Results: The mean age and diabetes duration was 54.1 ± 10.1 and 2.4 ± 3.4 years, respectively. Before the study start, metformin monotherapy was used by 60.4% of patients, and the most used combination was metformin plus sulfonylurea (39.6% of all the patients). Sitagliptin was the only used dipeptidyl peptidase-4 inhibitor with mean dose of 88.1 mg/day and 86.6 mg/day for the first and second 12 weeks. After 12 weeks, compared to the baseline, the mean fasting plasma glucagon decreased by 13.63 pg/ml, respectively (p < 0.001).
Trang 1EFFECTS OF SITAGLIPTIN AS ADD-ON BLOOD GLUCAGON
LEVEL IN PATIENTS WITH TYPE 2 DIABETES
Le Thi Viet Ha 1 ; Doan Van De 2
SUMMARY
Objectives: To evaluate the effects of dipeptidyl peptidase-4 inbibitors sitagliptin as add-on blood glucagon in patients with type 2 diabetes inadequately controlled with oral antidiabetic
drug monotherapy or combination Subjects and methods: An intervention study was conducted
on 101 adult patients with type 2 diabetes inadequately controlled with oral antidiabetic drug monotherapy or combination other than dipeptidyl peptidase-4 inhibitors with HbA1c from 7 to 10% The outcome measures were fasting plasma glucose, 2 hour postprandial glucose and HbA1c that were assessed at the baseline after 12 weeks A dipeptidyl peptidase-4 inhibitor was started with a half or full dose for the first 12 weeks and could increase to full dose for the last
12 weeks if started as half dose The other oral antidiabetic drug and their doses were kept unchainged during the whole study Results: The mean age and diabetes duration was 54.1 ± 10.1 and 2.4 ± 3.4 years, respectively Before the study start, metformin monotherapy was used by 60.4% of patients, and the most used combination was metformin plus sulfonylurea (39.6% of all the patients) Sitagliptin was the only used dipeptidyl peptidase-4 inhibitor with mean dose of 88.1 mg/day and 86.6 mg/day for the first and second 12 weeks After 12 weeks, compared to the baseline, the mean fasting plasma glucagon decreased by 13.63 pg/ml, respectively (p < 0.001) and the proportion of patients achieving American Diabetes Association
2015 fasting plasma glucose, 2 hour postprandial glucose and HbA1c targets significantly increased from 18.8%, 11.9% and 0% to 69.3%, 78.2% và 69.3%, respectively (p < 0.001),
the duration of the intervention was 12 weeks Conclusions: The add-on of the dipeptidyl
peptidase-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled with metformin alone or oral antidiabetic drug combinations resulted in improvements of glycemic control for a period of 12 weeks
* Keywords: Type 2 diabetes; Dipeptidyl peptidase inhibitor; Blood glucagon plasma
INTRODUCTION
The number of type 2 diabetes is
increasing all over the world, especially
in the developing countries It causes
numerous severe complications in almost
all body organs and systems, in particular
eyes, kidneys, nerves, heart and blood
vessels Type 2 diabetes has multiple pathophysiologic defects Besides the long well known defects such as insulin resistance, beta cell failure and increased hepatic glucose production, relatively new defects have been discovered Some of them are incretin defects and inappropriately
1 National Hospital of Endocrinology
2 103 Military Hospital
Corresponding author: Le Thi Viet Ha (drvietha72@gmial.com)
Date received: 07/12/2018
Date accepted: 18/02/2019
Trang 2increased glucagon secretion Multiple
pathophysiologic defects and progressive
beta cell failure results in failure of
multiple old oral antidiabetic drug (OAD)
combinations in the long run It is
necessary to develop new antidiabetic
drug classes that aim at these new
defects and complement the old OADs
effects One of the new OAD classes is
dipeptidyl peptidase (DPP)-4 inhibitors
that prolong endogenous incretins and
are rapidly inactivated by that enzyme
Incretins are gut hormones secreted in
response to nutrients (mainly carohydrate)
There are two incretins: glucagon like
peptide (GLP) - 1 and glucose-dependent
insulinotropic peptide (GIP) They simulate
insulin release and supress glucagon
release in response to a meal in a
glucose-dependent manner as well as
slow gastric emptying and enhance satiety
Add-on of DPP-4 inhibitors to ongoing
different OAD monotherapy or combinations
have been shown to improve blood
glucose control in numerous studies
abroad, but it has not been studied in
Vietnam The present study aims at:
Evaluating the effects of DPP-4 inhibitors
sitagliptin as add-on therapy on glucose
level in patients with type 2 diabetes
inadequately controlled with oral antidiabetic
drug (OAD) monotherapy or combination
in National Hospital of Endocrinology
SUBJECTS AND METHODS
1 Subjects
Patients with type 2 diabetes diagnosed
by American Diabetes Association (ADA)
2015 criteria and inadequately controlled
with OAD(s)
- Inclusion criteria:
+ Type 2 diabetic patients who were treated by oral hypoglycaemic drugs or combination non-DPP-4 combination therapy were given stable doses over 3 months
and failed to achieve glycemic control
+ The standard has not met the target based on GM from 7 mmol/L to ≤ 16 mmol/L
and has HbA1c from 7.0% to ≤ 10%
+ No anemia; age of 30 years or above;
agreed to participate in research
- Exclusion criteria:
+ Over 30 years old
+ Currently identified as healthy people based on medical history, physical examination and basic biochemical tests + No risk factors; FPG, HbA1c normal + Agree to participate in research
2 Methods
- Study design: This was an uncontrolled
trial evaluating effects on blood glucose of DDP-4 inhibitors added to other oral antidiabetic drug monotherapy or combination in patients with type 2 diabetes who did not reach HbA1c target
of below 7.0%
Oral antidiabetic drugs and their dosage remained unchanged throughout the follow-up period Sitagliptin, a DPP-4 inhibitor, is supplemented with a starting dose of 50 or 100 mg once a day In cases where the dose is increased to 100 mg per day at week 12 if HbA1c remains above 7.0%, if HbA1c is less than 7.0%, the dose should be reduced to 50 mg Intervention time is 12 weeks
Trang 3- Sample collection: All the patients
who met the inclusion and exclusion criteria
were recruited into the study
- Outcomes measures: The patients’
baseline characteristics that were assessed
included age, sex, BMI, diabetes duration,
use of oral diabetic drugs, and blood
glucose control indices (FPG, 2hPPG and
HbA1c) The last three measurements
were reassessed at weeks 12 and 24
The ADA 2015 targets of blood
glucose control were as follows: FPG:
4.4 - 7.2 mmol/L; 2hPPG: < 10 mmol/L;
HbA1c < 7.0%
- Statistical analysis: SPSS version
20.0 was used for data analysis The
effects of adding DPP-4 inhibitors on
blood glucagon were evaluated by
comparing the blood glucagon control
indices in weeks 12 at baseline by using
fraired t-test, and the rates of achieving
blood glucose control targets at those
points of time
RESULTS
1 Patients baseline characteristics
A total of 101 eligible patients with type 2 diabetes participated in the study, including 48 men (47.5%) and 53 women (52.5%) The mean age was 54.1 ± 10.1 years, which ranged from above 30 to 79 years, age group 50 - 59 years old accounted for 40.6% The mean diabetes duration (defined as time period elapsed since diabetes was diagnosed) was 2.4 ± 3.4 years Most patients had diabetes for less than
5 years (84.1%) Before the invention at baseline, all the patients were on oral antidiabetic drug(s) only (no patients was
on insulin) Metformin monotherapy was used by 60.4% and metformin and sulfonylurea combination by 39.6% of the patient The mean FPG, 2hPPG and HbA1c was 8.62 ± 1.67 mmol/L, 12.36 ± 2.36 mmol/L and 7.93 ± 0.83%, respectively
2 Baseline plasma glucagon indices
Table 1: Mean indices of plasma in glucagon control and diabetes group
Blood glucagon indices
(n = 30)
Control (n = 30)
Diabetis (n = 30)
p
Glucagon (pg/mL)
< 0.001
The mean plasma glucagon was 70.86 ± 12.73 pmol/mL, increased to 100.0%
Trang 43 Correlation between FPG, 2hPPG, HbA1c with plasma glucagon
Table 2: Correlation between FPG, 2hPPG, HbA1c with plasma glucagon indices baseline
Fasting plasma glucagon correlated with FPG, 2hPPG, HbA1c at the beginning with statistical significance
4 The effects of adding DPP-4 inhibitors on blood glucose weeks 12 compared
with baseline
Patients using oral hypoglycemic agents did not change during the study period All patients use sitagliptin 50 mg or 100 mg per daily
Table 3: Changes of blood glucose indices and fasting plasma glucagol at week
12 compared with baseline
(Values are mean ± SD)
Compared with the baseline values, the mean FPG, 2hPPG and HbA1c at week
12 decreased by 1.70 ± 2.06 mmol/L, 2.80 ± 2.26 mmol/L and 1.21 ± 0.86 mmol/L
Compared with the baseline values, the mean plasma glucagon at week 12 decreased
by 13.63 ± 9.60 pg/mL, significant statistically with p < 0.001
5 Correlation between FPG, 2hPPG, HbA1c with plasma glucagon at 12 week
Bảng 4:
Fasting plasma glucagon correlated with FPG, 2hPPG, HbA1c at 12 week, which
was statistically significant
Trang 5Table 5: Correlation between the variation of plasma glucagon at the change with
FPG, 2hPPG, HbA1c after 12 weeks
The variation of the plasma glucagon levels correlated with the change of with FPG,
respectively, but did not correlate with the changes of 2hPPG, HbA1c after 12 weeks
DISCUSSIONS
1 Baseline patients’ characteristics
The increased overweight or obese
prevalence in patients with type 2
diabetes may reflect the tendency in our
general population over time 84.1% of
patients had short duration of diabetes
less than 5 years Only small proportion
of patients had diabetes for more than
10% (5%) The baseline mean FPG,
2hPPG, HbA1c was 8.62 mmol/L, 12.36
mmol/L, 7.93%, respectively Most
patients did not achieve ADA 2015 PFG
and 2hPPG targets that were 81.2% and
88.1%, respectively All the patients had
baseline HbA1c > 7%
Most patients in our study were
outpatients so their blood glucose control
was better than inpatients’ one in other
domestic studies In a study by Nguyen
Thi Ho Lan, in type 2 diabetes patients
treated at National Hospital of Endocrinology
(NHoE), the baseline mean FPG and
HbA1c was 12.1 mmol/L and 9.8%;
in Nguyen Thi Duyen’s study, they were
10.32 mmol/L and 9.29%, respectively
[1, 2 ]
2 Use of OAD during the study
Before the intervention, all the patients were on oral antidiabetic drug(s) only (no patient was on insulin) 60.4% of patients used metformin monotherapy and 39.6%
of patients used metformin and sulfonylurea combination
3 Correlation between FPG, 2hPPG, HbA1c with fasting plasma glucagon baseline
We found that the correlation between fasting plasma glucagon and fasting plasma glucose and HbA1c in the initial group of patients, the initial fasting plasma glucagon correlated well with the severity, which was statistically significant with blood glucose at fasting This result suggests that fasting blood glucagon may
be one of the factors that contribute to hyperglycaemia
This finding is not similar to other authors’: In the control group, study by Nguyen Thi Duyen, serum glucagon concentration was moderately correlated with glucose concentration, r = 0.336,
p < 0.05, in the diabetic group, there was
no statistically significant correlation between
Trang 6fasting serum glucose concentrations and
glucose concentrations (p > 0.05)
Taborsky GJ et al (2010) studied the
physiologic effect of glucagon and
showed that when endogenous glucagon
levels increased glucose production from
the liver, primarily by the
glucose-degrading pathway, eg (10 pg/mL)
endogenous glucagon will increase
glucose production from the liver by about
25% Thus, glucagon excretion within the
physiological limits is responsible for
controlling glucose production within the
physiological limits of the body
Because the blood glucose of the
study group was higher than that of the
control group, which may indicate
elevated glucagon secretion, not only in
fasting but also after meals This may
explain the association between fasting
glucagon and postprandial glucose as
well as HbA1c
4 Effects of add-on of DPP-4 inhibitors
on blood glucose
In our study, effects of the add-on of
sitagliptin on the patients who were
already on other OAD monotherapy or
combinations, their blood glucose control
substantially improved with significant
reductions of the mean FPG, 2hPPG and
HbA1c, and high proportion of the patients
achieved blood glucose indices targets
After 12 weeks, compared with the baseline,
FPG, 2hPPG and HbA1c significantly
decreased by 1.7 ± 2.06 mmol/L, 2.8 ±
2.26 mmol/L and 1.21 ± 0.86%, respectively
Compared with the baseline values, the
mean glucagon after 12 weeks decreased
by -13.63 ± 9.60 pg/mL, significant with
p < 0.001
Concerning the blood glucose targets achievement, at week 12, about two thirds of the patients achieved ADA 2015 targets of FPG, 2hPPG and HbA1c
At week 12, 69.3%, 70.3% and 61.4% of the patients achieved the targets of FPG, 2hPPG and HbA1c, respectively, which substantially increases compared with the baseline when the proportion of the patients achieving the targets were only 18.8%, 11.9% and 0%, respectively
Numerous randomized control trials have proved that effects of sitagliptin
add-on add-on other OAD madd-onotherapy (mainly metformin) or combinations improved glycemic control compared with placebo
in type 2 diabetes patients not achieving blood glucose targets
Charbonnel et al studied effects of sitagliptin add-on (100 mg/day) on ongoing metformin monotherapy (≥ 1,500 mg/day)
in type 2 diabetes patients with mean HbA1c of 8% compared with continued metformin monotherapy alone [3] After
24 weeks, FPG and HbA1c in the sitagliptin add-on group significantly decreased by 1.4 mmol/L and 0.65% (both p values
< 0.001), respectively, compared with those indices in the metformin monotherapy group A significantly greater proportion of patients achieved an A1C < 7% with sitagliptin (47.0%) than with placebo (18.3%)
In a study by Chien et al [7], Taiwanese type 2 diabetes patients (n = 97) were randomized to receive the existing OAD combinations or add-on with sitagliptin (100 mg daily) for 24 weeks Compared with the change of 0.0% (95% confidence interval: -0.6% to 0.5%) from a baseline of 10.0% in the controlled arm,
Trang 7HbA1c change from a mean baseline of
9.5% was -1.14% ± 1.18 after add-on
sitagliptin (p < 0.0001)
In randomized controlled trials that
combination of sitagliptin and metformin
compared with metformin or sitagliptin
monotherapy as initial OAD therapy, the
former resulted in clearly better glycemic
control than the latter
Williams-Herman et al [8] compared
different sitagliptin and metformin
combinations with sitagliptin or metformin
monotherapy in type 2 diabetes
drug-nạve patients in a 54 week multinational
study At week 54, the HbA1c reduction
was the highest in the combination with
high metformin dose (S100/M2000 mg/day),
-1.8%, followed by the combination with low
metformin dose (S100 mg/M1000 mg/day),
-1.4%, monotherapy with higher metformin
dose (M2000 mg/day), -1.3%, monotherapy
with low metformin dose (M1000 mg/day),
-1.0% and monotherapy with sitagliptin
(100 mg/day), -0,8% Similarly, the proportion
of patients with an HbA1c < 7% at week
54 were 67%, 48% (S100/M1000), 44%,
25% and 23%, respectively The extents
of effects of adding sitagliptin on existing
OAD(s) therapy or those of combinations
of sitagliptin and metformin compared to
metformin or sitaglitin monotherapy are
different from study to study, because
patients’ characteristics varied However,
the improvement of glycemic control after
adding sitagliptin to existing OAD(s) or
better glycemic control of sitagliptin
combinations compared with metformin or
sitagliptin monotherapy has been proved
The mechanisms of action of DPP-4
inhibitors are different from those of other OAD classes such as biguanide, sulfonylureas and alpha-glucosidase inhibitors This explains additional effects
of adding DPP-4 inhibitors on the other OADs on glycemic control
5 Correlation between FPG, PPG, HbA1c with fasting plasma glucagon at
12 weeks
In our study, fasting plasma glucagon concentrations were strongly correlated with fasting plasma glucose, postprandial and HbA1c levels prior to treatment with DPP-4 inhibitor After 12 weeks of supplementation with DPP-4 inhibitors, these correlations were also noted: fasting serum glucagon concentrations were statistically significantly correlated with fasting plasma glucose, postprandial blood glucose and HbA1c Increased levels of fasting blood glucagon also reflect elevated glucagon secretion, both
at the time of fasting and after meals in patients with type 2 diabetes This suggests that glucagon secretion contributes to hyperglycemia, both after fasting and mean blood glucose levels through HbA1c Moreover, after 12 weeks of treatment with DPP-4 inhibitor, there was a positive correlation between changes of fasting plasma glucagon and fasting plasma glucose This adds to the evidence that a decrease in glucagon concentration by inhibiting DPP-4 enzymes may be a contributing factor to fasting plasma glucose However, after 12 weeks, there was no statistically significant correlation between fasting plasma glucagon changes with postprandial glucose change and HbA1c change This may be due to
Trang 8increased insulin secretion and the
effects of DPP-4 inhibitor which plays a
key role in postprandial and postprandial
hypoglycemia
CONCLUSIONS
The add-on of the DPP-4 inhibitor
sitagliptin in patients with type 2 diabetes
inadequately controlled with metformin
alone or OAD combinations resulted in
substantial improvements of glycemic
control for a period of 12 weeks After
12 weeks, compared with the baseline,
the mean FPG, 2hPPG and HbA1c
significantly decreased by 1.70 mmol/L,
2.80 mmol/L and 1.21% Compared with
the baseline values, the mean glucagon
at week 12 decreased by -13.63 ±
9.60 pg/mL, respectively (p < 0.001 for all),
the proportions of patients achieving ADA
2015 FPG, 2hPPG and HbA1c targets
significantly increased from 18.8%, 11.9%
and 0% to 69.3%, 70.3% and 61.4%,
respectively, with p < 0.001
REFFERENCES
1 Nguyễn Thi Duyên Khảo sát nồng độ
glucagon huyết tương và mối liên quan với
một số biểu hiện lâm sàng, cận lâm sàng ở
bệnh nhân đái tháo đường týp 2 Luận văn
Tốt nghiệp Bác sĩ Nội trú 2016
2 Nguyễn Thị Hồ Lan Nghiên cứu nồng
độ glucagon like peptide-1 ở bệnh nhân đái tháo đường týp 2 tại Bệnh viện Nội tiết TW Luận văn Chuyên khoa Cấp 2 2015
3 Charbonnel B, Karasik A, Liu J et al
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone Diabetes Care 2006, 29 (12), pp.2638-2643
4 Reasner C, Olansky L, Seck T.L et al
The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus Diabetes Obes Metab 2011, 13 (7), pp.644-652
6 Brazg R, Xu L, Dalla Man C et al Effect
of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes Diabetes Obes Metab 2007,
9 (2), pp.186-193
7 Ming-Nan Chien, Chun-Chuan Lee,
Wei-Che Chen et al Effect of sitagliptin as
add-on therapy in elderly type 2 diabetes patients with inadequate glycemic control in Taiwany International Journal of Gerontology
2011, 5, pp.103-106
8 Williams-Herman D, Khatami, Raz I
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus Sitagliptin Study
023 Diabetologia 2006, 49, pp.2564-2571.