vilda/Pio 50/15 mg q.d. 122 1.9 � 3.8 �7.1 � 5.1 0.164



HDL-cholesterol

Vilda/Pio 100/30 mg q.d. 140 12.1 � 2.1 �5.4 � 2.9 0.058

Vilda/Pio 50/15 mg q.d. 133 10.6 � 2.0 �7.1 � 2.7 0.009

Vildagliptin 100 mg q.d. 147 7.7 � 1.8


Non-HDL-cholesterol

Vilda/Pio 100/30 mg q.d. 140 �7.1 � 1.8 �6.8 � 2.5 0.008

Vilda/Pio 50/15 mg q.d. 133 �1.2 � 2.0 �0.8 � 2.7 0.759



FFA

Vilda/pio 100/30 mg q.d. 60 �9.9 � 8.7 �4.9 � 12.3 0.689

Vilda/pio 50/15 mg q.d. 55 �2.5 � 9.4 �1.4 � 12.6 0.911



Vilda/pio, vildagliptin/pioglitazone; FFA, free fatty acids.

Table 3 Common adverse events (AEs occurring in >3% of any treatment group)

n (%)

Pioglitazone 30 mg

q.d., n 5 161


50/15 mg q.d., n5 144


100/30 mg q.d., n 5 148

Vildagliptin 100 mg

q.d., n5 153

Any AE 83 (51.5) 66 (45.8) 75 (50.7) 78 (51.0)

Weight increased 8 (5.0) 3 (2.1) 11 (7.4) 1 (0.7)

Headache 5 (3.1) 5 (3.5) 9 (6.1) 5 (3.3)

Peripheral oedema 15 (9.3) 5 (3.5) 9 (6.1) 8 (5.2)

Dizziness 8 (5.0) 3 (2.1) 7 (4.7) 9 (5.9)

Upper respiratory

tract infection

7 (4.3) 5 (3.5) 6 (4.1) 6 (3.9)

Asthenia 2 (1.2) 4 (2.8) 5 (3.4) 3 (2.0)

Nasopharyngitis 6 (3.7) 4 (2.8) 4 (2.7) 4 (2.6)




(both in high- and low-dose combination) provided better

glycaemic control than the individual component mono-

therapy, essentially confirmed the prediction of an

enhanced glucose-lowering effect by combining the two

approaches. Most notably, despite a relatively high base-

line HbA1c (>8% in 70% of the patients), the high-dose

combination allowed 65% of patients to achieve the

ADA-recommended target level of HbA1c of <7.0% with

minimal hypoglycaemia (<1%) and with no increase in

body weight relative to pioglitazone monotherapy after

24-week treatment. There were also significant improve-

ments in total, LDL and non-HDL-cholesterol levels

with the high-dose combination relative to pioglitazone

monotherapy. In line with the potential for DPP-4 inhi-

bition to offer a novel approach to reducing cardiovas-

cular risk in patients with T2DM, it has also been shown

that 4-week treatment with vildagliptin significantly

decreased postprandial lipaemia [15]. Conclusions

regarding the influence of the vildagliptin/pioglitazone

combination on the overall cardiovascular-risk profile

will require further investigation.

This study also explored whether the dose-related AEs

of pioglitazone (e.g. oedema and weight gain) could be

avoided by using a lower dose of the TZD combined with

vildagliptin. As expected, it was found that, indeed, the

low-dose combination (vildagliptin 50 mg/pioglitazone

15 mg) elicited a significantly greater reduction in HbA1c

(�1.7%) than did pioglitazone monotherapy with 30 mg

(�1.4%) with fewer AEs of peripheral oedema (3.5 vs.

9.3%) and ‘weight increased’ (2.1 vs. 5%).

Given the contribution of both insulin resistance and

islet dysfunction to the development and progression of

T2DM [16], combining an insulin sensitizer-like pioglita-

zone and an agent such as vildagliptin, which improvesa-

and b-cell function, is a rational approach. One mecha-

nistic advantage this offers is that as shown in the present

study, there is no increase in hypoglycaemia, as seen

when insulin secretagogues are combined with insulin

sensitizers [17,18] because the insulinotropic effects of

vildagliptin are glucose dependent [19]. Also, unlike sul-

fonylureas, vildagliptin reduces inappropriate postmeal

glucagon secretion in patients with T2DM [7], which con-

tributes significantly to vildagliptin-mediated reductions

of postprandial hyperglycaemia [15]. This reduces the

‘demand’ for insulin, mitigating insulin resistance and

thus increasing measures of insulin sensitivity as

reported recently, both in drug-naive [20,21] and in met-

formin-treated patients [22].

The mechanism by which TZD activation of PPAR

gamma receptors reduces insulin resistance is now rela-

tively well understood [23]. Correcting lipotoxicity by

reducing FFA production and TG deposition in target tis-

sues, TZDs improve both hepatic and peripheral insulin

sensitivity [24]. Animal studies haveshownthatTZDsalso

decrease islet TG content [25], and this is the proposed

mechanism by which TZDs may improve islet function

[26]. Thus, multiple mechanisms are brought into play

with the combination of a DPP-4 inhibitor and a TZD and

allow better glycaemic control without hypoglycaemia.

Althougha stepwiseapproach to treatment startingwith

diet and exercise, addition and titration of a single oral

agent, then addition of a second agent is most commonly

used, success with this approach is often less than desired.

Clinical inertia leads to a progressive cycle of treatment

failure, with patients frequently failing to achieve or main-

tain therapeutic goals [5,6,27]. Further, findings from the

Epidemiology of Diabetes Interventions and Complica-

tions (EDIC) study of participants in the Diabetes Control

and Complications Trial (DCCT) emphasizes the critical

value of early and aggressive glycaemic control that results

in sustained benefits on diabetes complications [28]. Of

course, these findings need to be replicated in patients

with T2DM, but it is clear that there are good reasons to

make every attempt to get patients to glycaemic targets as

early and as safely as possible. Initial combination therapy

with a DPP-4 inhibitor and a TZD appears to hold consid-

erable promise in this regard.

In summary, first-line treatment with vildagliptin/pio-

glitazone (both high- and low-dose regimens) provided

better glycaemic control than each component monother-

apy with minimal hypoglycaemia. The high-dose combi-

nation (100/30 mg q.d.) allowed 65% of patients to

achieve target HbA1c < 7%, with a tolerability profile

comparable with pioglitazone (30 mg q.d.) mono-

therapy. The low-dose combination (50/15 mg q.d.) pro-

vided both efficacy and tolerability benefit over

pioglitazone 30 mg q.d. Thus, we conclude that the ini-

tial combination of vildagliptin, a highly selective DPP-

4 inhibitor suitable for once daily dosing, and the TZD

pioglitazone, simultaneously addresses the multiple

defects in T2DM through addressing complementary

mechanisms and appears to be an effective means to

achieving good glycaemic control while attenuating

drug-related AEs.

Acknowledgments

The authors acknowledge the investigators and staff at

the 145 participating sites, the operational support from

Yasmina Amiour, and the editorial assistance of, and help-

ful discussion with Beth Dunning Lower, PhD. This study

was funded by Novartis Pharmaceuticals Corporation. A

list of investigators is provided in the Appendix. This trial

(NCT00101803) is registered with ClinicalTrials.gov.


# 2007 Novartis


References

1 United Kingdom Prospective Diabetes Study (UKPDS)

Group. Intensive blood-glucose control with sulphony-

lureas or insulin compared with conventional treatment

and risk of complications in patients with type 2 diabe-

tes (UKPDS 33). Lancet 1998; 352: 837–853.

2 Riddle MC, Rosenstock J. Oral monotherapy and combi-

nation therapy. In: Cefalu WT, Gerich JE, LeRoith D

eds. The CADRE Handbook of Diabetes Management.

New York: Medical Information Press, 2004; 127–144.

3 American Diabetes Association. American Diabetes

Association (ADA) guidelines: clinical practice recom-

mendations. Diabetes Care 2006; 29 (Suppl. 1): S1–S85.

4 Nathan DM, Buse JB, Davidson MB et al. Management

of hyperglycemia in type 2 diabetes: a consensus algo-

rithm for the initiation and adjustment of therapy. A

consensus statement from the American Diabetes Asso-

ciation and the European Association for the Study of

Diabetes. Diabetes Care 2006; 29: 1963–1972.

5 Brown JB, Nichols GA, Perry A. The burden of treat-

ment failure in type 2 diabetes. Diabetes Care 2004; 27:

1535–1540.

6 Shah BR, Hux JE, Laupacis A, Zinman B, van WC. Clin-

ical inertia in response to inadequate glycemic control:

do specialists differ from primary care physicians? Dia-

betes Care 2005; 28: 600–606.

7 Ahren B, Landin-Olsson M, Jansson P-A, Svenson M,

Holmes D, Schweizer A. Inhibition of dipeptidyl pepti-

dase-4 reduces glycemia, sustains insulin levels and

reduces glucagon levels in type 2 diabetes. J Clin Endo-

crinol Metab 2004; 89: 2078–2084.

8 Mari A, Sallas WM, He YL et al. Vildagliptin, a dipep-

tidyl peptidase-IV inhibitor, improves model-assessed

b-cell function in patients with type 2 diabetes. J Clin

Endocrinol Metab 2005; 90: 4888–4894.

9 Ristic S, Byiers S, Foley J, Holmes D. Improved glycae-

mic control with dipeptidyl peptidase-4 inhibition in

patients with type 2 diabetes: vildagliptin (LAF237)

dose response. Diabetes Obes Metab 2005; 7: 692–698.

10 Pratley RE, Jauffret-Kamel S, Galbreath E, Holmes D.

Twelve-week monotherapy with the DPP-4 inhibitor

vildagliptin improves glycemic control in subjects with

type 2 diabetes. Horm Metab Res 2006; 38: 423–428.

11 Ahren B, Gomis R, Standl E, Mills D, Schweizer A.

Twelve- and 52-week efficacy of the dipeptidyl pepti-

dase IV inhibitor LAF237 in metformin-treated patients

with type 2 diabetes. Diabetes Care 2004; 27: 2874–

2880.

12 van Cauter E, Mestrez F, Sturis J, Polonsky KS. Estima-

tion of insulin secretion rates from C-peptide levels.

Comparison of individual and standard kinetic parame-

ters for C-peptide clearance. Diabetes 1992; 41: 368–

377.

13 Roden M, Laakso M, Johns D et al. Long-term effects of

pioglitazone and metformin on insulin sensitivity in

patients with Type 2 diabetes mellitus. Diabet Med

2005; 22: 1101–1106.

14 Burkey BF, Li X, Bolognese L et al. Combination treat-

ment of a DPP-IV inhibitor NVP-LA237 with pioglita-

zone completely normalized glucose tolerance in adult

obese zucker rats. Diabetes 2002; 51 (Suppl. 2): A338–

A339.

15 Matikainen N, Manttari S, Schweizer A et al. Vilda-

gliptin therapy reduces postprandial intestinal tri-

glyceride-rich lipoprotein particles in patients with

type 2 diabetes. Diabetologia 2006; 49: 2049–2057.

16 Kahn SE. The relative contributions of insulin resis-

tance and beta-cell dysfunction to the pathophysiology

of Type 2 diabetes. Diabetologia 2003; 46: 3–19.

17 Roberts VL, Stewart J, Issa M, Lake B, Melis R. Triple

therapy with glimepiride in patients with type 2 diabe-

tes mellitus inadequately controlled by metformin and

a thiazolidinedione: results of a 30-week, randomized,

double-blind, placebo-controlled, parallel-group study.

Clin Ther 2005; 27: 1535–1547.

18 Rosenstock J, Shen SG, Gatlin MR, Foley JE. Combina-

tion therapy with nateglinide and a thiazolidinedione

improves glycemic control in type 2 diabetes. Diabetes

Care 2002; 25: 1529–1533.

19 Mari A, Sallas WM, He YL, Watson C, Ligueros-Saylan

M, Foley JE. LAF237 is a DPP-4 inhibitor that improves

model-assessed b-cell function in drug-naive patients

with type 2 diabetes. Diabetologia 2004; 47 (Suppl. 1):

A284–A285.

20 D’Alessio DA, Watson CE, He YL et al. Restoration of

an acute insulin response to glucose (AIRg) in drug-

naıve patients with type diabetes (T2DM) by 3-month

treatment with vildagliptin. Diabetes 2006; 55 (Suppl. 1):

A108.

21 Radikova Z, Azuma K, Thomas E et al. Metabolic ef-

fects of incretin hormones I. Diabetologia 2006; 49: 401.

22 Ahren B, Pacini G, Foley JE, Schweizer A. Improved

meal-related b-cell function and insulin sensitivity by

the dipeptidyl peptidase-IV inhibitor vildagliptin in

metformin-treated patients with type 2 diabetes over

1year. Diabetes Care 2005; 28: 1936–1940.

23 Yki-Jarvinen H. Thiazolidinediones. N Engl J Med

2004; 351: 1106–1118.

24 Bajaj M, Suraamornkul S, Hardies LJ, Pratipanawatr T,

DeFronzo RA. Plasma resistin concentration, hepatic fat

content, and hepatic and peripheral insulin resistance

in pioglitazone-treated type II diabetic patients. Int J

Obes Relat Metab Disord 2004; 28: 783–789.

25 Matsui J, Terauchi Y, Kubota N et al. Pioglitazone

reduces islet triglyceride content and restores impaired

glucose-stimulated insulin secretion in heterozygous per-

oxisome proliferator-activated receptor-gamma-deficient

mice on a high-fat diet. Diabetes 2004; 53: 2844–2854.

26 Del Prato S, Marchetti P. Targeting insulin resistance

and beta-cell dysfunction: the role of thiazolidine-

diones. Diabetes Technol Ther 2004; 6: 719–731.




27 Saydah SH, Fradkin J, Cowie CC. Poor control of risk

factors for vascular disease among adults with pre-

viously diagnosed diabetes. JAMA 2004; 291: 335–342.

28 Writing Team for the Diabetes Control Trial. Sustained

effect of intensive treatment of type 1 diabetes mellitus

on development and progression of diabetic nephropathy:

the Epidemiology of Diabetes Interventions and Com-

plications (EDIC) study. JAMA 2003; 290: 2159–2167.

Appendix

List of Investigators

Czech Republic: Dr Stepan Svacina, Dr Zdenek Pistek, Dr

Zdena Pavlovka, Dr Eva Talasova, Dr Marie Hornackova.

India: Dr Mohan Y. Badgandi, Dr Rakesh Sahay, Dr Nikhil

Tandon, Dr C. S. Yagnik. Italy: Prof. Francesco Dotta, Dr

Mario Sprovieri, Dr Cecilia Invitti, Prof. Antonio Tiengo,

Dr Walter Donadon, Dr Ezio Degli Esposti, Dr Luigi Scian-

gula, Prof. Diego Geroldi. Korea: Prof. Moon-Kyu Lee,

Prof. Kun-Ho Yoon, Prof. Bong-Soo Cha, Prof. Jeong-Taek

Woo, Prof. Sun-Woo Kim, Prof. In-Ju Kim, Prof. Jeong-

Hyun Park, Prof. Dong-Seop Choi, Prof. Sung-Woo Park,

Prof. Kyung-Soo Ko, Prof. Sei-Hyun Baik, Prof. Hyoung-

Woo Lee, Dr Hye-Soon Kim, Prof. Tae-Sun Park, Prof.

Hak-Chul Jang. Slovakia: Dr Jaroslav Fabry, Dr Marian

Hranai, Dr Emil Martinka, Dr Marek Macko, Dr Jarmila

Okapcova, Dr Milan Behuncik. Taiwan: Dr Yi-Jen Hung,

Dr Chao-Hung Wang, Dr Chwen-Tzuei Chang, Dr Rue-

Tsuan Liu, Dr Chuen-Den Tseng, Dr Chien-Wen Chou,

Dr Ming-Chia Hsieh. United Kingdom: Dr Paul Goozee,

Dr Mary A. Whitehead, Dr Dennis M. Allin, Dr Najib See-

dat, Dr Barry Glekin, Dr Arun Baksi, Dr John Calvert, Dr

Hugh Jones. Dr John Langan, Dr Geoffrey Butcher. USA:

Dr Martin Lester, Dr Spencer B. Jones, Dr Andrew

Ahmann, Dr Arthur B. Pitterman, Dr John J. Champlin,

Dr Puneet Narayan, Dr Marc S. Rendell, Dr Sriranga V.

Prasad, Dr Kashif Latif, Dr Richard H. Egelhof, Dr Nay-

nesh R. Patel, Dr Anne M. Reddy, Dr Berto Zamora, Dr

Scott W. Yates, Dr Julio Rosenstock, Dr Jayaram B. Naidu,

Dr Hartmut Koelsch, Dr Lawrence Alder, Dr Jane E. Moss-

berg, Dr Robert S. Lipetz, Dr Richard M. Glover, Dr Gary A.

Tarshis, Dr Jewel A. Stevens, Dr Steven K. Elliott, Dr John

A. Mallory, Dr Alan D. Forker, Dr Daniel J. Suiter, Dr Thad

Clements, Dr Luis E. Morales, Dr James R. Shoemaker, Dr

Gary A. Erdy, Dr James E. Gutmann, Dr David C. Subich,

Dr Jeff Aalberg, Dr Alan V. Safdi, Dr Stephanie Young, Dr

Timothy L. Jackson, Dr Richard Kelly, Dr Marwan N. Sab-

bagh, Dr Harry S. Studdard, Dr Gregory Smith, Dr Richard

B. Christensen, Dr Paul W. Davis, Dr John G. Spangler, Dr

Timothy E. Folse, Dr Jane E. Rohlf, Dr Patrick Ogilvie, Dr

Michael W. Lin, Dr Ronald Sockolov, Dr John Gaffney, Dr

Mariusz Jerzy Klin, Dr Jill M. Constantine, Dr Antoinette

A. Pragalos, Dr Sherwyn L. Schwartz, Dr Larry L. Doehr-

ing, Dr Paula Springer, Dr Lyndon E. Mansfield, Dr V.

Jerome Mirkil, Dr Jerry R. Mitchell, Dr Kimy Charani, Dr

John W. McGettigan, Dr Andre Burton, Dr Ellis R. Levin,

Dr Michael Delphia, Dr Samuel T. Verzosa, Dr Michael A.

Azorr, Dr Eli Ipp, Dr Mario A. Henriquez, Dr Angelique

Barreto, Dr Floyd Willis, Dr John Earl, Dr Sajjad A. Savul,

Dr John Reinhardt, Dr Alexander White, Dr David M. Wit-

kin, Dr Ronald J. Sell, Dr Christopher J. Superczynski, Dr

Tracy T. Phillips, Dr Charles W. Knight, Dr Burton W.

Lazar, Dr Beth Koestler, Dr John Mageli, Dr Daniel B.

Sheerer, Dr John J. Eck, Dr Gregory A. Ledger, Dr Corey

G. Anderson, Dr Martin VanCleef, Dr Rafael Canadas, Dr

Joel N. Diamond, Dr Fatima Phillips.


# 2007 Novartis


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