Artikel Penelitian

J Indon Med Assoc, Volum: 61, Nomor: 11, November 2011 429
Glycemic Control in
Switching Insulin-based Regimen Among
Type 2 Diabetic Patients
Pradana Soewondo, Imam Subekti
on behalf of INTERBASE Study Group
Department of Internal Medicine, Faculty of Medicine Universitas Indonesia/
Dr. Cipto Mangunkusumo Hospital, Jakarta
Abstract: Appropriate diet and physical activity, maintaining a healthy body weight and proper
control of diabetes using oral anti diabetic (OAD) in people with diabetes type 2 will help
reduce its complications. However, some advance diabetic cases need insulin-based regimen to
aggressively lower blood glucose level. Local data was insufficient to determine whether type 2
diabetes patients on insulin were indeed attaining glycemia goals. The aim of this study was to
assess the clinical response of type 2 diabetic patients who were switched to another insulin
regimen to achieve glycemic control. The study was performed as a non-interventional prospec-
tive disease registry that mirror real life management of these subjects after a 3 month follow up.
To assess the clinical response, we performed measurement of fasting blood glucose level, HbA1c,
waist circumference and body weight. One hundred and fifteen type 2 diabetes patients who
were already on insulin therapy with unsatisfactory control of glycaemia parameters were
admitted in this study of an actual clinical setting. Only 93 cases have been examined in a 3
month follow up. Premix, Short-acting and Intermediate-acting insulin were the most popular
insulin-based regimens that previously been prescribed, while basal analogue insulin is the
most common regimen for switching therapy. The newly prescribed insulin-based regimen showed
significant reduction of important glycaemia parameters such as fasting blood glucose level and
HbA1c. Serum blood glucose was decreased 61.76 mg/dL (p<0.001) and the level of HbA1c was
also decreased 1.39 unit (p<0.001). In addition, waist circumference was significantly reduced
for 0.70 cm (p=0.041). However, there was a slight increase of body weight althoughnot statis-
tically significant (p=0.389). We concluded that switching insulin-based regimen for unsatis-
factory although glycemic control patient gave the probability to improve clinical response. J
Indon Med Assoc. 2011;61:429-34.
Keywords: Type 2 diabetes, Indonesia, insulin-based, switching regimen, Glycemic control
J Indon Med Assoc, Volum: 61, Nomor: 11, November 2011 430
Kontrol Glikemik pada Penderita DM Tipe 2
dengan Perubahan Rejimen Insulin
Pradana Soewondo, Imam Subekti,
atas nama INTERBASE Study Group
Departemen Ilmu Penyakit Dalam, Fakultas Kedokteran Universitas Indonesia/
Rumah Sakit Umum Pusat Dr. Cipto Mangunkusumo, Jakarta
Abstrak: Kontrol diabetes secara rutin dengan mengatur diet dan aktivitas fisik, menjaga berat
badan ideal dan konsumsi obat hipoglikemia oral (OHO) diharapkan dapat menurunkan
komplikasi kronik Diabetes Melitus tipe 2. Meskipun demikian, sejumlah kasus diabetes yang
lanjut memerlukan terapi insulin untuk menurunkan kadar glukosa darah secara agresif. Data
penelitian yang ada di Indonesia masih kurang mencukupi untuk menggambarkan pencapaian
target glikemik pada pasien DM tipe 2 yang menggunakan insulin. Tujuan penelitian ini adalah
menilai respons klinis pasien DM tipe 2 dengan perubahan rejimen insulin untuk pencapaian
target glikemik. Penelitian ini menggunakan desain studi registri non-interventional, prospektif,
mencerminkan penanganan DM tipe 2 sehari-hari setelah terapi selama 3 bulan. Untuk menilai
respons klinis, dilakukan pemeriksaan kadar glukosa darah puasa, HbA1c, lingkar pinggang
dan berat badan. Seratus lima belas pasien DM tipe 2 yang telah menggunakan insulin namun
belum mencapai kontrol glikemik kemudian diubah jenis terapi insulinnya selama 3 bulan dalam
kondisi klinis sehari-hari. Hanya 93 kasus yang dapat dinilai selama 3 bulan terapi. Insulin
premix, kerja pendek dan kerja menengah merupakan jenis insulin yang terbanyak digunakan
sebelumnya, sedangkan insulin basal analog adalah insulin terbanyak yang digunakan dalam
perubahan terapi. Perubahan jenis insulin yang baru menunjukkan penurunan parameter glikemik
yang bermakna, yakni kadar glukosa darah puasa dan HbA1c. Penurunan glukosa darah mencapai
61,76 mg/dL (p<0,001) dan penurunan kadar HbA1c mencapai 1,39 unit (p<0,001). Lingkar
pinggang juga menurun secara bermakna sebanyak 0,70 cm (p=0,041), walaupun berat badan
sedikit meningkat yang secara statistik tidak bermakna (p=0,389). Dari penelitian ini dapat
disimpulkan bahwa perubahan jenis insulin untuk mencapai kontrol glikemik dapat memberikan
perbaikan respons klinis pada pasien DM tipe 2. J Indon Med Assoc. 2011;61:429-34.
Kata kunci: DM Tipe 2, Indonesia, terapi insulin, perubahan rejimen, kontrol glikemik
Introduction
Indonesia is entering the epidemiological transition
period. The incidence and prevalence of major communi-
cable diseases tend to decrease while the chronic degenera-
tive disorders starts to increase. The Household surveys of
Ministry of Health showed the changes in cause of death
among Indonesian community. The 1966 Household survey
still showed that communicable diseases were major killers,
while the latest Household survey of 2008 showed that
the degenerative disorders have surpassed to first in the
ranks.
1
Based on data from BPS-Statistics Indonesia in 2003,
the prevalence of diabetes in urban area was 14.7%, rural
area was 7.2% and the majority (>90%) belonged to type-2
diabetes. More than 50% of diabetes patients are undiag-
nosed and only 30% of them are well controlled. The control
of type 2 diabetes could consist of the diet adjustment, exer-
cise and prescription of OADs.
2,3
In some advanced diabetic cases, the aggressive lower-
ing of blood sugar levels to reach target are often achieved
using insulin-based regimen. The United Kingdom Prospec-
tive Diabetes Study (UKPDS) showed that intensive insulin
treatment can lower the morbidity and mortality of the dis-
ease by decreasing its chronic complications.
4-6
However,
there was insufficient local data to determine whether type 2
diabetes patients on insulin were indeed attaining glycemia
goals. In addition, information was also lacking about sub-
sequent therapy for insulinized type 2 diabetes patients with
unsatisfactory control of glycemia parameters.
The objectives of this study were to assess the level of
glycemic control in Indonesian type 2 diabetes patients us-
ing insulin, to assess the physician management patterns
towards uncontrolled type 2 diabetes patients who were on
insulin treatment and the response of patients after swit-
ching to other insulin regimen after a 3-month follow up in
actual clinical setting.
Glycemic Control in Switching Insulin-based Regimen Among Type 2 Diabetic Patients
Glycemic Control in Switching Insulin-based Regimen Among Type 2 Diabetic Patients
J Indon Med Assoc, Volum: 61, Nomor: 11, November 2011 431
Methods
This study was performed as a non-interventional pro-
spective disease registry that mirror real life management of
these subjects (purely for observational study). Nineteen
study centers from four provinces in Indonesia (Jakarta,
West Java, East Java and Bali) have reported 115 type 2
diabetic patients who were currently receiving insulin treat-
ment but still had uncontrolled glycemia parameter (HbA1c
> 8%, data from the DiabCare Asia 2008 study demonstrates
the mean of HbA1c achieved was 8.1%), whose physicians
had decided to change the current insulin regimen to a new
insulin regimen due to any reason, and were willing to sign
a informed consent form.
All Data Collection Forms (DCFs) were verified for ex-
istence and eligibility of patients, and for the presence of
informed consent. A Source Data Verification was performed
in 63% of the sites.
The quantitative variables were compared by an analy-
sis of the variance and Students paired t-test (for param-
eters measured before and after the treatment period). All
statistical tests have been performed using 2-tailed tests at
5% level of significance or with adjustment if needed.
Results
The diabetic cases were equally distributed among male
and female patients with an average age of 54 years (SD =
8.8 years). The majority of cases belonged to 50 60 years
age group. The average body mass index was 24.1 kg/m
and the waist circumference was 88.3 cm. The HbA1c and
fasting blood glucose level at baseline were particularly high
(Table 1).
As all of the cases are in unsatisfactory state of glycae-
mia control, most of them suffered from diabetic complica-
tions. Neuropathy is the most common complication with
67.8% of subject show neurological signs. The second most
Table 1. Characteristic of Subjects
Variable N (%) Mean or Median
Gender (n=115)
Male 56 (48.7)
Female 59 (51.3)
Age (n=114) 54.0 +/- 8.8
61 + yrs 18 (15.8)
50 - 60 yrs 59 (51.8)
< 50 yrs 37 (32.5)
Education (n=112)
Low 28 (25.0)
Middle 56 (50.0)
High 28 (25.0)
Previous insulin(s) (n=115)
Rapid-acting 10 (8.7)
Short-acting 40 (34.8)
Intermediate-acting 32 (27.8)
Basal analogue 9 (7.8)
Premix 31 (27.0)
Previous OAD(s) (n=115)
Glimepiride 21 (18.3)
Acarbose 22 (19.1)
Metformin 63 (54.8)
Gliquidone 7 (6.1)
Glibenclamide 14 (12.2)
Gliclazide 30 (26.1)
Glibenclamide/Metformin 5 (4.3)
Other 3 (2.6)
Type 2 diabetes history (yrs, n=93) 6.1 +/- 4.9
Body Mass Index (kg/m, n=115) 24.1 +/- 4.4
Waist circumference (cm, n=106) 88.3 +/- 12.3
Systolic blood pressure (mmHg, n=115) 132.5 +/- 18.0
Diastolic blood pressure (mmHg, n=115) 81.9 +/- 8.8
HbA1c (%, n=115) 10.0 +/- 1.8
Fasting blood glucose (mg/dl, n=108) 223 (43-501)
0 10 20 30 40 50 60 70 80
Per c ent
Dysl ipidemia
Hypert ension
Vascular
Nephr opat hy
Neur opat hy
Ret i nopat hy
common complication is retinopathy with 30.7%, followed
by vascular diseases and nephropathy with 26.1% and 23.5%
respectively. Dislipidemia and hypertension are the two con-
comitant conditions of diabetes. More than 71% of cases
Figure 1. Clinical Signs of Diabetics Complication
Glycemic Control in Switching Insulin-based Regimen Among Type 2 Diabetic Patients
J Indon Med Assoc, Volum: 61, Nomor: 11, November 2011 432
Table 2. Means and Standard Devisition of Daily Does of the Previous and Current Insulin Regimen
Type of Insulin Previous Insulin Current Insulin
Number Mean SD Mi n Max Number Mean SD Mi n Max
Long-acting insulin 6 22.7 12.8 8 42 80 18.1 9.5 8 40
Intermediate insulin 26 16.2 7.8 8 40 Nil
Short acting insulin 33 30.2 16.1 6 75 2 60 0 60 80
Rapid acting insulin 9 30.7 12.2 18 60 12 21.8 13 6 48
Premix insulin 25 22.5 10.4 8 50 12 22.8 5.2 14 34
0 10 20 30 40 50 60 70 80 90
Percent
Rapid-act ing
Basal analogue
Int ermediat e-act ing
Short -act ing
Premix
Pre New
Figure 2. Previous and Newly Prescribed Insulin-based Regimens
also suffered from dislipidemia and almost 48% have high
blood pressure (figure 1).
The most common prescribed insulin-based regimens
are short-acting (34%), followed by intermediate-acting
(27.8%) and premix (27%). Basal analogue (7.8%) and rapid-
acting (8.7%) were rarely prescribed as first line insulin-based
regimens. The daily dose administration of short- and rapid-
acting insulin was higher than other regimens (table 2). Know-
ing that these previously prescribed insulin regimens showed
unsatisfactory response of glycemia control, the doctors
agreed to switch to new insulin regimen.
The newly prescribed regimens are dominated with
basal analogue (85.2%) and only few patients were given
premix (13%) or rapid-acting Insulin (9.6%) (figure 2). The
daily dose administration of short-acting insulin was the
highest among insulin regimens (Table 2). After therapy was
changed, patients received either insulin alone or combina-
tion with OAD, depending on the new treatment. Approxi-
mately 20% of patients with basal analogue insulin received
only basal insulin during the study, while others received
combination therapy with OAD(s) (table 3). These patients
were followed up after a therapeutic period of 3 months.
Only 93 patients returned to the study centers and could be
examined.
After a 3 month period using newly prescribed insulin-
based regimen, there are significant improvements of some
Table 3. Distribution of Subjects According to Current Insu-
lin Regimen and Concomitant Oral Therapy (n=93)
Concomitant Current insulin regimen Total
Oral Therapy Gl argi ne Gl ul i si ne Premix
Glimepiride 11 0 0 11
Arcabose 10 0 0 10
Metformin 19 1 6 26
Gliquidone 8 1 0 9
Glibenclamide 3 0 2 5
Pioglitazone 1 0 0 1
Glibenclamide/ 5 1 0 6
Metformin
Gliclazide 4 0 3 7
Glipizide 1 0 0 1
No concomitant 16 0 1 17
oral therapy
Total 78 3 12 93
J Indon Med Assoc, Volum: 61, Nomor: 11, November 2011
Glycemic Control in Switching Insulin-based Regimen Among Type 2 Diabetic Patients
433
important glycemia parameters. Level of HbA1c decreased
from 9.83+1.71% to 8.44+1.85% (p<0.001), and fasting blood
glucose level also decreased from 227.88+86.92 mg/dL to
166.12+72.35 mg/dL (p<0.001).
The waist circumference decreased from 88.2+12.3 cm
to 87.5+11.9 cm (p=0.041), while body weight showed a gain
of 0.26 kg from 64.88+13.45 kg up to 65.15+12.54 kg although
not statistically significant (p=0.389).
Table 4 shows the distribution of the same parameters
based on their changes from baseline. HbA1c was improved
in 91.5% and fasting blood glucose in 78.3% of the patients.
The waist circumference showed a good response in 40.3%
of the cases and although a mean gain of 0.26 kg was seen
after a 3-month follow-up period, the body weight actually
decreased in 42.5% of the patients.
Table 4. Distribution of Changes in Glycemic Parameters,
Body Weight and Waist Circumference
Parameters Better off Stable Worse
HbA1c 91.5 % 0.0 % 8.5 %
Fasting Blood Glucose 78.3 % 1.2 % 20.5 %
Body weight 42.5 % 23.8 % 33.8 %
Waist circumference 40.3 % 32.5 % 27.3 %
Discussion
This assessment of the actual clinical setting consists
115 type 2 of diabetes patients who have been prescribed
insulin-based regimen with unsatisfactory glycemic control.
After switching to newly prescribed regimen, they were moni-
tored for 3 month period. As an actual clinical setting, this
study did not intervene with those who failed to visit health
facility for final assessment. There was 11.4% drop out rate
which could not be assessed.
All cases were in the unsatisfactory state of glycemic
control in which baseline of HbA1c and fasting blood glu-
cose were particularly high (table 1). These findings were
consistent with the inclusion criteria and might reflect pa-
tients low education regarding glycemic control. We can also
predict that all subjects in this study were already on their
late stage of diabetes with poor beta cell function.
Most of the patients already had diabetic complications,
which might be caused by the poorly controlled blood glu-
cose. Neuropathy was the most prevalent diabetic complica-
tion among subjects followed by retinopathy, vascular di-
seases and nephropathy, advanced diabetes usually is ac-
companied with other serious underlying health problems
that could heighten its risk.
Insulin-based regimens that have been previously pre-
scribed varied from one center to another. Regimens that
belong to short-acting insulin group were the most popular
among clinicians and were prescribed to 34% of diabetic
patients. Groups of intermediate-acting insulin and Premix
insulin were the second most common regimen used by dia-
betic patients, while Rapid-acting insulin group was rarely
prescribed. Though almost all of subjects were given OAD
as a combination with insulin, these 115 patients still did not
show satisfactory response to treatment and were switched
to different insulin-based regimen.
Short-acting insulin was the most popular regimen
among clinicians, which might be caused by its lower price.
Palmer et al
7
reported that although treatment with insulin
analogue was associated with decreased incidence of long
term complication and improved quality of life, it was associ-
ated with higher cost.
7-9
Aside from economical reason, the
availability of reguler insulin product is higher than ana-
logue. Intermediate-acting insulin was also commonly used
by the clinicians as a basal insulin because it is cheaper.
10-13
Premix insulin was also commonly prescribed because of its
relative convenience in dosing.
14
These patients did not
show satisfactory response to treatment. These findings
might be caused by many factors. Aside from the treatment
regimen, there were other factors, such as patient compli-
ance and adherence.
15
The newly prescribed insulin-based regimen was domi-
nated by basal analogue insulin group with 85.2% of type 2
diabetic patients used this specific regimen as their new treat-
ment. Premix group are still being used by 13% of subject,
followed by rapid-acting with 9.6%, while other type of regi-
men was not written in the new prescription. Unfortunately,
11.4% of subject failed to revisit the center after 3 month
follow up period. Since this assessment was intended as an
actual clinical setting, the investigator did not intervene by
contacting them. The final analysis was only implemented
for 93 subjects who completed the study.
The change to basal analogue insulin therapy was in
accordance with the diabetic treatment algorithm. Basal ana-
logue insulin regimen is preferable than other regimen be-
cause of its longer duration of action compared to other
insulin regimen and its convenience in once daily dosing.
Other than basal analogue insulin, we could also use premix
insulin as it can provide both basal analogue and prandial
insulin coverage.
14
By changing insulin-based treatment, there was signifi-
cant glycemia response that could be detected after 3 month
period. HbA1c was the most sensitive glycemia component
for this insulin change. Almost 92% of completed cases show
improvement of HbA1c with a reduction of 1.39%. HbA1c
measurement reflects the last 3 month glycemia condition
and it has been proven to be the best estimator for glycemic
control, compared to fasting blood glucose and other gly-
caemia parameters.
Fasting blood glucose also showed a very significant
response to the switching insulin regimen. More than 78%
of subjects experienced an average 61.76 milligram/dL re-
duction of fasting blood glucose after being switched to
other insulin regimen for a 3 month period. The waist circum-
ference as one of glycemia parameters also decreased sig-
Glycemic Control in Switching Insulin-based Regimen Among Type 2 Diabetic Patients
J Indon Med Assoc, Volum: 61, Nomor: 11, November 2011 434
nificantly with an average of 0.70 cm. There is an interesting
phenomenon that almost 43% of subject showed good re-
sponse in reducing body weight, but in overall there was an
average of 0.26 kg weight gain experienced by type 2 diabe-
tes patients at the 3 month follow up visit, though it was not
statistically significant. The good response of important gly-
caemia parameters to the changing of insulin-based regimen
might reflects the probability of treatment saturation for spe-
cific regimen due to complex biological processes. The satu-
rated regimen needs to be replaced with other regimen to
enable better response in type 2 diabetes patient.
Conclusion
It was concluded that despite the prescription of insu-
lin-based regimens combined with OAD for type 2 diabetes
patients, there were still cases of unsatisfactory glycemic
control that need medification of insulin regimen. Medification
of insulin-based regimen gave better result for the type 2
diabetes patients.
Acknowledgement
The authors are especially grateful to all investigators
who have participated in INTERBASE study: Dr. Sulistiawaty
Ohnio, SpPD, Dr. Maxwadi Maas, SpPD, Dr. Eliana Taufik,
SpPD, Dr. Asep Saepul Rohmat, SpPD, Dr. Arief Wibowo,
SpPD, Dr. Anton Cahaya, Dr. Sutji Muljati, Dr. Mery Harita,
Dr. Hadi Sunaryo, SpPD, Dr. Maria Meilitasari Harlim, SpPD,
Dr. R. Eka, SpPD, Dr. Nunik K.Kartikawati, Dr. Ishak S.Dinata,
SpPD, Dr. G. Wisito, SpPD, Dr. Agatha Maharani, SpPD, Dr.
Johannes Lusida, SpPD, Dr. Ratna Saraswati, SpPD, Dr. J. M.
Maitriya, SpPD
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