Sakamoto et al.

Cardiovascular Diabetology 2012, 11:92 CARDIO

http://www.cardiab.com/content/11/1/92 VASCULAR
DIABETOLOGY

ORIGINAL INVESTIGATION Open Access

Comparison of vildagliptin twice daily vs.

sitagliptin once daily using continuous glucose
monitoring (CGM): Crossover pilot study
(J-VICTORIA study)
Masaya Sakamoto1*, Rimei Nishimura1,2, Taiga Irako1, Daisuke Tsujino1, Kiyotaka Ando1 and Kazunori Utsunomiya1

Abstract
Background: No previous studies have compared the DPP-4 inhibitors vildagliptin and sitagliptin in terms of blood
glucose levels using continuous glucose monitoring (CGM) and cardiovascular parameters.
Methods: Twenty patients with type 2 diabetes mellitus were randomly allocated to groups who received
vildagliptin then sitagliptin, or vice versa. Patients were hospitalized at 1 month after starting each drug, and CGM
was used to determine: 1) mean (± standard deviation) 24-hour blood glucose level, 2) mean amplitude of
glycemic excursions (MAGE), 3) fasting blood glucose level, 4) highest postprandial blood glucose level and time, 5)
increase in blood glucose level after each meal, 6) area under the curve (AUC) for blood glucose level ≥180 mg/dL
within 3 hours after each meal, and 7) area over the curve (AOC) for daily blood glucose level <70 mg/dL. Plasma
glycosylated hemoglobin (HbA1c), glycoalbumin (GA), 1,5-anhydroglucitol (1,5AG), immunoreactive insulin (IRI),
C-peptide immunoreactivity (CPR), brain natriuretic peptide (BNP), and plasminogen activator inhibitor-1 (PAI-1)
levels, and urinary CPR levels, were measured.
Results: The mean 24-hour blood glucose level was significantly lower in patients taking vildagliptin than sitagliptin
(142.1 ± 35.5 vs. 153.2 ± 37.0 mg/dL; p = 0.012). In patients taking vildagliptin, MAGE was significantly lower
(110.5 ± 33.5 vs. 129.4 ± 45.1 mg/dL; p = 0.040), the highest blood glucose level after supper was significantly lower
(206.1 ± 40.2 vs. 223.2 ± 43.5 mg/dL; p = 0.015), the AUC (≥180 mg/dL) within 3 h was significantly lower after
breakfast (484.3 vs. 897.9 mg/min/dL; p = 0.025), and urinary CPR level was significantly higher (97.0 ± 41.6 vs.
85.2 ± 39.9 μg/day; p = 0.008) than in patients taking sitagliptin. There were no significant differences in plasma
HbA1c, GA, 1,5AG, IRI, CPR, BNP, or PAI-1 levels between patients taking vildagliptin and sitagliptin.
Conclusions: CGM showed that mean 24-h blood glucose, MAGE, highest blood glucose level after supper, and
hyperglycemia after breakfast were significantly lower in patients with type 2 diabetes mellitus taking vildagliptin
than those taking sitagliptin. There were no significant differences in BNP and PAI-1 levels between patients taking
vildagliptin and sitagliptin.
Trial registration: UMIN000007687
Keywords: Vildagliptin, Sitagliptin, Continuous glucose monitoring (CGM), Brain natriuretic peptide (BNP),
Plasminogen activator inhibitor-1 (PAI-1)

* Correspondence: m-sakamoto@umin.ac.jp
1
Division of Diabetes, Metabolism and Endocrinology, Department of Internal
Medicine, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi,
Minato-ku, Tokyo 105-8461, Japan
Full list of author information is available at the end of the article

© 2012 Sakamoto et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Sakamoto et al. Cardiovascular Diabetology 2012, 11:92 Page 2 of 7
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Introduction DPP-4 inhibitors vildagliptin and sitagliptin, using CGM

The number of patients with type 2 diabetes mellitus is to evaluate blood glucose levels and analyze fluctuations
rapidly increasing worldwide, especially in Asian coun- in blood glucose levels. We also compared cardiovascu-
tries, because of an aging population and changes in lar parameters between patients taking vildagliptin and
dietary habits. The management of blood glucose levels sitagliptin by measuring plasma levels of brain natri-
has become a significant medical issue. The short-term uretic peptide (BNP) and plasminogen activator
aim of diabetes treatment is control of blood glucose inhibitor-1 (PAI-1).
levels, and the long-term aim is avoidance of the compli-
cations of diabetes [1].
Subjects and methods
Glycosylated hemoglobin (HbA1c) level reflects the
Subjects
blood glucose level over the preceding 2 months, and
Patients with type 2 diabetes mellitus who had poor con-
can be used to diagnose diabetes or to evaluate blood
trol of blood glucose levels (HbA1c 6.5–9.5%) in spite of
glucose control in patients known to be diabetic. Clinical
diet and exercise therapy for 1 month or longer, with or
and observational studies have reported that reducing
without oral antidiabetic treatment, were included in the
HbA1c levels results in a lower incidence of cardiovas-
study. Exclusion criteria were: 1) type 1 diabetes melli-
cular complications in diabetic patients with a shorter
tus, 2) severe ketosis, coma, or reduced level of con-
time since diagnosis [2,3], but not in diabetic patients
sciousness due to diabetes within the past 6 months, 3)
with a longer time since diagnosis [4,5]. Starting treat-
severe infection, pre- or postoperative, or severe trauma,
ment for diabetes at an earlier stage is therefore thought
4) history of laparotomy or ileus, 5) chronic intestinal
to be important for decreasing the risk of cardiovascular
disease associated with a disorder of digestion or absorp-
events.
tion, 6) severe hernia, or stenosis or ulcer of the large
Current diabetes treatment programs aim to lower
intestine, 7) pregnancy, possible pregnancy, or breast-
HbA1c levels. However, recent clinical studies have
feeding, 8) moderate or severe renal dysfunction (cre-
found that hypoglycemia and postprandial hypergly-
atinine clearance <50 mL/min, serum creatinine level
cemia are also associated with the development of car-
≥1.5 mg/dL in men or ≥1.3 mg/dL in women), 9) severe
diovascular disease [6,7]. Treatment choices should
hepatic dysfunction, 10) insulin treatment, 11) treatment
therefore consider control of variations in blood glucose
with antidiabetic agents other than sulfonylureas, 12)
levels, as well as HbA1c levels, to reduce the risk of car-
history of hypersensitivity to any of the ingredients of
diovascular events. Continuous glucose monitoring
the study drugs and 13) judged to be unsuitable for par-
(CGM) and self-monitoring of blood glucose routinely
ticipation for medical reasons. Patients were given
record variations in blood glucose levels [8]. CGM can
detailed explanations of the study protocol. Those who
evaluate changes in blood glucose levels, because it
provided informed consent were included in the study.
allows recording over several days.
The study protocol was approved by the Ethical Com-
DPP-4 inhibitors are oral antihyperglycemic drugs that
mittee of the Jikei University School of Medicine. The
have recently become available for diabetes treatment.
Clinical Trial registration No. is UMIN000007687.
They enhance the actions of incretin, which promotes
insulin secretion and suppresses glucagon secretion de-
pending on blood glucose levels [9], thereby improving Methods
blood glucose control without inducing hypoglycemia. Figure 1 shows a summary of the study protocol.
Various effects of incretin such as pancreatic β-cell pro- Patients were randomly allocated to the V/S or S/V
tection and cardiovascular protection [10] are expected group at the beginning of study period. During Stage I,
to reduce the risk of development of cardiovascular dis- the V/S group received vildagliptin 100 mg daily
eases. DPP-4 inhibitors are considered effective for the (50 mg in the morning and 50 mg in the evening) and
treatment of type 2 diabetes mellitus in Asian patients, the S/V group received sitagliptin 50 mg daily (in the
including Japanese patients, who often have insufficient morning). This reflects the normal doses of these drugs
insulin secretion [11,12], in contrast to Caucasian used in Japan. After 1 month of treatment, patients
patients who usually have insulin resistance. However, were hospitalized for 4 days, and blood glucose levels
few studies have examined differences in the control of were measured for two consecutive days using CGM
blood glucose levels between different DPP-4 inhibitors. (CGMS-gold; Medtronic Minimed, Northridge, CA,
Sitagliptin and vildagliptin are known to have different USA). During Stage II, the V/S group received sitaglip-
efficacy in suppressing DPP-4 activity. We conducted a tin (50 mg daily) and the S/V group received vildaglip-
crossover pilot study named Jikei-Vildagliptin and sita- tin (50 mg twice daily). After 1 month of Stage II
gliptin with CGM TO Real blood glucose control in type treatment, subjects were hospitalized for another 4 days
2 diAbetes (J-VICTORIA). This study compared the to measure blood glucose levels. Administration of
Sakamoto et al. Cardiovascular Diabetology 2012, 11:92 Page 3 of 7
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V/SGroup vildagliptin 100mg/day Sitagliptin 50mg/day

Observation period

S/VGroup Sitagliptin 50mg/day vildagliptin 100mg/day

Hospitalization Hospitalization
CGM/blood examination/ CGM/blood examination/
urinalysis urinalysis

One month or longer 0 month 1 month 2 month

Figure 1 Study protocol. After an outpatient observation period of 1 month or longer, patients were randomized to the V/S group which
initially received vildagliptin (50 mg twice daily) or the S/V group which initially received sitagliptin (50 mg once daily). The drugs were then
switched so that the V/S group received sitagliptin and the S/V group received vildagliptin. " indicates continuous glucose monitoring (CGM) on
the second and third hospital days. Identical meals were given to all patients during hospitalization.

other antihyperglycemic drugs was prohibited during Variations in 24-h blood glucose levels measured by
the study period. CGM during treatment with sitagliptin and vildagliptin
The followings values were calculated using CGM are shown in Figure 2, and blood glucose indexes
data: 1) mean 24-h (± standard deviation) blood glucose derived from CGM results are shown in Table 2.
level, 2) mean amplitude of glycemic excursions The mean 24-h blood glucose level was significantly
(MAGE), 3) fasting blood glucose level, 4) highest post- lower in patients taking vildagliptin than patients taking
prandial blood glucose level and time, 5) increase in sitagliptin (p = 0.012) during both the night (00:00 to
blood glucose level after each meal, 6) area under the 08:00) and the day (08:00 to 24:00). The standard devi-
curve (AUC) for blood glucose level ≥180 mg/dL within ation of blood glucose levels was lower in patients taking
3 h after each meal, and 7) area over the curve (AOC) vildagliptin than patients taking sitagliptin, but this dif-
for daily blood glucose level <70 mg/dL. ference was not significant. MAGE was significantly
Other data collected were plasma HbA1c, glycoalbu- lower in patients taking vildagliptin than patients taking
min (GA), 1,5-anhydroglucitol (1,5AG), immunoreactive sitagliptin (p = 0.040). Although there was no significant
insulin (IRI), C-peptide immunoreactivity (CPR), BNP, difference in preprandial glucose levels between drugs,
PAI-1, and 24-h urinary CPR levels. The subjects both the highest postprandial glucose level within 3 h
ingested identical meals during hospitalization, and were (peak value) and the amplitude of increase in glucose
advised not to change their level of exercise. level (the difference between the preprandial value and
the peak value within 3 h) were lower in patients taking
vildagliptin than patients taking sitagliptin after each
Statistical analysis
meal. The peak value after dinner was significantly lower
Data are shown as the mean ± standard deviation. The
in patients taking vildagliptin than patients taking sita-
paired t-test was used to compare values between
gliptin (p = 0.015). There was no difference in the time
patients taking different drugs, with the level of signifi-
taken to reach the highest postprandial glucose level be-
cance set at p < 0.05. Statistical analysis of data was per-
tween patients taking vildagliptin and patients taking
formed using the Statistical Package for Social Sciences
sitagliptin.
software, version 19.0 (SPSS, Chicago, IL, USA).

Table 1 Baseline patient characteristics

Results
Characteristic Value
A total of 20 patients were enrolled in the study, with a
mean age of 55.2 ± 15.5 years, mean body mass index of Age (years) 55.2 ± 15.5
25.1 ± 5.4 kg/m2, mean HbA1c level of 7.9 ± 0.7%, and Gender (M/F) 13/7
mean time since diagnosis of diabetes of 4.5 ± 3.7 years. Body Mass Index (Kg/m2) 25.1 ± 5.4
Before enrollment in the study, 8 patients were taking a Diabetes Duration (years) 4.5 ± 3.7
DPP-4 inhibitor in combination with a sulfonylurea and HbA1c (%) 7.9 ± 0.7
12 were taking a DPP-4 inhibitor only (Table 1). The
Treatment
mean time since diagnosis of diabetes was relatively
short (4.5 years). None of the patients had clinical stage None (diet/exercise) 12
IV peripheral arterial occlusive disease or lower limb SU 8
amputation. HbA1c = glycosylated hemoglobin; SU = sulfonylurea.
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Figure 2 Glucose levels over 24 h during treatment with vildagliptin or sitagliptin in 20 patients. Data are mean ± standard deviation.

The AUC (>180 mg/dL) within 3 h was smaller after between 50 mg and 100 mg for both drugs found that
each of breakfast, lunch, and dinner in patients taking the efficacy of vildagliptin and sitagliptin were compar-
vildagliptin than patients taking sitagliptin, and this dif- able [14,15].
ference was significant after breakfast (p = 0.025). The Kishimoto et al. reported that sitagliptin effectively
AOC (<70 mg/dL) was comparable for vildagliptin (95.6 reduced postprandial blood glucose fluctuations and sta-
mg/min/dL) and sitagliptin (16.2 mgmin/dL). bilized blood glucose levels [16]. Sitagliptin may also
There were no differences between in plasma HbA1c, work as a vasoprotective agent in diabetes by blocking
GA, and 1,5-AG levels, which are indexes of blood glu- the AGE-RAGE axis [17]. Marfella et al. compared vilda-
cose control, between patients taking vildagliptin and gliptin (100 mg daily) and sitagliptin (100 mg daily)
patients taking sitagliptin. There was no significant using CGM, and reported a better MAGE in the vilda-
change in mean body weight in either group during the gliptin group, although there was no difference in mean
study period. 24-h blood glucose level between the groups [18]. Rizzo
There were also no differences in plasma BNP, PAI-1, et al. reported recently that reductions in oxidative stress
IRI, or CPR levels between patients taking vildagliptin and markers of systemic inflammation were greater in
and patients taking sitagliptin, but the urinary CPR level patients with type 2 diabetes taking vildagliptin than
was significantly higher in patients taking vildagliptin those taking sitagliptin [19]. These results were obtained
than patients taking sitagliptin (p = 0.008) (Table 3). in Caucasian patients, and it important to also compare
the effects of these drugs in Asian patients, including
Discussion Japanese patients, because there are differences in causes
The influence of the DPP-4 inhibitors vildagliptin of diabetes, insulin secretion, and background character-
(100 mg daily) and sitagliptin (50 mg daily) on blood istics between Caucasian and Japanese patients.
glucose levels in patients with type 2 diabetes mellitus The reason for the differences in drug efficacy (mean
was investigated in this crossover study. Mean 24-h blood glucose level and MAGE) observed in this study is
blood glucose level and MAGE were significantly lower considered to be that sitagliptin 50 mg daily results in
in patients taking vildagliptin than patients taking less than 70% suppression of DPP-4 activity over 24 h
sitagliptin. [20] whereas vildagliptin 50 mg twice daily results in
Differences in drug efficacy between vildagliptin and 80% or greater suppression of DPP-4 activity over 24 h
sitagliptin have been investigated in a few studies. A [21]. It is also possible that the different mode of binding
comparison of the randomized trials conducted in Japan with DPP-4 and the different frequency of drug adminis-
showed that vildagliptin 100 mg daily resulted in lower tration results in a greater reduction in blood glucose
HbA1c levels (by approximately 0.3%) than sitagliptin level after supper and breakfast in patients taking vilda-
50 mg daily [13]. A meta-analysis of studies using doses gliptin [22].
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Table 2 Parameters of glucose variability in patients taking vildagliptin (100 mg daily) or sitagliptin (50 mg daily)
Vildagliptin Sitagliptin P-value
24-h mean glucose level (mg/dL) 142.1 ± 14.0 153.2 ± 29.7 0.012*
0:00 to 08:00 (night) mean glucose level (mg/dL) 117.4 ± 22.1 130.9 ± 26.3 0.042*
08:00 to 24:00 (day) mean glucose level (mg/dL) 154.1 ± 25.6 164.4 ± 35.3 0.043*
SD over 24 h (mg/dL) 35.5 ± 12.6 37.0 ± 13.9 0.542
Preprandial glucose level (mg/dL) 110.5 ± 33.5 129.4 ± 45.1 0.040*
Preprandial glucose level (mg/dL) 128.1 ± 16.2 133.5 ± 26.8 0.282
lunch 109.1 ± 22.2 120.9 ± 44.8 0.165
Highest postprandial glucose level within 3 hours after each meal (mg/dL) 112.4 ± 21.1 116.6 ± 24.7 0.221
Highest postprandial glucose level within 3 hours after each meal (mg/dL) 211.0 ± 40.0 228.0 ± 58.4 0.117
lunch 188.6 ±37.7 203.1 ± 50.3 0.172
supper 206.1 ± 40.2 223.2 ± 43.5 0.015*
Time from start of meal to the highest postprandial glucose level (minutes)
breakfast 76.0 ± 18.0 86.0 ± 28.4 0.204
lunch 93.3 ± 30.2 99.0 ± 35.6 0.579
supper 81.8 ± 24.6 93.0 ± 26.4 0.223
Differences between preprandial and highest postprandial glucose level for each meal (mg/dL)
breakfast 83.0 ± 37.1 94.5 ± 46.3 0.185
lunch 79.5 ± 31.8 82.3 ± 33.9 0.774
supper 93.7 ± 35.7 106.6 ± 43.2 0.065
AUC (≧180 mg/dL) for glycemic variability within 3 h of each meal (mgmin/dL)
breakfast 484.3 ± 541.1 897.9 ± 1097 0.025*
lunch 306.0 ± 554.8 630.5 ± 1017.2 0.152
supper 523.5 ± 618.3 703.4 ± 676.4 0.106
AOC (<70 mg/dL) for glycemic variability in 24 h(mgmin/dL)
95.6 ± 243.0 16.2 ± 61.2 0.183
Data are mean ± standard deviation. Paired-sample t-test. * p < 0.05.
AUC = area under the curve; AOC = area over the curve.

For patients taking vildagliptin it is possible that sup-

pression of glucagon secretion by the evening dose leads
to a lower AUC (≥180 mg/dL) after breakfast, and sup-
Table 3 Glucose and cardiovascular parameters in pression of glucagon secretion by the morning dose
patients taking vildagliptin (100 mg daily) or sitagliptin leads to a lower peak in blood glucose level after supper.
(50 mg daily)
These results seem to support a twice daily administra-
vildagliptin sitagliptin p-value
tion schedule for vildagliptin.
HbA1c (%) 7.54 ± 0.93 7.64 ± 0.93 0.211 Postprandial hyperglycemia has been reported to trig-
GA (%) 19.8 ± 3.47 20.1 ± 3.31 0.087 ger vascular disorders and cause cardiovascular events,
1,5AG (μg/mL) 7.68 ± 5.60 7.49 ± 6.16 0.389 and is more common in patients with high HbA1c levels
IRI (μU/mL) 7.26 ± 4.44 6.94 ± 4.37 0.735 [23]. Selection of a DPP-4 inhibitor that effectively sup-
CPR (ng/mL) 2.14 ± 0.92 1.95 ± 0.78 0.302
presses postprandial hyperglycemia contributes to the
maintenance of ideal HbA1c levels.
U-CPR (μ/day) 97.0 ± 41.6 85.2 ± 39.9 0.008*
It is interesting that urinary CPR level and variations
BNP (pg/mL) 7.00 ± 9.24 8.03 ± 8.40 0.283 in blood glucose level were higher in patients taking vil-
PAI-1 (ng/mL) 36.6 ± 14.9 40.6 ± 23.1 0.231 dagliptin than patients taking sitagliptin. We postulate
GA = glycoalbumin; 1,5-AG = 1,5-anhydroglucitol; IRI = immunoreactive insulin; that the higher level of DPP-4 inhibition over 24 h in
CPR = C-peptide immunoreactivity; BNP = brain natriuretic peptide; PAI- patients taking vildagliptin, compared with patients tak-
1 = plasminogen activator inhibitor-1.
Data are mean ± standard deviation. Paired-sample t-test. * p < 0.05. ing sitagliptin, inhibits the destruction of incretin, which
Sakamoto et al. Cardiovascular Diabetology 2012, 11:92 Page 6 of 7
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enhances endogenous insulin secretion, thereby improv- Financial support

ing MAGE and achieving a more stable reduction in Financial support for this study was provided by the Japan Diabetes
Foundation.
blood glucose levels. A relationship between MAGE and
oxidation stress has also been reported [24], suggesting
that improvement of MAGE by vildagliptin administra- Acknowledgments
We thank all the study participants. We acknowledge Kimie Shida for data
tion might suppress oxidation stress and decrease the in-
administration. We are grateful to the Nutrition Department of Jikei
cidence of adverse cardiovascular events in the long University Hospital for providing standardized meals for the subjects during
term. This possibility should be further elucidated in fu- hospitalization.
ture studies.
Author details
As DPP-4 inhibitors are reported to lower BNP level 1
Division of Diabetes, Metabolism and Endocrinology, Department of Internal
[25], and vildagliptin is reported to suppress PAI-1 pro- Medicine, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi,
Minato-ku, Tokyo 105-8461, Japan. 2Graduate School of Public Health,
duction [26], this study measured BNP and PAI-1 levels
University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
to evaluate cardiovascular parameters, but no differences
were observed between patients taking vildagliptin and Received: 29 July 2012 Accepted: 30 July 2012
Published: 6 August 2012
sitagliptin. Linagliptin, other DPP-4 inhibitor, has been
reported to be beneficial in terms of cardiac protection
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doi:10.1186/1475-2840-11-92
Cite this article as: Sakamoto et al.: Comparison of vildagliptin twice
daily vs. sitagliptin once daily using continuous glucose monitoring
(CGM): Crossover pilot study (J-VICTORIA study). Cardiovascular
Diabetology 2012 11:92.

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