26 Journal of The Association of Physicians of India Vol.

63 December 2015

Original Article

Treatment of Type 2 Diabetes with a Breakable

Extended Release Gliclazide Formulation in
Primary Care: The Xrise Study
V Mohan1, V Chopra2, D Sanyal3, S Jain4, J Jayaprakashsai5

Abstract Editorial Viewpoint

Objective: This study examines whether a new, scored and breakable Breakable gliclzide XR
once daily gliclazide tablet formulation, gliclazide XR 60 mg, that enables is targeted to improve
a simple 2-steps titration, can improve glycemic control rates in the patient compliance in a
community. simple 2-st ep t it r a t i o n
targeted towards primary
Methods: In a prospective multicenter study of 4 months duration,
care setting of urban
organised in the primary care setting of urban India, type 2 diabetes
India.
patients, uncontrolled with diet alone or metformin monotherapy,
received 1 (60 mg), 1 (90 mg), or 2 (120 mg) tablets of gliclazide XR 60 I t wa s f o u n d e f f e c t i ve
in monotherapy as
mg to achieve a target fasting plasma glucose of 126 mg/dl, or HbA1c
well as with metformin
of 7%. The primary outcome was the frequency of patients achieving
combination.
glycemic control.
Results: Two hundred eleven investigators recruited 679 patients patients receiving hypoglycaemic
distributed throughout India. On intention to treat analysis, the number medication, nearly 80% are treated
(%, 95% confidence interval, CI) of patients achieving glycemic control with oral hypoglycaemic agents
was, 526 (81.9, 78.8 to 84.6); with gliclazide XR 60 mg 1 tablet, 285 (42.0, (OHA) alone, and only about a
38.3 to 45.7); 1 tablets, 143 (21.1, 18.2 to 24.3); and 2 tablets, 98 (14.4, third achieve HbA1c levels of less
12.0 to 17.3). Hypoglycaemic episodes were reported by 27 (4.0, 2.8 to 5.7) than 7%. 3
patients. Mean (95% CI) FPG decreased by 78.3 (73.9 to 82.7, P<0.01) mg/ Important reasons for this
dl; with 1 tablet gliclazide XR 60 mg, by 66.0 (61.1 to 70.9, P<0.01) mg/dl; low rate of glycemic control are
1- tablets, by 80.1 (71.2 to 88.5, P<0.01) mg/dl; and 2 tablets, by 106.5 inadequate compliance with OHA
(93.4 to 119.5, P<0.01) mg/dl. HbA1c decreased by 1.5 (1.3 to 1.5, P<0.01). that require multiple daily dosage,
Conclusion: In primary care, once daily, breakable extended release and hypoglycaemia. It has been
gliclazide XR 60 mg, with a simple two step titration to administer reported that in type 2 diabetic
maximum recommended dosage is effective in achieving short term patients who change from a
glycemic control with a low frequency of hypoglycaemia, in monotherapy multiple daily dose, to a once daily
or in combination with metformin. OHA formulation, compliance
increases by 23%, and that this is
reflected in lower HbA1c levels. 4
The ADVANCE study assessed a
hypoglycaemic treatment regimen
Background that includes exercise, control of
based on once daily gliclazide
diet, blood sugar, blood pressure,

A ccording to the ICMR INDIAB MR, as monotherapy in untreated

and dyslipidemia. Community
study, there are an estimated patients, or as combination
surveys suggest that among
62 million patients with diabetes in treatment in patients uncontrolled
India. 1 These numbers are expected
to increase to over 100 million by 1
Dr. Mohans Diabetes Specialities Centre andMadras Diabetes Research Foundation, Chennai, Tamil Nadu;
2030. 2 The majority are treated 2
Hashu Advani Medical Centre, Mumbai, Maharashtra; 3KPC Medical College, Kolkata, West Bengal; 4Diabetes,
by physicians in the setting of Thyroid and Women Health Clinic, Ghaziabad, Uttar Pradesh; 5123 Diabetes Hospital, Hyderabad, Telangana
Received: 26.09.2014; Revised: 12.01.2015; Accepted: 14.01.2015
primary care, who adopt a strategy
 Journal of The Association of Physicians of India Vol. 63 December 2015 27

Table 1: Baseline characteristics of gliclazide MR would translate into was allowed at the discretion of
type 2 diabetic patients, a greater frequency of patients the physician. All medications
untreated or uncontrolled achieving glycemic control were purchased by patients from
with metformin under conditions of primary care the market. Patients were followed
N=679 practice. Since then, a new once up and reassessed after 15, 30,
Demographic characteristics daily gliclazide tablet formulation, 60, 90 and 120 days of treatment.
Age (years) 52.2 10.9 gliclazide XR 60 mg that is scored At each follow-up visit, FPG and
Male 435 (64.1%) and breakable into identical 30 mg blood pressure were measured, and
Female 244 (35.9%) halves has been introduced. patients asked about the frequency
Duration of diabetes (yrs) 4.1 4.1
The objectives of this study were of hypoglycaemic episodes and
Diabetes treatment status
to examine the clinical, biochemical, other side effects since the previous
Untreated, uncontrolled 451 (66.4%) visit. Compliance was assessed
on diet
and adverse effects of gliclazide XR
60 mg as monotherapy in untreated by recording the number of days
Uncontrolled on 228 (33.6%)
patients, or as combination overall hypoglycaemic treatment
metformin
Current smoker 123 (18.1%) treatment in patients uncontrolled metformin and gliclazide XR 60 mg
with metformin in the primary care was missed since the previous visit.
Family history of diabetes 343 (50.5%)
Associated disease setting of India, when titrated in The dose of gliclazide XR 60 mg
Hypertension 156 (23%) three steps (60, 90 and 120 mg), to could be titrated, at the discretion
Coronary Artery Disease 2 (0.3%)
achieve a target FPG of 126 mg/dl of the investigator, to 90 mg (1 +
or HbA1c of 7%. tablet, by breaking the scored
Dyslipidemia 53 (7.8%)
tablet) at day 30, and 120 mg (2
Nephropathy 1 (0.1%) Patients and Methods tablets) at day 60, to achieve a
Associated treatment
FPG of less than 126 mg/dl or
ACEIs 63 (9.3%) Selection of Study Investigators
closest to it, consistent with the
ARBs 67 (9.9%) Primary care physicians
Beta-blockers 25 (3.7%)
clinical condition of the patient.
experienced in the management of Biochemical tests, including HbA1c,
Calcium antagonists 45 (6.6%) diabetes with adequate clinical and done at baseline were repeated at
Statin 136 (20%) laboratory facilities, from different the end of the study at 120 days. (up
Body mass index 27.1 8.4 parts of India were considered. Of titration was based on FPG, which
Blood pressure (mm Hg) these, those who accepted the study
Systolic 138 17
was measured at each visit)
protocol were invited to participate
Diastolic 87 10 Statistical Analysis
in the study.
Laboratory parameters The primary outcomes were
Selection of Patients
FPG (mm/dl) 193 58 the number of patients achieving
HbA1c (%) 8.8 1.1 During the study period, glycemic control, defined as a FPG
Plasma lipids (mg/dl) investigators identified consecutive equal to or less than 126 mg/dl or
Total cholesterol 213 60 type 2 diabetic outpatients of HbA1c equal to or less than 7% at
Total triglycerides 181 66 any age and either sex, who the end of 120 days, on intention to
LDL cholesterol 114 31 were receiving diet alone, or treat analysis, and mean changes
HDL cholesterol 47 22 metformin monotherapy, with in FPG and HbA1c from baseline
Serum creatinine (mg/dl) 1.1 0.4 a fasting blood sugar (FPG) of after treatment with gliclazide XR
ACEI: Angiotensin converting enzyme more than 126 mg/dl. Of these, 60 mg for 120 days. Other outcomes
inhibitors; ARB: Angiotensin receptor patients with no contraindication were the mean change in plasma
blockers; FPG: Fasting plasma glucose t o a s u l p h o n yl u r e a , o r k n o w n lipids, frequency of hypoglycaemic
All values mean SD, nos. (%) hypersensitivity to gliclazide were episodes, and compliance with
with metformin. Gliclazide MR selected. gliclazide XR 60 mg. Changes in
was incrementally titrated up to Study Design, Assessments and Follow continuous variables were tested for
120 mg, to achieve a target HbA1c Up significance by the standard error
level of 6.5%. There was significant After giving their written of difference in means. Categorical
reduction in composite micro and informed consent, patients data were expressed as percentages
macrovascular risk, with a very we r e a s s e s s e d a t b a s e l i n e f o r with their 95% confidence intervals
low frequency of hypoglycaemia. 5 demographic, clinical, treatment, (CI). Significance was defined as a
H o we ve r , i t i s n o t c l e a r f r o m and biochemical characteristics p value of less than 0.05.
these results, based on a strict shown in Table 1. They were then
adherence to the randomized prescribed 60 mg (1 tablet) of Results
protocol, whether the expected gliclazide XR 60 mg to be taken
The 211 investigators distributed
improvement in compliance and once a day after breakfast.
in 51 Indian cities, recruited 679 type
less hypoglycaemia with once daily Treatment of associated disease
28 Journal of The Association of Physicians of India Vol. 63 December 2015
90%
68%
45%
23%
0%
60 mg (1 Tab) 90 mg (1 Tab)
Fig. 1: Frequency of patients with type 2 diabetes
requiring different dosage strengths of gliclazide
XR 60 mg to achieve glycemic control (FPG <126
mg/dl or HbA1c <7%)
2 diabetic patients uncontrolled
with diet alone or metformin
monotherapy. At baseline (Table 1),
64.1% were males with a mean age
of 52.2 years, and type 2 diabetes of
4.1 years duration. Of these, 66.4%
had received diet alone, and 33.6
metformin monotherapy. Mean
FPG was 192.6 mg/dl and HbA1c
8.2%. A family history of diabetes
was present in 50.5%, a history of
smoking in 18.1%, hypertension
23% and dyslipidemia 7.8%. ACE
or ARBs were being administered
to 19.2% and 10.3% received other
antihypertensive and statins 20%.
Mean body mass index was 27.1
kg/m 2, and blood pressure 138/87
mmHg. During the 120 days study,
48 (7.1%) patients were lost to
follow up.
On intention to treat analysis
(Figure 1), the number (%, 95%
confidence interval, CI) of patients
achieving a FPG of less than 126
mg/dl, or HbA1c of less than 7%
was, 526 (81.9, 78.8 to 84.6); for
those receiving treatment with
gliclazide XR 60 mg 1 tablet 285
(42.0, 38.3 to 45.7); 1 tablets, 143
(21.1, 18.2 to 24.3); and 2 tablets,
98 (14.4, 12.0 to 17.3). In subgroup
analysis, patients achieving a FPG
of less than 126 mg/dl, or HbA1c
of less than 7% was, among those
receiving gliclazide XR 60 mg
monotherapy, 362 (80.3, 76.4 to
83.7); and gliclazide XR 60 mg plus
metformin, 194 (85.1, 79.9 to 89.1).
After 120 days of treatment,
me a n ( 9 5 % C I ) F PG d ec reas ed
by 78.3 (73.9 to 82.7, P<0.01)
0.
-27.5
-55.
mg/dl
-82.5
-110.
-137.5
120 mg (2 Tab) All (n=679)
Fig. 2: Decrease in FPG after treatment with gliclazide XR
60 mg in patients with type 2 diabetes
mg/dl. In subgroup analysis,
the decrease was, among those
receiving gliclazide XR 60 mg
monotherapy, 84.2 (78.0 to 90.4,
P<0.01) mg/dl; gliclazide XR 60 mg
plus metformin, 67.6 (62.4 to 72.8,
P<0.01) mg/dl; 1 tablet gliclazide
XR 60 mg, 66.0 (61.1 to 70.9, P<0.01)
mg/dl; 1 tablets, 80.1 (71.2 to 88.5,
P<0.01) mg/dl; and 2 tablets, 106.5
(93.4 to 119.5, P<0.01) mg/dl (Figure
2). HbA1c decreased by 1.5% (1.3 to
1.5, P<0.01).
The number (%, 95% CI)
of patients complaining of
hypoglycaemic episodes was
27(4.0, 2.8 to 5.7) during the 120
days of treatment with gliclazide
XR 60 mg. No other side effects
were reported.
Mean (95% CI) total cholesterol
decreased by 24.9 (24.9, 21.8 to
28.0, P< 0.01) mg/dl; low density
lipoprotein cholesterol by 12.6
(10.9 to 14.4, P< 0.01) mg/dl; and
total triglycerides by 31.3 (26.0 to
36.7, P< 0.01) mg/dl; and serum
creatinine, 0.09 (0.07 to 0.1, P<0.01)
mg/dl. The mean increase of 0.71
mg/dl in high-density lipoprotein
was not significant. Mean (95% CI)
number of days during the 120 days
study when study medication was
not taken, was 0.6 (0.3 to 0.8).
Discussion
In the setting of primary care in
India, the addition of once daily
gliclazide XR 60 mg to the treatment
regimen of type 2 diabetic patients
uncontrolled on diet or metformin
-66
-80.1 -78.3
-106.5
60 mg (1 Tab) 90 mg (1 Tab) 120 mg (2 Tab) All (n=679)
for 120 days resulted in several
benefits. About 8 out of 10 patients
were ab le t o achieve gl yc emi c
control both in monotherapy and
in combination with metformin.
Average FPG decreased by more
than a third, and HbA1c by about
a fifth from baseline. Only four
out of 100 patients complained
of mild symptoms suggestive of
hypoglycaemia, that did not lead
to withdrawal of treatment. No
other side effects were reported,
and the treatment did not adversely
influence plasma lipids or serum
creatinine, in fact it decreased
the total cholesterol, low density
lipoprotein and total triglycerides.
Compliance with once daily
gliclazide XR 60 mg with or without
m e t f o r m i n wa s h i g h , w i t h a n
average of less than a day missed,
out of the 4-month treatment.
The efficacy, safety, and
compliance of this new long acting,
once a day, breakable formulation,
gliclazide XR 60 mg in type 2
diabetic patients has not been
previously reported. However,
the observed reduction in HbA1c
of 1.5% is consistent with the
efficacy of sulphonylureas 6 . The
low frequency of hypoglycaemia
reported by patients is also
consistent with the previously
reported risk with gliclazide, as
being about half that of glimepiride
and glipizide. 7
In the context of urban India,
a survey among 20,666 randomly
selected households showed that,
among those with type 2 diabetes,

only 37% were under control. More
than 80% of patients were receiving
OHA and only 41% were compliant
with treatment. 3 Therefore, a key
strategy for improving control rates
in the community is to increase
patient compliance with OHA
medication.
In this respect, one measure
is to harness technology for the
development of OHA formulations
that are long acting with once
daily administration. This was
demonstrated in a systematic review
of adherence with medications for
type 2 diabetes that showed a
23% increase in compliance when
patients change from a multiple
daily dose to a once daily OHA
formulation. 4 Another measure that
could improve compliance, and is
related to OHA formulation, is to
reduce the number of tablets the
physician needs to prescribe, and
patient needs to take, especially
during step-wise up titration of
dosage. This can be achieved by
developing tablet formulations that
retain their long acting once daily
characteristic, but are breakable
into identical halves.
Gliclazide XR 60 mg was
developed in pursuance of this
goal, and is presently the only
long acting once daily OHA that
is scored and breakable into two
halves. The formulation is based
on a specially developed embedded
polymer mesh technology, by
which gliclazide granules of graded
size, individually enclosed in a
polymer of appropriate viscosity,
are distributed randomly in the
tablet. This enables each of the
broken halves to contain a 30 mg
dose that is accurate, reliable, and
with identical pharmacokinetic
characteristics.
These features may serve
to explain the combination of
acceptable efficacy, low risk of
Journal of The Association of Physicians of India Vol. 63 December 2015
hypoglycaemia, and near complete
compliance observed in this
study. Furthermore, the results
suggest that the successful risk
reduction treatment strategy of
the ADVANCE study, 5 based on
long acting gliclazide, titrated in
30 mg steps as monotherapy or
in addition to metformin, can be
easily applied to primary care (as
opposed to strict adherence to a
randomized protocol), with a high
degree of compliance and low risk
of hypoglycaemia.
The study has limitations. The
treatment was not compared with
other once daily sulphonylurea
formulations using a randomized
protocol. Since all drugs were
purchased by the patient, the
d i s p e n s i n g c h e m i s t m a y h a ve
changed the dose or brand of
prescribed medication, and the
measure of compliance may not be
entirely attributable to the study
treatments. At baseline, BMI of
patients was measured. However,
during the follow up weight was
not monitored, and the effect of
the study treatment on weight
gain could not be assessed. The
results are over the short term, and
the possible benefit over a longer
period is not known. However,
patients studied were recruited by
physicians distributed throughout
urban India, representing type
2 diabetes in primary care, and
the treatment was administered
under conditions of actual clinical
practice.
The results of this study suggest
that gliclazide XR 60 mg is effective
in achieving short-term glycemic
control with a low frequency of
hypoglycemia in monotherapy or in
combination with metformin. This
new, scored, breakable extended
release gliclazide XR 60 mg is a
useful new once daily treatment for
the management of type 2 diabetes
29
in primary care
Acknowledgement
Authors are thankful to Serdia
Pharmaceuticals (India) Pvt. Ltd.,
the manufacturers of Diamicron XR
60 mg for providing organizational
support to conduct the study. The
authors would also like to express
gratitude to all the participating
sites.
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