Introduction

Type 2 diabetes mellitus (T2DM) represents a global disease burden, with the greatest increase in
prevalence predicted for economically developing countries [1]. Although significant improvements in
diabetes management have been made over the last two decades, a sizable number of patients still
fail to achieve and maintain good glycaemic control [2-4].
Vildagliptin, a potent and selective inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, has been
shown to be highly efficacious and well tolerated, with low risk of hypoglycaemia and weight gain in
patients with T2DM when administered as monotherapy or in combination with other antidiabetic
medications, such as metformin [5,6].
The Vildagliptin Clinical Use in the Real World (GUARD) study was designed to assess the clinical
effectiveness and safety of vildagliptin treatment with or without metformin in patients with T2DM
studied in routine clinical evidence collected from randomized controlled trials (RCTs) with data on
vildagliptin, prescribed as part of routine care, collected from a diverse, multi-ethnic population
observed in clinical practices around the world.

Panel
Mechanism of vildagliptin
P-value
Covariance
Standard deviation
ចុងបញ្ច ប់នៃការសិក្សានៃេះ នតើន ង
ើ មាៃសំៃរួ អ្វើសួរនៅកាៃ់នេជ្ជបណ្ឌិតេ ិញដែររនេ?
ឺ

Methods
The methods are described in more detail in Supporting Information (Appendix S1). The GUARD
study was a multicenter, post-authorization, non-interventional, prospective study that pooled data for
analysis from studies conducted in Asia, the Middle East, Central America and Africa, according to one
umbrella protocol. The study complied with all required guidelines, local regulations and the
Declaration of Helsinki.
Male and female outpatients (aged ≥ 18 years) with an established diagnosis of T2DM, who had
been prescribed vildagliptin or vildagliptin added to metformin (free dose combination or single-pill
combination) according to local prescribing information, and who consented to data collection, were
eligible for study inclusion.
 During the observational period of 24+/-6weeks, data from three routine patient visits were recorded:
the baseline visit (day1), visit 2(12+/-4weeks) and a final visit (visit3)at study end (24+/-6weeks).
The primary effectiveness endpoint was change in mean glycated haemoglobin (HbA1c)
concentration from baseline to final visit at 24+/-weeks. Key secondary endpoints included the
proportion of patients reaching a target HbA1c of </-6.5 and </=7.0% at week 24, changes in body
weight and body mass index (BMI) from baseline to week 24, and the number of patients
experiencing a hypoglycaemic event. Safety and tolerability were assessed by adverse event (AE) and
serious AE (SAE) reporting.
Supportive analyses of covariance were performed to assess the change from baseline HbA1c in
relation to different patient subgroups, categorized according to baseline HbA1c, patient age and
obesity status.
Results
The results are described in more detail in Supporting Information (Tables S1-S6, Figure S1 and
Appendix S2). 19 331 patients were pooled for analysis: 3511 in the vildagliptin group and 15 820 in
the vildagliptin plus metformin group. The majority of patients included in the study were from Asia
(Table S2). A summary of patient demographics and baseline characteristics for the overall study
population and each treatment group is provided in Table S3. Overall, patients had a mean [standard
deviation (s.d)] age of 48.8 (9.92) years with 1238 patients (6.4%) aged >/-65 years and 5120
patients (26.5%) classified as obese (BMI>/-30kg/m2). The study included more men (65.0%) more
men than women. The mean (s.d) duration of diabetes was 2.9(4.13) years and the mean (s.d)
baseline HbA1c was 8.40 (0.86)%, with a high proportion of patients (n=8765, 45.3%) in the > 8-9%
HbA1c range. Baseline HbA1c range. Baseline HbA1c values for each patient sub-population (defined
by patient age and obesity status) are provided in Table S4.
At study end, vildagliptin with or without metformin was associated with statistically significant and
clinically meaningful reductions in mean HbA1c concentrations from baseline (Figure 1A). The mean
(s.d.) reductions in HbA1c from baseline were -1.27% (0.83) in the overall study population,-
1.17%(0.80) in the vildagliptin group and -1.29% (0.84) in the vildagliptin plus metformin group
(p<0.0001). Significant reductions in mean HbA1c from baseline to week 24 were consistently
observed across subgroups of patients with different baseline HbA1c values (Figure 1B), and
regardless of patient age (Figure 2A), and obesity status (Figure 2B). Overall, 43.6% of patients
achieved an HbA1c target of </-7.0% at week 24 (Figure S1).
 Modest, but statistically significant reductions from baseline in mean body weight and mean BMI
were observed at week 24 in the overall population, the vildagliptin group and the vildagliptin plus
metformin group (Appendix S2).
Data on hypoglycaemic events were collected on a hypoglycaemic event-specific reporting form in
addition to AE recording. The number of patients with hypoglycaemic events during the study was 96
(0.5%) overall; this varied slightly from the frequency of hypoglycaemic events recorded as AEs,
which were 0.3% overall. AEs were reported in 699 patients (3.6%); the majority were unrelated to the
medication of interest (Table S5).
Discussion
Data from the GUARD study are in line with key findings of RCTs [5,6] and of other non-interventional
studies of vildagliptin used in routine clinical practice [7-9]. Furthermore, the GUARD study extends the
assessment of vildagliptin effectiveness and safety in real-world settings to a large multi-ethnic
population, predominantly from developing economic areas, where poor glycaemic control is a
pressing problem and some of the sharpest rises in T2DM prevalence are predicted [1]. Despite a large
proportion of patients presenting with relatively high HbA1c values at baseline, significant and clinically
relevant HbA1c reductions were observed with reasonable target achievement rates in patients
receiving vildagliptin with or without metformin. HbA1c reductions and control rates were in line with
other large observational study data [7]. An important clinical consideration is that significant
reductions in HbA1c from baseline were consistently observed, regardless of baseline HbA1c, age or
obesity status.
Given that weight gain and hypoglycaemic side effects from antidiabetic medication are well known
barriers to optimum glycaemic control, it is reassuring that HbA1c reductions in the GUARD study were
accompanied by modest, but statistically significant reductions in body weight from baseline and a low
hypoglycaemic event incidence rate, in line with data from clinical trials [5,10].
Overall, vildagliptin with or without metformin was generally well tolerated, with the majority of AEs
and SAEs considered to be unrelated to the medication of interest. There were a low number of AEs
reported, which is not uncommon in observational research.
The GUARD study did not investigate the mechanism of action of vildagliptin, nor was it intended to
shape treatment guidelines. Limitations include the non-randomized, open-label, uncontrolled design,
which can introduce the potential for observer and selection bias. In addition, there were no
standardized methods for clinical assessments. The heterogeneity of the population, including
differences in diet, dyslipidaemia and healthcare access, may potentially alter clinical outcomes.
Although some variation in the mean daily metformin dose at baseline was evident across the
countries, it is noteworthy that overall there was no appreciable increase in mean daily metformin dose
over the study period for each country. Despite these limitations, the large heterogeneous sample
studied in a real-world clinical practice setting provides a valuable addition to the information already
available on vildagliptin.
In conclusion, in this large multi-ethnic patient population with T2DM studied in routine clinical
practice, vildagliptin treatment, with or without metformin, provided statistically significant and clinically
relevant reductions in HbA1c from baseline, irrespective of baseline HbA1c, age or obesity status. In
addition, vildagliptin treatment with or without metformin was generally well tolerated.
R. Rosales1, E. Abou Jaoude2, M. Al-Arouj3,
A. Fawwad4, A. Orabi5, P. Shah6, S. DiTommaso7, J. Vaz8 & Z. A. Latif9
1
St. Luke’s Medical Center, Quezon City, Philippines
2
Department of Medicine, Middle East Institute of Health,
Bsalim, Lebanon
3
Dasman Diabetes Institute, Dasman, Kuwait
4
Baqai Institute of Diabetology & Endocrinology, Baqai Medical
University, Karachi, Pakistan
5
Faculty of Medicine, Zagazig University, Zagazig-Sharkia,
Egypt
6
Gujarat Endocrine Centre, Ahmedabad, India
7
Novartis Pharma AG, Basel, Switzerland
8
Novartis Healthcare Pvt. Ltd., Hyderabad, India
9
Ibrahim Memorial Diabetes Centre, BIRDEM Hospital,
Dhaka, Bangladesh
Acknowledgements
The authors acknowledge all investigators at the participating centres and all patients for their
commitment to the study, which was supported by Novartis Pharma AG, Basel, Switzerland. The
authors wish to thank Dr Sashka Hristoskova, Dr Abhijit Shete, Shalma Basu Patnaik and Dr Mahomed
Kadwa from Novartis Pharma AG for their critical review of, and suggestions for, the article. The authors
were assisted in the preparation of this text by professional medical writers Gregor Fyfe and Chris
Cammack of CircleScience, part of KnowledgePoint360, an Ashfield Company; this support was funded
by Novartis Pharma AG and its relevant affiliates.
Conflict of interest
This study was funded by Novartis Pharma AG and its respective affiliates. R. R., E. A. J., M. A. –A.,
A.F., A. O., P. S. and Z. A. L. received investigators fees/research support for the conduct of the study.
In addition, M. A. –A. and P. S. received consultancy fees for advisory/speaker engagements from
Novartis AG and its affiliates. S. Di T. is an employee of Novartis Pharma AG and its affiliates. S. Di T. is
an employee of Novartis Pharma AG and J. V. is an employee and shareholder of Novartis Healthcare
Pvt. Ltd., Hyderabad, India.
All authors participated in the development and writing of the paper and take full responsibility for
the content of the paper. All authors were involved in data collection, analysis and/or interpretation of
the results, as well as the critical revision and approval of the article.