This study compared the effectiveness of vildagliptin combination therapy to other oral anti-diabetes combination therapies without vildagliptin in usual care settings in Latin America. Over 12 months of follow-up, the study found that patients treated with vildagliptin-based combinations had greater success in lowering A1c levels by at least 0.3% without side effects like weight gain or hypoglycemia, compared to other combination therapies. For patients with baseline A1c over 7%, vildagliptin combinations more often helped patients achieve an A1c under 7% without side effects. The incidence of adverse events was low and similar between the treatment groups. The study provides real

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Comparative effectiveness of vildagliptin in
combination with other oral anti-diabetes agents
in usual-care conditions: the EDGE–Latin America
study
Carlos O. Mendivil, Eduardo Márquez-Rodríguez, Iván D. Ángel, Gustavo Paz,
Cruz Rodríguez, Jorge Almada & Ofelia Szyskowsky
To cite this article: Carlos O. Mendivil, Eduardo Márquez-Rodríguez, Iván D. Ángel, Gustavo
Paz, Cruz Rodríguez, Jorge Almada & Ofelia Szyskowsky (2014) Comparative effectiveness of
vildagliptin in combination with other oral anti-diabetes agents in usual-care conditions: the
EDGE–Latin America study, Current Medical Research and Opinion, 30:9, 1769-1776, DOI:
10.1185/03007995.2014.928274
To link to this article: http://dx.doi.org/10.1185/03007995.2014.928274
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Published online: 11 Jun 2014.
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2. Current Medical Research & Opinion Vol. 30, No. 9, 2014, 1769–1776
0300-7995 Article RT-0124.R1/928274
doi:10.1185/03007995.2014.928274 All rights reserved: reproduction in whole or part not permitted
Original article
Comparative effectiveness of vildagliptin in
combination with other oral anti-diabetes agents
in usual-care conditions: the EDGE–Latin
America study
Carlos O. Mendivil*
Universidad de los Andes, School of Medicine, Bogota´,
Colombia
Fundacio´n Santa Fe de Bogota´, Section of
Endocrinology, Bogota´, Colombia
Eduardo Ma´rquez-Rodrı´guez*
Instituto Jalisciense de Metabolismo, Guadalajara,
Me´xico
Hospital A´ ngeles del Carmen, Guadalajara, Me´xico
Iva´n D. A´ngel
Escuela de Nutricio´n y Diete´tica, Universidad de
Antioquia, Medellı´n, Colombia
Gustavo Paz
Hospital Carlos Andrade Marı´n, Quito, Ecuador
Cruz Rodrı´guez
InCardio, Maturı´n (Mo´nagas), Venezuela
Jorge Almada
Novartis Latin America, Mexico City, Mexico
Ofelia Szyskowsky
Clı´nica Santa Isabel, Buenos Aires, Argentina
Address for correspondence:
Carlos O. Mendivil, Universidad de los Andes, School
of Medicine, Cra 7a # 116-05, Of. 413, Bogota,
Colombia.
Tel.: +57 321.373.5051;
carlosolimpo@gmail.com
Keywords:
Anti-diabetics – Diabetes – Dipeptidyl peptidase-IV
inhibitors – Vildagliptin
Accepted: 21 May 2014; published online: 11 June 2014
Citation: Curr Med Res Opin 2014; 30:1769–76
Abstract
Objective:
To assess the proportion of patients on vildagliptin add-on dual therapy who respond to treatment over a
12 month follow-up, relative to comparator oral anti-diabetes dual therapy, in a usual care setting.
Research design and methods:
Participants were patients with type 2 diabetes (T2DM) aged 18 years and older from 311 centers in
Argentina, Colombia, Ecuador, Mexico and Venezuela. Patients were taking monotherapy with an oral anti-
diabetes drug (OAD), and were prescribed a new add-on OAD based on the judgment of their personal
physician. According to this choice, patients were assigned to one of the two cohorts: vildagliptin or
comparator OADs.
Main outcome measures:
The primary endpoint was the proportion of patients achieving an A1c drop 40.3% without edema,
hypoglycemia, weight gain or discontinuation due to gastrointestinal (GI) events. The secondary endpoint
was the proportion of patients with baseline A1c !7% who reached the goal of an A1c 57% without
hypoglycemia or weight gain.
Results:
The per-protocol population (a subset of the intention-to-treat population that excluded patients with pre-
specified protocol deviations) comprised 3773 patients, 3002 in the vildagliptin cohort and 771 in the
comparator cohort. The proportion of patients reaching the primary endpoint was higher in the vildagliptin
cohort (60.3%) than the comparator cohort (50.7%), OR 1.48 (95% CI: 1.25–1.73). The same was observed
for the secondary endpoint (44.8 versus 33.1%) OR 1.64 (95% CI: 1.37–1.98). The incidence of adverse
events was low and similar between treatment cohorts.
Conclusion:
In a usual care setting, patients treated with a vildagliptin combination succeeded in lowering A1c to57%,
without weight gain, hypoglycemia or peripheral edema more often than patients treated with comparator
combinations, without increased risk of adverse events. Key limitations are the observational nature of the
study and its relatively limited 12 month timeframe.
Introduction
During the past three decades, the developing world has experienced a dramatic
rise in the prevalence of type 2 diabetes mellitus (T2DM), and Latin America
has not been the exception. The International Diabetes Federation (IDF)
*These authors contributed equally to the
development of this study.
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3. estimated for Latin America in the year 2011 a regional
age-adjusted prevalence of diabetes of 9.2% in adults1
, a
huge figure for a region of 577 million people trying to
escape from poverty and underdevelopment. Diabetes
imposes a high economic burden in this subcontinent: at
least 3.1 billion dollars a year in 2003 for Mexico, Central
America, the Caribbean and South America, in direct
medical costs alone, according to the Pan-American
Health Organization (PAHO)2
. Most of these costs are
derived from the chronic complications of the disease, as
they result in hospitalizations with expensive diagnostic
and therapeutic procedures. Even though a tight control
of glycemia and other risk factors has proven to prevent the
appearance of the chronic complications of T2DM3
, the
rates of goal achievement are remarkably low in both
industrialized4
and developing countries5
. Achievement
of treatment goals is the mainstay of T2DM care, but
given the progressive nature of the condition this often
requires the simultaneous use of lifestyle changes and a
combination of drugs6–8
.
In addition to efficacy, recent guidelines suggest that
effectiveness, tolerability, cost and patient preferences
may influence the outcomes of therapy and should be con-
sidered when choosing anti-diabetes drugs9
. Usual prac-
tice, usual care studies provide essential information
about the results of an intervention when all factors poten-
tially impacting treatment outcomes are taken into
account. Despite the pivotal role of randomized controlled
trials on the initial determination of efficacy, the general-
izability of their results can be quite limited, and there is an
increasing recognition of the importance of pragmatic
trials10–12
.
EDGE (Effectiveness of Diabetes control with
vildaGliptin and vildagliptin/mEtformin) is a prospective,
1 year, usual care observational study conducted world-
wide, that assesses the effectiveness and tolerability of vil-
dagliptin, a dipeptidyl peptidase-IV (DPP-4) inhibitor,
added to monotherapy with an oral anti-diabetes drug
(OAD), compared to any two-OAD combination without
vildagliptin (pooled). Physicians enrolled patients with
T2DM inadequately controlled using one OAD, when a
second glucose-lowering agent was considered. This study
sought to assess the effectiveness and tolerability of vilda-
gliptin combinations versus other OAD two-agent com-
binations, but also to illustrate the advantages and
limitations of large usual care studies. Most multinational
clinical trials or post-marketing studies include very few or
no patients from Latin America, so there is a great paucity
of reliable information on the pharmacological manage-
ment of T2DM that is unmistakably applicable to our
population. EDGE–Latin America aims to contribute in
filling this gap.
In this manuscript, we report on the effectiveness and
tolerability of vildagliptin combinations versus other OAD
two-agent combinations for patients enrolled in Latin
American countries (Argentina, Colombia, Ecuador,
Mexico and Venezuela).
Methods
Study design
EDGE was a 12 month, observational, multicenter, post-
authorization, prospective cohort study in which 45,868
patients from 2957 centers in 27 countries from Europe,
Central and Latin America, Asia and Middle East were
evaluated. Of these, 4145 patients were enrolled from
311 sites in Argentina, Colombia, Ecuador, Mexico and
Venezuela. Adult patients (aged 418 years) with T2DM
and inadequate glycemic control while receiving OAD
monotherapy with a sulfonylurea (SU), metformin, thia-
zolidinedione (TZD), metiglinide, or alpha-glucosidase
inhibitor (AGI), and for whom a second oral anti-diabetic
agent (OAD) was considered, were eligible. Patients who
were planned to initiate a DPP-4 inhibitor other than
vildagliptin, or a glucagon-like peptide-1 (GLP-1)
mimetic/analogue, or who required three or more OADs
at study entry were excluded, as were patients changed
from one OAD or OAD class to another at the time of
study entry, prior to adding a new OAD. Patients who were
using insulin at the time of study entry and patients with a
history of hypersensitivity to any of the study drugs or drugs
of similar chemical classes were excluded.
Participants were required to provide written or oral
informed consent (per country regulations) to have data
collected and agree to follow all local medication labeling
or prescribing requirements of their new OAD. Physicians
chose glucose-lowering treatment for their patients at their
discretion. To ensure non-interventional status, patient
enrollment was agreed after the treatment decision was
made. Suitable patients fell into one of two cohorts (vil-
dagliptin or comparator). The term index therapy is used
to represent the combination treatment initiated at enroll-
ment. For any index therapy, a fixed dose combination,
when available, was allowed13
. The choice of the initial
monotherapy and the decision to intensify was entirely
determined by each treating physician individually.
Data collection
Demography (age, gender, race, height, ethnicity), body
weight, medical history, date of diagnosis of T2DM, anti-
diabetes medications taken prior to study entry, newly
initiated add-on OAD (second component of index medi-
cation), other medications (by class), most recent A1c test
date and result, and any other laboratory test dates and
results were collected at baseline during a routine office
visit. After 12 months, the final data collected included
body weight, changes to newly initiated index OAD, most
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4. recent A1c test data and result, other laboratory test dates
and results, adverse events and study completion status.
Interim assessments could occur at any time between base-
line and final study data collection, or early termination.
Laboratory testing was performed on patients in line
with normal medical practice and/or as defined by local
prescribing information and/or at a time period judged
appropriate by the physician. Because of the ‘real-world’
nature of the study, central laboratories were not used.
However, A1c measurements were performed in the parti-
cipating centers using National Glycohemoglobin
Standardization Program (NGSP)-approved methodolo-
gies from commercial manufacturers. In keeping with the
non-interventional observational design employed, moni-
toring was conducted only at centers with high enrolment
(about 5% of centers). However, physicians were requested
to maintain source documents for each patient, including
signed informed consent forms.
Effectiveness and tolerability endpoints
Primary endpoint
The primary endpoint was defined as the proportion of
patients having a treatment response (A1c reduction
40.3% from baseline to month 12) while presenting no
tolerability findings (peripheral edema, proven hypogly-
cemic event, discontinuation due to a gastrointestinal
(GI) event, or weight gain !5%). Patients who could
not be categorized as a success or failure (e.g. due to missing
A1c or body weight data at 12 month endpoint) were con-
sidered non-evaluable. Non-evaluable patient data were
considered failures in calculation of the odds ratio (OR)
for success. The main analysis of the primary endpoint
utilized the per-protocol (PP) population; data were cen-
sored if patient changed index therapy. Patients were
defined as having proven hypoglycemia if they experi-
enced any hypoglycemic event as defined below, con-
firmed by the opinion of the physician, at any time
during the 12 month observation period: i. symptoms sug-
gestive of hypoglycemia that resolved promptly on the
administration of oral carbohydrate, ii. symptoms suggest-
ive of hypoglycemia accompanied by a plasma glucose
below 3.1 mmol/L (56 mg/dL), or iii. symptoms suggestive
of hypoglycemia and patient unable to initiate self-
treatment therefore requiring assistance of a third party
or hospitalization.
Secondary endpoint
The secondary endpoint was defined as the proportion of
patients with a baseline A1c !7% who achieved an A1c
57% without experiencing proven hypoglycemia or
weight gain !3%.
Analysis of primary and secondary effectiveness
and tolerability endpoints
Data were collected at baseline and at any time point
in the next 12 months, with a required reporting at 12
months. This manuscript constitutes a post-hoc analysis
of the global EDGE study and, as such, it provides
mainly descriptive statistics. For the primary and second-
ary endpoints, the probability of success was analyzed using
a binary logistic regression model to calculate odds ratios
(ORs) and their 95% confidence intervals (CIs). The OR
expresses the odds in favor of success in the vildagliptin
group relative to odds in favor of success in the comparator
OADs group. Given the post-hoc nature of this analysis,
only the unadjusted OR and a single multivariate model
(as an exploratory analysis) are provided. The between-
groups difference in A1c drop was analyzed using
ANCOVA, with treatment group as a fixed factor and
baseline A1c as the model covariate.
Ethics
The protocol for EDGE was approved by the following
Independent Review Boards (IRBs) in each country:
Argentina: Comite´ Independiente de E´tica para Ensayos
en Farmacologı´a Clı´nica de la Fundacio´n de Estudios
Farmacolo´gicos y de Medicamentos ‘Profesor Luis M.
Zieher’, Colombia: Comite´ Independiente de E´tica e
Investigacio´n Biome´dica AVANZAR, Ecuador: Comite´
de Bioe´tica de la Universidad San Francisco de Quito,
Me´xico: Instituto Mexicano de Educacio´n Me´dica e
Investigacio´n Clı´nica S.C., Venezuela: Comite´ de E´tica
del CENREV – Centro Nacional De Retina Y Vı´treo.
We obtained written informed consent from participants
in all countries except Mexico, where local regulations
allow IRBs to authorize a verbal informed consent in stu-
dies with minimal risk like this one. The consent was rec-
orded at the medical record and at the case report form. All
Ethics Committees/IRBs involved in the study approved
the consent procedure.
Results
Patient populations and baseline characteristics
The enrolled population comprised 4145 patients with
documented informed consent, but 296 patients (229 in
the vildagliptin and 67 in the comparator cohort) were
excluded due to inadequate source documentation or prob-
lems with the quality or accuracy of data entry (Figure 1).
The intention-to-treat (ITT) population, used for baseline
demographics and safety analyses, comprised 3065 and 781
patients receiving dual therapy with newly prescribed vil-
dagliptin or a non-vildagliptin OAD added to prior
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5. monotherapy, respectively. The per-protocol population
was a subset of the ITT population that excluded partici-
pants with pre-defined protocol deviations (Figure 1).
The per-protocol population was used for the analyses of
effectiveness endpoints and comprised 3002 patients in
the vildagliptin, and 771 in the comparator cohort. The
number of patients with a baseline A1c57% whose treat-
ment was intensified during the study were 288 (9.4%)
in the vildagliptin cohort, and 66 (8.4%) in the compara-
tor cohort.
The baseline characteristics of the ITT population are
summarized in Table 1. Study participants were on average
55.9 years old, had been diagnosed with diabetes 5.6 years
ago, had a BMI of 29.5 kg/m2
, and an A1c level of 8.5%.
The sex distribution was almost even. Hypertension was
present in 46.1% of participants, lipid disorders in 32.9%,
established macrovascular complications in 5.3% and
established microvascular complications in 4.8%. The vil-
dagliptin and comparator groups were similar in important
clinical variables like sex distribution, body-mass index
and baseline A1c, and had small but statistically signifi-
cant differences in other variables: participants in the com-
parator group were on average 2 years older (p50.001),
their T2DM had lasted 0.9 years longer (p50.001), had
a higher prevalence of hypertension (49.4 vs 45.2%,
p ¼ 0.034), lipid disorders (36.2 vs 32.0%, p ¼ 0.025) and
a slightly higher prevalence of microvascular complica-
tions (6.7 vs 4.4%, p ¼ 0.008).
The different OAD combination schemes received
by the ITT population in each group are displayed in
Table 2. In the vildagliptin cohort, the most frequent
combination was with metformin (80%). After metfor-
min, the most frequent coexisting therapy was SUs, fol-
lowed by TZDs, AGIs and in the last place metiglinides.
Conversely, in the comparator group the most frequent
combination therapy was metformin þ SUs (62%), fol-
lowed by metformin þ TZDs, SU þ TZDs, metiglinides þ
metformin, AGIs þ metformin, AGIs þ sulfonylureas,
metiglinides þ TZDs, AGIs þ TZDs and in the last
place metiglinides þ SUs.
Primary and secondary endpoints
Table 3 shows the success rates and ORs for the primary
and secondary endpoints. The percentage of patients
in the vildagliptin group who successfully reached the pri-
mary endpoint of a decrease in A1c40.3%, without per-
ipheral edema, hypoglycemia, discontinuation due to GI
side-effects or hypoglycemia was 60.3%. In the comparator
group this percentage was 50.7%. This difference resulted
in an OR of 1.48 (95% CI: 1.26–1.73). As indicated in
Table 3, a similar advantage for vildagliptin-based thera-
pies was seen for the secondary endpoint, with 44.8% of
vildagliptin-treated patients compared to 33.1% of com-
parator-treated patients reaching the secondary endpoint,
resulting in an OR of 1.64 (95% CI: 1.37–1.98).
The mean change in A1c at 12 months by treatment
group is illustrated in Figure 2: À1.70% (95% CI: À1.74–
À1.67) in vildagliptin-treated patients and À1.50% (95%
CI: À1.58–À1.43) in comparator-treated patients (ana-
lysis not pre-specified in protocol).
Safety analyses
The number of patients with any reported adverse event in
any primary system organ class was 202 in the vildagliptin
cohort (6.6%) and 124 in the comparator cohort (25.9%).
Table 4 summarizes adverse events that occurred during
the study, listed by system organ class. There were four
deaths reported among the 3065 patients in the vildaglip-
tin cohort ITT population, and one death among the 781
4,145
enrolled*
3,294
Vildagliptin cohort
229
Insufficient data
quality
67
Insufficient data
quality
3,065
ITT**
63
Protocol
deviations
3,002
Per protocol***
540
Discontinued
848
Comparator cohort
781
ITT**
771
Per protocol***
10
Protocol
deviations
118
Discontinued
663
Patients
completed
2,525
Patients
completed
Figure 1. Patient population and flow. *The enrolled population includes all
patients who gave documented informed consent. **The intention-to-treat
(ITT) population is a subset of the enrolled population and includes all
patients who were assigned to new treatment at study start. Sites and/or
patients identified with quality and compliance findings, irregular data were
excluded from the ITT analysis population. ***The per-protocol (PP)
population is a subset of the ITT population. The PP population was used for
the analyses of effectiveness endpoints. Patients with the following
deviations at baseline assessment were excluded from the per protocol
population: patients receiving DPP-4 inhibitors at baseline or within 1 month
prior to baseline; patients receiving GLP-1 mimetics/analogues at baseline
or within 1 month prior to baseline; patients receiving insulin at baseline;
patients receiving only newly initiated monotherapy or more than two oral
anti-diabetes medications at baseline; drug-naive patients at baseline
(patients not taking any diabetic medication prior to baseline); patients who
swapped from one oral anti-diabetes medication or class to another at
baseline; patients receiving vildagliptin at baseline or 30 days prior to
baseline or five half-lives prior to baseline; patients receiving more than one
oral anti-diabetes medication prior to baseline.
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6. patients in the comparator cohort ITT population.
Hypoglycemia was reported by 7 patients (0.23%) in the
vildagliptin cohort, and by 10 patients (1.28%) in the
comparator cohort. After adjusting for baseline weight by
ANCOVA, the change in body weight for patients in the
vildagliptin-therapies cohort was À3.05 kg (95% CI:
À3.27–À2.85), while in the comparator cohort this
weight change was À2.50 kg (95% CI: À2.94–À2.08).
Given the presence of small but significant differences
between groups in some baseline variables, we ran a multi-
variable logistic regression model that included as pre-
dictors (besides treatment group), the following
covariates: age, diabetes duration, hypertension (yes/no),
lipid disorders (yes/no), and microvascular complications
(yes/no). After multivariable adjustment, the odds of
achieving the primary endpoint were still significantly
Table 3. Primary and secondary efficacy and tolerability endpoints.
Vildagliptin Comparator
Sample size for primary endpoint n ¼ 3002 n ¼ 771
Sample size for secondary endpoint n ¼ 2422 n ¼ 626 OR (95% CI) p Value
Primary Endpoint
Decrease in A1c40.3%, no hypoglycemia, no weight
gain, no discontinuation for gastrointestinal events, no
peripheral edema
1810 (60.3) 391 (50.7) 1.48 (1.25–1.73) 50.001
Secondary Endpoint
Among participants with baseline A1c !7%: achieve-
ment of A1c57% at end of study without proven
hypoglycemic events or weight gain !3%
1085 (44.8) 207 (33.1) 1.64 (1.37–1.98) 50.001
Analyses were performed on the per-protocol population. The per-protocol (PP) population is a subset of the ITT population from which patients with any of the
following deviations from the protocol were excluded: use of DPP-4 inhibitors at baseline or within 1 month prior to baseline, use of GLP-1 mimetics/analogues at
baseline or within 1 month prior to baseline, use of insulin at baseline, use of more than two oral anti-diabetes medications at baseline, use of no anti-diabetes drug
(drug-naive patients) at baseline, change from one oral anti-diabetes medication or class to another at baseline, use of vildagliptin at baseline or 30 days prior to
baseline and use of more than one oral anti-diabetes medication prior to baseline. Only unadjusted ORs are shown.
Table 2. Index medications by study group (ITT population).
Vildagliptin cohort* (n ¼ 3065) Comparator cohort* (n ¼ 781)
Vildagliptin þ n (%) Combination n (%)
Metformin 2451 (80.0) Metformin þ Sulfonylureas 483 (62.0)
Sulfonylureas 439 (14.3) Metformin þ Thiazolidinediones 148 (19.0)
Thiazolidinediones 132 (4.31) Sulfonylureas þ Thiazolidinediones 89 (11.4)
Alpha glucosidase inhibitors 25 (0.82) Metiglinides þ Metformin 29 (3.72)
Metiglinides 15 (0.49) Alpha glucosidase inhibitors þ Metformin 13 (1.67)
Alpha glucosidase inhibitors þ Sulfonylureas 8 (1.03)
Metiglinides þ Thiazolidinediones 4 (0.51)
Alpha glucosidase inhibitors þ Thiazolidinediones 3 (0.39)
Metiglinides þ Sulfonylureas 2 (0.26)
*For three patients in the vildagliptin cohort and two in the comparator cohort, it was not possible to identify the index medication.
Table 1. Demographic and patient baseline characteristics (ITT population).
Characteristic Vildagliptin Comparator Total p Value
n ¼ 3065 n ¼ 781 n ¼ 3846
Age (years) 55.5 Æ 12.5 57.5 Æ 11.7 55.9 Æ 12.4 50.001
Female sex (%) 1597 (52.1) 426 (54.6) 2023 (52.6) 0.22
BMI (kg/m2
) 29.5 Æ 5.33 29.3 Æ 5.2 29.5 Æ 5.3 0.24
Baseline A1c (%) 8.5 Æ 1.7 8.5 Æ 1.66 8.5 Æ 1.69 0.42
Duration of T2DM (years) 5.5 Æ 6.1 6.4 Æ 6.2 5.66 Æ 6.1 50.001
Hypertension (%) 1385 (45.2) 386 (49.4) 1771 (46.1) 0.034
Lipid disorders (%) 981 (32.0) 283 (36.2) 1264 (32.9) 0.025
Macrovascular disease (%) 154 (5.0) 51 (6.5) 205 (5.3) 0.094
Microvascular disease (%) 134 (4.4) 52 (6.7) 186 (4.8) 0.008
Data are means Æ SD or n (%).
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7. higher in the vildagliptin group (OR 1.54, 95% CI 1.32–
1.81), with a point estimate very similar to that found in
the univariate model.
Sensitivity analysis
In a sensitivity analysis, we evaluated the frequency of the
primary endpoint only in patients whose treatment
included metformin (metformin þ vildagliptin in the vil-
dagliptin cohort, and metformin þ other OAD in the com-
parator cohort). The results did not differ from those in the
complete study sample: the percentage achievement
of the primary study endpoint was 58.1% (1424/2451)
in the vildagliptin group and 45.9% (309/673) in the com-
parator group (p50.001).
Discussion
There is a very limited body of evidence from large studies
regarding the effectiveness of anti-diabetes medications as
used in everyday practice14,15
. This unmet need is felt
around the world, but particularly so in Latin America,
a continent where the prevalence of T2DM has exhibited
a sharp increase in recent times, in parallel with the costs,
morbidity and mortality associated with inadequate man-
agement of the disease, and where economic resources
available to treat chronic complications are sparse.
The results from EDGE–Latin America contribute to fill
this gap.
First and foremost, the results from EDGE confirm the
low achievement of glycemic goals among patients with
T2DM, highlighting a seemingly intractable problem of
clinical inertia despite calls from virtually every T2DM
guideline in the world to be proactive and aggressive in
the pursuit of treatment goals9
. A previous study in
Mexican patients with T2DM in Mexico found a rate
of a goal A1c 57% in only 37% of 2439 patients, while
the percentage of patients reaching the composite end-
point that included simultaneously A1c, blood pressure
and low-density lipoprotein cholesterol goals was a mere
3%5
. A cross-sectional analysis of the quality of care pro-
vided by specialists in Argentina to 1888 patients with
T2DM from 43 centers across the country found that
39.7% of patients were treated with a single anti-diabetes
drug, 35.3% with two drugs and 9.4% with three drugs.
The average time from diagnosis to initiation of insulin
therapy was 12 years16
. Likewise, in a review of medical
records of patients with T2DM attending the diabetes
clinics at the Salvadorean Social Security Institute, the
goal of a fasting plasma glucose level between 70 and
120 mg/dL was achieved by only 26.9% of patients17
.
While it is true that T2DM management in Latin
America appears to be less than perfect, studies in different
countries show a comparable reality. A nationwide,
Table 4. Adverse events by primary system class and cohort (ITT
population).
Primary System Organ Class (SOC) Vildagliptin
(n ¼ 3065)
Comparator
(n ¼ 781)
Infections and infestations 52 (1.7%) 30 (3.9%)
Gastrointestinal disorders 29 (1.0%) 17 (2.2%)
Metabolism and nutrition disorders 17 (0.6%) 15 (1.9%)
Nervous system disorders 22 (0.7%) 10 (1.3%)
Musculoskeletal and connective tissue
disorders
14 (0.5%) 15 (1.9%)
General disorders and administration
site conditions
11 (0.4%) 7 (0.9%)
Vascular disorders 11 (0.4%) 4 (0.5%)
Renal and urinary disorders 9 (0.3%) 3 (0.4%)
Respiratory, thoracic and mediastinal
disorders
4 (0.1%) 8 (1%)
Injury, poisoning and procedural
complications
6 (0.2%) 1 (0.1%)
Psychiatric disorders 4 (0.1%) 3 (0.4%)
Cardiac disorders 3 (0.1%) 2 (0.3%)
Neoplasms benign, malignant and
unspecified
2 (0.1%) 3 (0.4%)
Skin and subcutaneous tissue disorders 4 (0.1%) 1 (0.1%)
Blood and lymphatic system disorders 3 (0.1%) 1 (0.1%)
Eye disorders 2 (0.1%) 1 (0.1%)
Hepatobiliary disorders 3 (0.1%) 0 (0%)
Investigations 2 (0.1%) 1 (0.1%)
Immune system disorders 1 (0%) 1 (0.1%)
Reproductive system and breast
disorders
1 (0%) 1 (0.1%)
Ear and labyrinth disorders 1 (0%) 0 (0%)
Pregnancy, puerperium and perinatal
conditions
1 (0%) 0 (0%)
Endocrine disorders 0 (0%) 0 (0%)
Surgical and medical procedures 0 (0%) 0 (0%)
TOTAL 202 (6.7%) 124 (16.1%)
Adverse events were coded according to the Medical Dictionary for
Regulatory Activities (MedDRA), version 14.0. Primary system organ classes
are presented in descending order of total frequency of adverse events. A
patient with multiple occurrences of an adverse event under one cohort is
counted only once in the adverse event category. A patient with multiple
adverse events within a primary system organ class is counted only once in
the total row for that cohort. Switches from vildagliptin þ metformin fixed
dose to vildagliptin as add-on dual therapy to metformin and vice versa were
not counted as treatment change. Total also contains patients without initial
dual therapy.
−1.50 *−1.70*
p<0.001p<0.001
4.0
5.0
6.0
7.0
8.0
9.0
Vildagliptin Comparator
A1c(%)
p<0.001
Figure 2. Glycated hemoglobin levels at study end (dark bars) versus
baseline (clear bars) in the ITT population, by group. *ANCOVA-adjusted
change in A1c.
Current Medical Research & Opinion Volume 30, Number 9 September 2014
1774 Vildagliptin combination effectiveness in Latin America Mendivil et al. www.cmrojournal.com ! 2014 Informa UK Ltd
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8. population-based survey of goal achievement (including
laboratory values plus lifestyle and weight/waist circumfer-
ence goals) among T2DM patients in Spain, found that
despite a majority of patients reaching an A1c57% (71%),
none of the study participants attained all of the eight pre-
established treatment goals, and only three patients previ-
ously diagnosed with diabetes achieved seven of them18
.
This finding is especially worrisome coming from a country
with universal health coverage and a health system
strongly focused on primary care and preventive medicine.
In the United States, a recent analysis of diabetes care
between the years 1999 and 2010 including more than
100,000 patients found 51.3% of them (in 2010) to have
an A1c57%. The common objective of A1c, LDL chol-
esterol and blood pressure goal attainment plus no tobacco
use was met by only 14.3% of patients19
. In the Asian
continent, a study of glycemic control in more than
238,000 Chinese patients with T2DM found between
17.8% and 36.1% of them to have an A1c57%, depending
on their pharmacologic regime20
. Even in Canada, a coun-
try with an internationally acclaimed health system, the
Diabetes Registry to Improve Vascular Events [DRIVE]
revealed that scarcely 53% of T2DM patients were satis-
factorily reaching the A1c goal. The percentage keeping
A1c under the 7% limit for the entire 12 month follow-up
was 39%21
. Finally, in a 5 year survey that focused on
developing countries from Asia, Eastern Europe and
Latin America (International Diabetes Management
Practice Study – IDMPS), and enrolled 9901 patients
with T2DM, the overall rate of achievement of A1c
57% was 36.4%22
.
In EDGE–Latin America, when vildagliptin was added
as a second anti-diabetes agent, 60.3% of patients success-
fully reached the primary endpoint of a decrease in A1c
40.3% without peripheral edema, hypoglycemia, discon-
tinuation due to GI side-effects or an increase in body
weight !5%. The proportion of patients who started the
study with an A1c47% and went on to reach an A1c57%
after 12 months without weight gain !3% or proven hypo-
glycemia was 44.8% in the vildagliptin cohort. The ORs
showed significantly greater odds of achieving the compos-
ite goals with vildagliptin therapies compared to all other
combination therapies. A sensitivity analysis limited to
patients in whom the combination drug was metformin
(metformin plus vildagliptin in the vildagliptin group
versus metformin plus any other oral anti-diabetic in the
comparator group), did not modify at all the central find-
ing of the study. The percentage of participants who
achieved the primary endpoint was higher in the vildaglip-
tin than in the comparator group in all participating coun-
tries (data not shown). A growing body of evidence
suggests that when it comes to glycemic targets, ‘how’ to
reach them may be just as important as ‘whether or not’ to
reach them23–26
. Within that context, EDGE–Latin
America found a considerably high rate of good glycemic
control without major adverse effects, with the use of vil-
dagliptin-based therapies in patients of our biological and
cultural type. This finding confirms and complements
what has been observed in prior studies about the efficacy
and effectiveness of vildagliptin27–32
.
One of the main limitations of the study is the some-
what heterogeneous group of patients, as the study sample
included participants from both specialized centers and
private office doctors. This may have impacted the overall
results because of insufficient quality and missing data
which needed to be excluded from the effectiveness ana-
lyses. Another important consideration is that, being a
post-hoc analysis, this report shares all the limitations of
secondary analyses. Nevertheless, most of those methodo-
logical concerns are relevant for studies of a small sample
size, in which subgroup imbalances and confounding can
have a greater impact in the observed results. To that
effect, it is important to point out that EDGE–Latin
America has a sample size larger than most clinical trials
or post-marketing analyses undertaken entirely in Latin
America up until now. It is likely that safety events were
underreported, as their detection and reporting was based
on a voluntary scheme. It is important to note, however,
that this is the most widely used method to identify adverse
events of new drugs in clinical practice28
. Overall, the
rates of adverse events were low and similar between treat-
ment cohorts. The open design of the study allowed doc-
tors to select any drug based on their clinical judgment, but
this (plus the exclusion of patients on other DPP-4 inhibi-
tor therapy) resulted in an imbalance in treatment arms
favoring the novel drug of the sponsoring company.
Nevertheless, the comparator group was still fairly numer-
ous, and the differences between groups did not alter the
odds of the primary endpoint in a multivariable analysis.
Conclusion
EDGE–Latin America found that over a 1 year follow-up
timeframe and under usual care conditions, patients with
T2DM who received vildagliptin as a second-line therapy
were more likely to successfully lower A1c to57% without
weight gain, hypoglycemia or peripheral edema than
patients who received comparator oral anti-diabetes
drugs. Because of its effectiveness, cost and cumulative
experience with its use, metformin will continue to be
the mainstay of pharmacological T2DM treatment. The
results of EDGE–Latin America show that, under usual
practice conditions in our countries, vildagliptin is an
effective and safe add-on therapy to metformin.
Transparency
Declaration of funding
This study was funded by Novartis Pharma AG. The sponsor and
steering committee had equal roles in determining study design,
Current Medical Research & Opinion Volume 30, Number 9 September 2014
! 2014 Informa UK Ltd www.cmrojournal.com Vildagliptin combination effectiveness in Latin America Mendivil et al. 1775
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9. protocol finalization and data interpretation. The funder
was involved in study design and data collection but did
not have involvement in data analysis, decision to publish
or preparation of the manuscript. All authors had final responsi-
bility for the data, content, and decision to submit
for publication.
Declaration of financial/other relationships
J.A. has disclosed that he was an employee of Novartis AG at the
time of execution of this study. O.S. has disclosed that she is a
consultant to Novartis AG. C.O.M., E.M.-R., I.D.A´ ., G.P. and
C.R. have disclosed that they have no significant relationships
with or financial interests in any commercial companies related
to this study or article.
CMRO peer reviewers on this manuscript have no relevant
financial or other relationships to disclose.
Acknowledgements
The authors thank Carlos Garcı´a and Marcia Kayath from
Novartis Latin America, as well as Roberto Altamira from
Novartis Mexico for their support and commitment to the exe-
cution of this study.
References
1. IDF. Diabetes Atlas 2012. Available at: www.idf.org/diabetesatlas. Last
accessed 05 June 2014
2. Barcelo A, Aedo C, Rajpathak S, Robles S. The cost of diabetes in Latin
America and the Caribbean. Bull World Health Organ 2003;81:19-27
3. Pedersen O, Gaede P. Intensified multifactorial intervention and cardio-
vascular outcome in type 2 diabetes: the Steno-2 study. Metabolism
2003;52:19-23
4. Ali MK, McKeever-Bullard K, Saaddine JB, et al. Achievement of goals in U.S.
diabetes care, 1999–2010. N Eng J Med 2013;368:1613-24
5. Lavalle-Gonza´lez FJ, Chiquete E, de la Luz J, et al.; IDMPS-3W collaborative
group (Mexico). Achievement of therapeutic targets in Mexican patients with
diabetes mellitus. Endocrinol Nutr 2012;59:591-8
6. UK Prospective Diabetes Study Group. Effect of intensive blood-glucose
control with metformin on complications in overweight patients with type 2
diabetes (UKPDS 34). Lancet 1998;352:854-65
7. UK Prospective Diabetes Study Group. Intensive blood-glucose control
with sulphonylureas or insulin compared with conventional treatment
and risk of complications in patients with type 2 diabetes (UKPDS 33).
Lancet 1998;352:837-53
8. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose
control in type 2 diabetes. N Engl J Med 2008;359:1577-89
9. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in
type 2 diabetes: a patient-centered approach: position statement of the
American Diabetes Association (ADA) and the European Association for the
Study of Diabetes (EASD). Diabetes Care 2012;35:1364-79
10. Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutical
trials. J Clin Epidemiol 2009;62:499-505
11. Treweek S, Zwarenstein M. Making trials matter: pragmatic and explanatory
trials and the problem of applicability. Trials 2009;10:37
12. Ware JH, Hamel MB. Pragmatic trials – guides to better patient care? N Engl J
Med 2011;364:1685-7
13. Mathieu C, Barnett AH, Brath H, et al. Effectiveness and tolerability of second-
line therapy with vildagliptin vs. other oral agents in type 2 diabetes: a real-life
worldwide observational study (EDGE). Int J Clin Pract 2013;67:947-56
14. Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness
and safety of medications for type 2 diabetes: an update including
new drugs and 2-drug combinations. Ann Intern Med 2011;154:602-
13
15. Roumie CL, Hung AM, Greevy RA, et al. Comparative effectiveness of sulfo-
nylurea and metformin monotherapy on cardiovascular events in type 2 dia-
betes mellitus: a cohort study. Ann Intern Med 2012;157:601-10
16. Luongo AM, Lo´pez-Gonza´lez E, Garcia AB, et al.; en nombre del Grupo
FRADYC. Evaluacio´n del tratamiento de la Diabetes Tipo 2 realizado por
especialistas en Argentina. Rev ALAD 2011;1:78-87
17. Alvarenga RL, Molina JM, Go´chez N, Rodrı´guez PA. Caracterizacio´n de
pacientes que asisten al programa de clı´nicas metabo´licas del Instituto
Salvadoren˜o del Seguro Social. Rev ALAD 2012;3:310-19
18. Navarro-Vidal B, Banegas JR, Leo´n-Mun˜oz LM, et al. Achievement of cardi-
ometabolic goals among diabetic patients in Spain. A nationwide population-
based study. PLoS One 2013;8:e61549
19. Ali MK, Bullard KM, Saaddine JB, et al. Achievement of goals in U.S. diabetes
care, 1999–2010. N Engl J Med 2013;368:1613-24
20. Ji LN, Lu JM, Guo XH, et al. Glycemic control among patients in China with
type 2 diabetes mellitus receiving oral drugs or injectables. BMC Public Health
2013;13:602
21. Braga MF, Casanova A, Teoh H, et al.; Diabetes Registry to Improve Vascular
Events [DRIVE] Investigators. Poor achievement of guidelines-recommended
targets in type 2 diabetes: findings from a contemporary prospective cohort
study. Int J Clin Pract 2012;66:457-64
22. Chan JC, Gagliardino JJ, Baik SH, et al.; IDMPS Investigators. Multifaceted
determinants for achieving glycemic control: the International Diabetes
Management Practice Study (IDMPS). Diabetes Care 2009;32:227-33
23. Duckworth W, Abraira C, Moritz T, et al.; VADT Investigators. Glucose control
and vascular complications in veterans with type 2 diabetes. N Engl J Med
2009;360:129-39
24. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, et al.
Intensive blood glucose control and vascular outcomes in patients with
type 2 diabetes: the ADVANCE collaborative group. N Engl J Med
2008;358:2560-72
25. Duckworth WC, Evans GW, Gerstein HC, et al. Intensive glucose control and
macrovascular outcomes in type 2 diabetes. Diabetologia 2009;52:2288-98
26. Abraira C, Duckworth WC, Moritz T; VADT Group. Glycaemic separation and
risk factor control in the Veterans Affairs Diabetes Trial: an interim report.
Diabetes Obes Metab 2009;11:150-6
27. Bader G, Geransar P, Schweizer A. Vildagliptin more effectively achieves a
composite endpoint of HbA1c57% without hypoglycaemia and weight gain
compared with glimepiride after 2 years of treatment. Diabetes Res Clin Pract
2013;100:e78-81
28. Bolli G, Dotta F, Colin L, et al. Comparison of vildagliptin and pioglitazone in
patients with type 2 diabetes inadequately controlled with metformin.
Diabetes Obes Metab 2009;11:589-95
29. Bolli G, Dotta F, Rochotte E, Cohen SE. Efficacy and tolerability of vildagliptin
vs. pioglitazone when added to metformin: a 24-week, randomized, double-
blind study. Diabetes Obes Metab 2008;10:82-90
30. Ferrannini E, Fonseca V, Zinman B, et al. Fifty-two-week efficacy and safety of
vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inad-
equately controlled on metformin monotherapy. Diabetes Obes Metab
2009;11:157-66
31. Filozof C, Gautier JF. A comparison of efficacy and safety of vildagliptin and
gliclazide in combination with metformin in patients with type 2 diabetes
inadequately controlled with metformin alone: a 52-week, randomized
study. Diabet Med 2010;27:318-26
32. Garber AJ, Schweizer A, Baron MA, et al. Vildagliptin in combination with
pioglitazone improves glycaemic control in patients with type 2 diabetes fail-
ing thiazolidinedione monotherapy: a randomized, placebo-controlled study.
Diabetes Obes Metab 2007;9:166-74
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