Download after add-on of sitagliptin(Sita) in Japanese type 2 diabetic patients

The efficacy of ‘Basal supported Oral
Therapy ’ with ‘Sitagliptin’ in Japanese type 2
diabetes patients:
Yoshihiko Suzuki HDC Atlas Clinic,
Objective
to clarify the effectiveness of ‘basal supported oral therapy:(BOT)’ with oral
hypoglycemic agents (OHA) and glargine(Gla) after add-on of sitagliptin(Sita) in
Japanese type 2 diabetic patients on cross-sectional study.
Methods
●18 patients with type 2 diabetes (13 men and 5 women) aged (38- 89 y/o,
60.5±13.7 y/o.) were enrolled. The subjects were previously treated with
BOT(OHA±Gla) without incretin treatment.
●They added sitagliptin upon BOT(OHA±Gla) therapy. Concomitant oral drugs
included sulfonylureas, α-glucosidase inhibitors, metoformin, and pioglitazone.
●The primary analysis assessed whether add-on of sitagliptin was associated with
the change of HbA1c and weight-gain.
Results
Hemoglobin Aic (HbA1c) improved significantly from 8.4±1.4 % at baseline to
7.2±1.2% after 12 weeks of add-on therapy with sitagliptin (p<0.01), and the insulin
dosage was reduced on average from 16.3±6.8 U/day to 14.7±7.1 U/day. Body
weight increased slightly but not significantly and severe hypoglycemia was not
observed.
Conclusion
The addition of sitagliptin provided significant improvement in HbA1c and was
generally well tolerated. In other clinical trial by using mainly mixed insulin
injections twice daily and adding sitagliptin, HbA1c decreased by 0.6% within 4
month. In this study, HbA1c decreased by 1.2% within 3 months. These findings
suggest that add-on therapy with sitagliptin on glargine could improve glycemic
control strongly compared with multiple insulin injection therapy. Because glargine
and sitagliptin are once daily medications, the combination increased QOL of patients.
Subject
18 patients with type 2 diabetes (13 men and 5 women) aged (38- 89 y/o, 60.5±13.7
y/o.) were enrolled. Type 2 diabetes was diagnosed from clinical criteria according to
the Japan Diabetes Society guidelines. They were all patients periodically attending
HDC Atlas Clinic. They were all Japanese, prescribed adequate diet/exercise therapy
by specialists and nutritionists and received other appropriate treatment depending on
their condition.
Enrolled patients were all receiving BOT (OHA+Gla+Sita). The present treatment
was identical. All of them were previously treated with BOT(OHA+Gla) without
incretin treatment. The prescription of sitagliptin was added on the BOT(OHA+Gla)
therapy. So, their baseline was the time of add-on sitagliptin medication. Inclusion
criteria was type 2 diabetes on BOT(OHA+Gla) therapy for at least 3 months, and
hemoglobin A1c (HbA1)≧6.5% (National Glycohemoglobin Standardizaion Program
[NGSP] value).
Exclusion criteria were 1) type 1 diabetes, 2) treatment with insulin formulation
other than once daily glargine injection, 3) treatment with oral DPP4-inhibitor agents
other than sitagliptin, 4) treatment with steroids, 5)severe hypoglycemia or recurrent
asymptomatic hypoglycemia, 6)severe infection, 7) patients scheduled for surgery or
those with serious trauma, 8) pregnant or nursing women and those who might be
pregnant, and 9) other patients whom the investigation judged to be inappropriate for
the study, and 10) patients who beforehand started sitagliptin with other antidiabetic
oral agents and afterwards added glargine injection were also excluded.
Each patient provided informed consent for monthly blood tests. This study was
approved by the institutional review board of Hanzoumon Diabetes City Atlas Clinic.
This study was conducted in accordance with the principles of the Declaration of
Helsinki. All subjects were given an explanation of this clinical study and written
informed consent was obtained voluntarily from each subject
Treatment
Throughout the five months observation period, the dose of oral antidiabetic agents
including sitagliptine (50mg or 100mg), dose of glargine, timing of glargine injection
was adjusted carefully according to the patient’s life style, and glucose daily excursion
curve judged by self monitoring blood glucose (SMBG) test.
Dose modifications of OHA were not principally allowed during the treatment phase.
However, if there was a tendency and a risk of progressive hyperglycemia in patients
on concomitant sulfonylurea (SU) or metformin therapy, dose titration was allowed.
Also, to get better glycemic control, dose modification of glarigine was adjusted
principally. Insulin was down-titrated if 2 or more self-monitored blood glucose
reading were 4.4 mmol/L or less (=<80 mg/dL). Sitagliptin dose was not changed and
remained as same of 50mg or 100mg during five months.
To prevent the severe hypoglycemia, every necessary adjustment was done
individually, according to the patients’ condition. For instance, when the patients were
afraid of hypoglycemia during the night, diabetologists gave an advice to start glargine
in the morning. When the subjects were afraid of hypoglycemia during the day time,
the subjects injected glargine in the morning without using sulfonylurea (SU). If there
was a risk of hypoglycemia in patients on concomitant SU therapy, dose reduction of
SU therapy was allowed. All of these dose and timing administration were conducted
under the direction of expert diabetologists.
Fasting plasma glucose (FPG) was taken as a sample, but was not analyzed. Because
some patients of BOT (OHA+Gla+Sita) were likely to have glycemic state near
hypoglycemia at home in the morning, it disturbs the taking of ‘actually fasting-state’
sampling at out-department of our institutes. To prevent the hypoglycemia, the subjects
often took some sugars and/or breakfast at home. Therefore, not only FPG but also
other lipid parameters were not analyzed due to the contamination. HbA1c and weight
were measured in all patients prior to starting combination therapy with sitagliptin
(Week 0, baseline), as well as in 1 month, 2nd month, 3rd month, 4th month, and 5th
month after the initiation of combination therapy. The incidence of severe
hypoglycemia during the treatment period was also evaluated.
Statistical analysis
In all patients, the changes of HbA1c and body weight, BMI in month 1st from 5th
versus baseline were evaluated by the one-factor repeated measure ANOVA. For all
analyses, p<0.05 was taken to indicate statistical significance. Data in the text and
Tables are expressed as the mean ± standard deviation (S.D.), while data in the
Figures are shown as the mean ± standard error (S.E.).
Results
●Patient characteristics
The subjects consisted of 13 men and 5 women with a mean age of 63.4±13.3
years and a mean diabetes duration of 13.9±10.9 years. As for complication, three
subjects showed background retinopathy and three subjects had preproliferative
retinopathy while the others did not show any signs of retinopathy. Six subjects
had microalubuminemia, and two subjects had macroalbuminuria, and the urine
tests of the other subjects were normal.
●Change of HbA1c
HbA1c was 8.4±1.4 % at baseline. After add-on of sitagliptin, HbA1c decreased
to 7.9±1.1% at 1st month (p<0.01), 7.4±1.0 % at 2nd month(p<0.01), 7.2±1.0 %
at 3rd month(p<0.01), 7.2±1.0 at 4th month(p<0.01), and 7.2±1.1% at 5th
month(p<0.01).
Figure.１ Change of HbA1c after the add-on of sitagliptin on
BOT(OHA+Gla) therapy.
There was significant difference between the 6 conditions.
*:p<0.05. **;p<0.01, by the paired t-test (vs. baseline)
●Changes of Body Weight
On baseline, body weight was 69.1±17.9 kg. After add-on of sitagliptin, body
weight increased to 69.4±18kg at 1st month, 69.8±18.0 kg at 2nd month,
70.1±16.5kg at 3rd month, 70.0±18.8kg at 4th month, and 70.4±18.8kg at 5th
month. Increase of 1.3kg at 5th moth from baseline was not statistically significant.
Figure 2. Change of body weight after the add-on of sitagliptin
●Changes of BMI
Body mass index was 25.7±5.7 kg on baseline. After the switching, weight
increased to 25.8±5.7 kg at 1st month, 26.0±5.8 kg at 2nd month, 26.0±5.9 kg
at 3rd month, 26.0±6.0 kg at 4th month, and 26.1±5.9 kg at 5th month. Changes
of body mass index are presented in Fig.3. Body mass index was not
significantly higher compared with that in baseline.
Figure 3. Change of body mass index after the add-on
of sitagliptin
●Hypoglycemia
There were episodes of mild hypoglycemia in eight subjects during these five
months. There were no episodes of moderate/severe hypoglycemia. Four
patients experienced mild hypoglycemia within one month after add-on
sitagliptin therapy. All of them prevented the hypoglycemia by down-titration of
insulin dose during the first month period and could prevent mild hypoglycemia
by compliance with the instructions for added food (3). No patient discontinued
BOT (OHA+Gla+Sita) therapy.
●Change of Therapeutic Medication.
The difference between baseline and after 5th month represents the
characteristics of therapeutical change (Table 1).
Discussion
When patients of diabetes are supplemented with BOT (OHA + Gla), DPP4 inhibitors
could have a complementary effect. Because additional early intrinsic insulin secretion
from pancreas by DPP4 inhibitors works on postprandial hyperglycemia, and because
the basal insulin works during one day long, the combination of these two medications
is conceptually suitable for suppressing the whole day profile of hyperglycemia in type
2 diabetes.
The result of this study showed the clear evidence that once daily insulin with
glargine and sitagliptin is suitable as the combination therapy of BOT. It confirmed a
concept, supporting the previous studies (8,9). Especially, our result supports the
report of Katsuno et al. and their stratified analysis.
In this study, HbA1c decreased of -1.2% in 3 months. In the clinical phase 3 trial (CP3-trial) for the approval of sitagliptin by Minister of Health in Japan, patients were
mainly the subjects with mixed insulin injection or intermediate type insulin injection
twice daily (7). And the result of the C-P3-trial was decline of HbA1c, -0.6% in four
months. Compared with these previous studies (6,7,8,9), the decline of HbA1c (-1.2%)
in this study was remarkably superior. Interestingly, Taneda et al. reported similar
phenomenon that the result of BOT with long-time acting insulin and with sitagliptin
was superior to those of intermediate-acting insulin, Mix type insulin and multiple
injections (10).
Various explanations are possible. In C-P3-trial, the starting dose of sitagliptin was
all 50mg. However, in this study, 58% of the subjects started 100mg of sitagliptin
from the beginning, which made the hypoglycemic effect of sitagliptin stronger. In
addition, 7 (36%) out of 19 subjects increased the dose of glargine to suppress the
hyperglycemia. This up-titration of glargine decreased HbA1c during the early
phase of this observation. In addition, the close titration of concomitant drugs
might have contributed to the sharp decline of HbA1c after the add-on of sitagliptin.
In C-P3-trial, the curve of HbA1c presents the nadir at 3rd – 4th month after the
combination therapy (7). In this study, nadir was at the 3rd – 4th month of HbA1c
curve. The same timing of HbA1c’s nadir in this study seems to be a characteristic
of the DPP4 inhibitors, when added on insulin therapy.
In this study, the concomitant sitagliptin therapy resulted in the slightly decrease
of the insulin dose. Because sitagliptin could improve postprandial glucose, both by
glucose-dependent increase of insulin secretion and glucacon suppression, the
advantages of combination therapy are not only improvement of glycemic control,
but also a reduction of the insulin dose. In addition, reduction of hypoglycemia risk
and alleviation of psychological stress can be expected.
Although the statistically insignificant, the undesired effect of BOT
(OHA+Gla+Sita) therapy was increased body weight. Several explanations are
possible. Weight gain is typically observed with insulin therapy because of
improved glycemic control (11). Otherwise, relatively high insulin concentration.
caused by glargine, and added sitagliptin might prevent lipolysis, thereby causing
weight-gain. Furthermore, the anorectic effect of sitagliptin might have been so weak
to prevent the weight-gain.
To overcome this problem, several solutions can be considered. According to the
GeatGoal Duo study, usage of lixisenatide on BOT(OHA+Gla) might solve this
problem of weight-gain (12). Because lixisenatide has stronger anoretic effect than
sitagliptin, it could prevent overeating, thereby losing weight, and also reduce HbA1c.
In the future, adding of SGLT2（sodium-glucose cotransporter 2）inhibitor on
BOT(OHA+Gla+Sita) therapy might be an another solution, because SGLT2
inhibitor can reduce the weight and improve glycemic control, independently of
blood insulin concentration (13, 14).
As for AEs, hypoglycemia episode was few. Add-on of sitagliptin can narrow the
range of glucose fluctuation (15). It has contributed a lot to the stabilization of
glycemic control, thereby preventing the increase of hypoglycemia. The results were
consistent with the similar previous studies (5,6,7,8,9,10).
In conclusion, it was confirmed that BOT(OHA+Gla+Sita) therapy reduced HbA1c
distinctively. An excellent hypoglycemic effect of ‘glargine’ based BOT plus
sitagliptin can be expected compared with other insulin formulations plus sitagliptin.
Because glargine injection is once daily, it raises QOL. The safety was confirmed by
the low incidence of hypoglycemia. Thus, this concomitant therapy is surely effective
in patients with poor glycemic control. Since this was a cross-sectional observation
study, further large-scale studies are warranted in the future.
References
1. Quinzler R, Ude M, Franzmann A, Feldt S, Schüssel K, Leuner K, Müller WE, Dippel FW, Schulz M.Treatment duration (persistence) of
basal insulin supported oral therapy (BOT) in Type-2 diabetic patients: comparison of insulin glargine with NPH insulin.Int J Clin Pharmacol
Ther. 2012 Jan;50(1):24-32.
2. Y. G. Kim, S. Hahn, T. J. Oh, S. H. Kwak, K. S. Park, Y. M. Cho. Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4
inhibitors between Asians and non-Asians: a systematic review and meta-analysis. Diabetologia. (2013) 56: 696-708
3. Meguro S, Sano M, Suzuki Y. A new preventive strategy for hypoglycemia incorporating added food diet in patients with type 2 diabetes
who received sitagliptin therapy. Endocr Res. 2012;37(4):175-81.
4. Harashima SI, Tanaka D, Yamane S, Ogura M, Fujita Y, Murata Y, Seike M, Koizumi T, Aono M, Wang Y, Inagaki N. Efficacy and
safety of switching from Basal insulin to sitagliptin in Japanese type 2 diabetes patients. Horm Metab Res. 2013 45(3):231-8.
5. Charbonnel B, Steinberg H, Eymard E, Xu L, Thakkar P, Prabhu V, Davies MJ, Engel SS.Efficacy and safety over 26 weeks of an oral
treatment strategy including sitagliptin compared with an injectable treatment strategy with liraglutide in patients with type 2 diabetes
mellitus inadequately controlled on metformin: a randomised clinical trial. Diabetologia. Apr 19. (2013) [Epub ahead of print]
6. Annichi T. et al. Investigation of add-on effect of sitagliptin to Mix type twice daily insulin injection. Journal of Japan Diabetes Society.
2013; 56(3): 201
7. Kadowaki T, Tajima N, Odawara M, Minamide T, Kawashima M, Yanagida D, Okamoto T, Ferreira J.C.A. Efficacy and safety of
sitagliptin add-on therapy in Japanese patients with type 2 diabetes on insulin monotherapy. Diabetol Int DOI 10.1007/s13340-013-0109-z
8. Katsuno T, Ikeda H, Ida K, Miyagawa JI, Namba M.Add-on therapy with the DPP-4 inhibitor sitagliptin improves glycemic control in
insulin-treated Japanese patients with type 2 diabetes mellitus. Endocr J. 2013 Feb 2. [Epub ahead of print]
9. Arnolds S, Dellweg S, Clair J, Dain MP, Nauck MA, Rave K, Kapitza C. Further improvement in postprandial glucose control with
addition of exenatide or sitagliptin tocombination therapy with insulin glargine and metformin: a proof-of-concept study. Diabetes Care. 2010
33(7):1509-15.
10. Taneda K et al.The investigation of Add-on effect of sitagliptin onto the type 2 diabetes patients with insulin therapy. Journal of the Japan
Diabetes Society. 56:201:2013.(Japanese without English abstract)
11. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes:scientific review. JAMA. 2002;287:360–72.
12. Riddle MC, Forst T, Aronson R, Sauque-Reyna L, Souhami E, Silvestre L, Ping L, Rosenstock J. Adding Once-Daily Lixisenatide for
Type 2 Diabetes Inadequately Controlled With Newly Initiated and Continuously Titrated Basal Insulin Glargine: A 24-Week, Randomized,
Placebo-Controlled Study (GETGOAL-DUO-1). Diabetes Care. 2013 Apr 5. : (Apr 5. [Epub ahead of print],
13. Schemithner G et al. Canagliflozin Compared With Sitagliptin for Patients
With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control
With Metformin Plus Sulfonylurea: A 52-week randomized trial. Diabetes Care. 2013 Apr 5. [Epub ahead of print]
14. List JF, Woo V, Morales E, Tang W, Fiedorek FT.Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes
Care. 2009;32(4):650-7.
15. Mori Y, Taniguchi Y, Miyazaki S, Yokoyama J, Utsunomiya K. Effects of add-on treatment with sitagliptin on narrowing the range of
glucose fluctuations in Japanese type 2 diabetes patients receiving insulin therapy. Diabetes Technol Ther. 2013 Mar;15(3):237-40. doi:
10.1089/dia.2012.0214. Epub 2013 Feb 12.