The effects of sitagliptin add on on insulin resistance, beta cell function in patients with type 2 diabetes who were taking oral hypoglycemic agent

Journal of military pharmaco-medicine n08-2018

THE EFFECTS OF SITAGLIPTIN ADD-ON ON INSULIN RESISTANCE,
BETA CELL FUNCTION IN PATIENTS WITH TYPE 2 DIABETES
WHO WERE TAKING ORAL HYPOGLYCEMIC AGENT
Le Thi Viet Ha1; Doan Van De2
SUMMARY
Objectives: To evaluate the effects of sitagliptin add-on on insulin resistance and beta cell
function in patients with type 2 diabetes who were taking other oral hypoglycemic agent(s).
Subjects and method: 101 patients with type 2 diabetes mellitus diagnosed by WHO (1998)
criteria, who were taking hypoglycemic agent(s) other than d ipeptidyl peptidase-4 inhibitors.
The study compared insulin resistance and beta-cell function assessed with HOMA2 before and
after sitagliptin to other oral hypoglycemic agent(s) in type 2 diabetic patients for those 2 periods:
Received 50 mg of sitagliptin for week 1 to 12, and 100 mg for week 13 to 24. Results: The mean
age was 54.13 ± 10.11 years old, the female and male mad up 52.5% and 47.5%, respectively.
The mean fasting plasma glucose and HbA1c was 8.62 ± 1.67 mmoL/L and 7.93 ± 0.83%,
respectively. After 24 weeks, fasting plasma glucose, HbA1c and fasting plasma C -peptide
level decreased by 1.91 ± 1.90 mmoL/L, 1.45 ± 1.0% and 0.34 ± 0.2 8 nmoL/L, respectively.
The HOMA2-IR assessed by C-peptide (HOMA2-IR-Cp) decreased by 1.04 ± 0.81 and HOMA
% B assessed by C-peptide (HOMA2- %B-Cp) increased by 14.90 ± 34.55%. All the changes
were statistically significant. After 24 weeks, the percentage of patients with increased
HOMA2-IR-Cp decreased from 93.1% (baseline) to 78.2%, and the percentage of patients with
decreased HOMA2-%B-Cp decreased from 69.0% to 50.6%. The both changes were statistically
significant. Conclusion: Sitagliptin addition to other hypoglycemic agent(s) in patients with type 2
diabetes improved beta-cell function and decreased insulin resistance along with improved
blood glucose levels.
* Keywords: Type 2 diabetes; Sitagliptin; Insulin resistance; Beta cell function.

INTRODUCTION

Until now, at least 8 pathological

mechanisms of type 2 diabetes mellitus
(T2DM) have been revealed, including
insulin resistance, beta cell function failure,
decreased secretion of incretins or decreased
response of beta and alpha cells to
incretins. Dipeptidyl peptidase-4 (DPP-4)

inhibitors are relatively new hypoglycemic
agents that prolonge existence of endogenous
incretins in blood, which in turn stimulate
insulin secretion and supress glucagon
one in glucose-dependent manner [5].
Numerous studies around the world have
demonstrated that these drugs improve
blood glucose control and sitagliptin is an

1. National Hospital of Endocrinology
2. 103 Military Hospital
Corresponding author: Le Thi Viet Ha ()
Date received: 05/08/2018
Date accepted: 27/09/2018

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Journal of military pharmaco-medicine n08-2018
agent of this class also improve insulin
resistance [6]. However, until now, in Vietnam
there has been no study evaluating effects
of add-on of DDP-4 inhibitors on insulin

resistance and beta cell functions in
patients with T2DM who were taking other
hypoglycemic agents. Therefore, we
conducted the present study to: Evaluate
the effects of sitagliptin add-on on insulin
resistance, beta cell function in patients
with type 2 diabetes who were taking oral
hypoglycemic agent(s).

acute stroke, acute myocardial infarction,
cachexia.

SUBJECTS AND METHODS

The study examined changes of insulin
resistance and beta cell fuction after
adding of sitagliptin for 24 weeks to other
hypoglycemic agents in patients with
T2DM. The hypoglycemic agent(s) and
their doses were remained unchanged for
the whole study.

1. Subjects.
101 patients with T2DM diagnosed by
WHO (1998) criteria [1] who were taking
hypoglycemic agent(s) other than DPP4 inhibitors.
* Inclusion criteria:
The patients with T2DM were recruited
in the study if they met all the following:
- HbA1c ranged from 7.0% to 10.0%.

- Fasting plasma glucose (FPG)
< 16 mmoL/L.
- Currently use of hypoglycemic agent (s)
(other than DPP-4 inhibitors) in stable
doses for at least last 3 months before the
recruitment.
- Giving consent to participate in the
study.
* Exclusion criteria:
Patients were excluded if they had any
of the following:
- Severe or acute illness such as coma
or pre-coma, unstable angina pectoris,

- Stage III or higher of chronic kidney
disease.
- Liver enzyme levels ≥ 3 times of the
upper normal limits.
- Current use of any of DPP4 inhibitors,
GLP-1 receptor agonists or insulin.
- Refuse to participate in the study.
2. Methods.
* Study design:

Sitagliptin was started with a daily
dose of 50 mg or 100 mg that was
maintained for the first 12 weeks. For the
next 12 weeks, the daily dose increased
from 50 mg to 100 mg or decreased from
100 mg to 50 mg if HbA1c in week 12 was

above 7% or below 6.5%, respectively.
* Sample collection: Any eligible patient
was recruited until the sufficient number.
* Information collection: Age, sex, BMI,
FPG, HbA1c, fasting plasma C-peptide (FPC)
at baseline and in week 24.
HOMA2 indices were calculated based
on FPG (mmoL/L) and FPC (nmoL/L) levels
with HOMA2 calculator, version 2.2.3
(2013) by Oxford University (the United
Kingdom): HOMA2 for beta cell function
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Journal of military pharmaco-medicine n08-2018
(HOMA2-%B-Cp) and HOMA2 for insulin
resistance (HOMA2-IR-Cp) [2].
Insulin resistance state was defined if
HOMA2-IR-Cp was above 75th percentiles
of HOMA2-IR-Cp of the control (WHO
1999 criteria) [3].
Beta cell function decrease was
defined if HOMA2-%B-Cp was below
the mean - 1 SD of HOMA2-%B-Cp of
the controls.
* Data analyses:

Table 2: Blood glucose indices, insulin
resistance and beta cell function.
Indices (n = 101)

Value

FPG (mmoL/L)*

8.62 ± 1.67

FPG target achievement [% (n)]

81.2 (82)

HbA1c (%)*

7.93 ± 0.83

FPC (nmol/l)*

1.16 ± 0.36

Increased FPC [% (n)]

89.1 (90)

HOMA2-IR-Cp*

SPSS 20.0 was used to calculate
mean values and rates, compare mean
values by t-test and paired t-test.

3.03 ± 0.97

Increased HOMA2-IR-Cp [% (n)]
HOMA2-%B-Cp*

73.51 ± 25.14

Decreased HOMA2-%B-Cp [% (n)]

RESULTS

Table 1: General characters of subjects.
Patients
(n= 101)

Percents

Male

48

47.5

Female

53

52.5

General (n) %

101

100.0

Mean ± SD age

54.13 ± 10.11

Mean ± SD year

2.4 ± 3.4

Percents (%) < 5 year

84.1%

A total of 101 patients with type 2
diabetes participated were eligible in
the study, including 48 men (47.5%) and
53 women (52.5%). Mean age was 54.1 ±
10.1 years. Mean diabetes duration was
2.4 ± 3.4 years. Most patients had diabetes
for less than 5 years (84.1%).
144

81.2 (82)

(* Mean ± SD)

1. Baseline characteristics

Characters

91.1 (92)

* Use of hypoglycemic agent(s) before
the study:
Before the study all the patients took
oral hypoglycemic agents, as metformin
monotherapy or metformin and sulfonylurea
in 60.4% (61 patients) and 39.6% (40 patients),
respectively.
2. Changes of blood glucose indices,
insulin resistance and beta cell function.
Table 3: Use of sitagliptin during the
study.
Weeks 1
to 12 n (%)

Week 13
to 24 n (%)

p

Sitagliptin
50 mg/day

24 (23.8)

27 (26.7)

> 0.05

Sitagliptin
100 mg/day

77 (76.2)

74 (73.3)

> 0.05

Mean ± SD
(mg/day)

88.1 ± 21.4

Sitagliptin use

86.6 ± 22.2 > 0.05


Journal of military pharmaco-medicine n08-2018
All the patients took daily 50 mg or 100 mg of sitagliptin for the whole study. For the
first 12 weeks daily dose of 50 mg and 100 mg was used in 23.8% and 76.2% of the
patients, respectively. For the second 12 weeks, the former and the latter dose was
used in 26.7% and 73.3%, respectively. The changes were not significant.
Table 4: Changes of blood mean values of glucose indices, fasting plasma C-peptide,
HOMA2-%B-Cp and HOMA2-IR-Cp after 24 weeks.
Index

Baseline (n = 87)

Week 24 (n = 87)

Changes (%)

p

FPG (mmoL/L)

8.50 ± 1.61

6.59 ± 0.95

-1.91 ± 1.90

< 0.001

HbA1c (%)

7.87 ± 0.82

6.41 ± 0.74

-1.45 ± 1.00

< 0.001

FPC (nmoL/l)

1.18 ± 0.36

0.84 ± 0.19

-0.34 ± 0.28

< 0.001

76.06 ± 25.16

90.96 ± 27.51

14.90 ± 34.55

< 0.001

3.07 ± 0.97

2.03 ± 0.49

-1.04 ± 0.81

< 0.001

HOMA2-%B-Cp (%)
HOMA2-IR-Cp

After 24 weeks, FPG, HbA1c, fasting plasma C-peptide and HOMA2-IR-Cp significantly
decreased. In contrary, HOMA2-%B-Cp significantly increased.

Table 5: Changes of the rates of increased HOMA2-IR-Cp and decreased HOMA2%B-Cp after 24 weeks.
Index

Baseline (n = 87)

Week 24 (n = 87)

p

Increased HOMA2-IR-Cp (> 1,650)

81 (93.1)

68 (78.2)

0.001

Decreased HOMA2-%B-Cp (< 88.48%)

60 (69.0)

44 (50.6)

< 0.01

After 24 weeks, the rate of increased HOMA2-IR-Cp significantly diminished. In contrary,
the rate decreased HOMA2-%B-Cp significantly declined.
DISCUSSION
1. Baseline characteristics of patients.
The percentage of men and women

was not different in the study. The rate of
type 2 diabetes is changed in with
research and geographical areas. T2DM
in patients was not controlled with oral
hypoglycemic monotherapy or combination
not including DPP-4 inhibitors, found that
FPG and HbA1c did not achieve treatment
goals, similar to other studies in the

country [2]. This may be due to diabetes
over 5 years and FPG control is difficult
due to outpatient treatment.
The mean HOMA2-IR-Cp was 3.03 ±
0.97 and the rate of increased HOMA2IR-Cp was 91.1%, that were similar to the
above cited others study [1, 2]. The mean
HOMA2-%B-Cp was 73.51 ± 25.14% that
was higher in comparison to the study by
Nguyen Thi Thu Thao and the study by
Nguyen Thi Ho Lan reporting the mean
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Journal of military pharmaco-medicine n08-2018
HOM2-%B-Cp of 51.91 ± 37.41 ng/mL
and 47.1 ± 36.6 ng/mL, respectively. This
suggests that ß-cell function decreased
and increased insulin resistance may be
due to patients being studied for type 2
diabetes.
All the patients used hypoglycemic

agent(s) before the start of the study.
About two thirds of the patients (60.4%)
used metformin alone and the rest
(39.6%) combination of metformin and
sulfunylurea. All the hypoglycemic agent(s)
and their doses that had been used before
the stusy remained unchanged for the
whole study period.
All the patients took daily 50 mg or
100 mg of sitagliptin for the whole study.
For the first 12 weeks daily dose of 50 mg
and 100 mg was used in 23.8% and
76.2% of the patients, respectively. For
the second 12 weeks, the former and the
latter daily dose was used in 26.7% and
73.3%, respectively, which resulted in a
decrease of mean daily dose from 88.1
mg to 86.6 mg, however, all the changes
were not significant.
2. Changes of blood glucose
indices, insulin resistance and beta
cell function after adding sitagliptin.
After 24 weeks of sitagliptin add-on,
there were significant improvements in
blood glucose control, insulin resistance
and beta cell function. Compared to the
baseline, after 24 weeks FPG and HbA1c
significantly decreased by 1.91 ± 1.90
mmoL/L and 1.45 ± 1.0%, respectively.
FPC significantly decreased by 0.34 ±

0.28 nmoL/L. The beta cell function
markedly improved as that the mean
HOMA-%B-Cp significantly raised by
146

14.90 ± 34.55% from 76.06 ± 25.16% to
90.96 ± 27.51%, and the rate of decreased
HOMA2-%B-Cp significantly declined
from 69.0% to 50.6%. In the contrary,
the insulin resistance status substantially
diminished as that the mean HOMA2-IRCp significantly decreased by 1.04 ± 0.81,
from 3.07 ± 0.97 to 2.03 ± 0.49, the rate
of increased HOMA2-IR-Cp significantly
declined from 93.1% to 78.2%.
Numerous studies abroad have
demonstrated blood glucose, insulin
resistance and beta cell function improving
effects of sitagliptin when added to other
hypoglycemic agents [4, 5]. Charbonnel et
al compared addition of daily 100 mg of
sitagliptin with placebo in 245 T2DM
patients who had a mean HbA1c of 8%
and were taking a stable metformin daily
dose of 1,500 mg [6]. After 24 weeks,
FPG and HbA1c in the sitagliptin group
significantly decreased by 0.9 mmoL/L
and 0.67% (p < 0.001 for both), respectively;
HOMA-%B significantly increased by
19.5% (p < 0,001), insulin sensitivity index
QUICKI significantly increased by 0.003

(p < 0,010). Meanwhile FPG in the control
group FPG significantly increased by
0.5 mmoL/L, and HbA1c, HOMA-%B and
QUICKI did not significantly change.
Hermansen et al compared addition of
daily 100 mg of sitagliptin with placebo in
441 T2DM patients with baseline HbA1c
of 8.34%, who were on glimepiride alone
or combination with metformin [7]. After
24 weeks, the sitagliptin group had HbA1c
reduction by 0.74% and HOMA-%B
increase by 12% relatively to the placebo
one. In a meta-analysis from 6 studies of
effects of different DPP-4 inhibitors on
insulin resistance, only sitagliptin significantly


Journal of military pharmaco-medicine n08-2018
decreased insulin resistance by a
weighted mean reduction of 0.38 (95%CI:
-0.69, -0.08) [8].
The favorable effects of DPP-4 inhibitors,
including sitagliptin, for improving betacell function among patients with T2DM
are biologically plausible. DPP-4 inhibitors
prolong endogenous incretins existence in
blood by suppressing DPP-4. Prolonged
blood Incretins stimulate beta cell secret
insulin and may restore beta-cell function
and survival. In respect to effects on
insulin resistance, only sitagliptin, but not

the other DPP-4 inhibitors, could significantly
improve insulin resistance. This finding
needs to be confirmed in future studies.
CONCLUSION
In patients with T2DM uncontrolled with
metformin alone or its combination with
other oral hypoglycemic agents, add-on of
DPP-4 inhibitor sitagliptin for 24 weeks
resulted in significant improvement of
beta cell function and insulin resistance in
addition to improvement in blood glucose.
Suggestions
DPP-4 inhibitors should be early added
in treatment of patients with T2DM
uncontrolled with metformin alone or its
combination in order to improve beta
cell function and insulin resistance, which
result in improvement of blood glucose.
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