JAPI VOL. 53 MAY 2005 www.japi.

org 441
Original Article
Efficacy of Once- or Twice-daily Extended Release
Metformin Compared with Thrice-daily Immediate
Release Metformin in Type 2 Diabetes Mellitus
A Bhansali, SR Masoodi
Abstract
Background : The extended-release formulation of metformin (MXR) prolongs drug absorption in the upper
gastrointestinal tract and permits once-daily dosing in patients with type 2 diabetes mellitus (T2DM). This
newer formulation may enhance patient compliance with oral therapy compared to conventional immediate-
release metformin (MIR) in T2DM.
Objectives : To analyse whether a switch from thrice daily MIR to once or twice daily MXR would achieve
comparable degrees of glycemic control in patients with type 2 diabetes mellitus (T2DM).
Methods : We conducted an open study of the efficacy and tolerability of MXR in 40 patients with T2DM who
had achieved moderate or good glycemic control with MIR alone or in combination with other
antihyperglycemic agents. After a lead in period of 3 months patients were switched over to a specific brand
of MIR at baseline (Visit 0). Patients were subsequently followed for 4 more visits. These visits were done
monthly, after taking MIR in a dose of 1-2 g/day (Visit 1); MXR as a single dose at dinner but 0.5g less than
baseline dose of MIR (Visit 2); MXR, 1-2 g/day as a single dose at bedtime, with strength same as that of
baseline dose of MIR (Visit 3); and MXR, 1-2 g/day in two divided doses keeping dose same as baseline MIR
(Visit 4). Glycemic control was assessed by a four-point glucose profile (fasting and three postprandial levels)
at each visit.
Results : At visit 2, when patients had been on 500 mg lesser dose of MXR for 1 month, glucose profile
worsened. However, glycemic control, at visit 3, returned to earlier levels when dose of MXR was increased
back to original dose. Overall the MXR formulation was well tolerated with minor gastrointestinal adverse
effects, reported by only 3 patients.
Conclusion : Patients with T2DM who had been receiving thrice-daily MIR achieved comparable glycemic
control when therapy was switched to once- or twice daily MXR at the same total daily dose.
reduces hepatic glucose overproduction, and peripheral
tissues (particularly skeletal muscle), where it enhances
glucose uptake.
4-9
Recent evidence suggests that
metformin exerts its anti-diabetic effects through
inhibition of complex 1 of the mitochondrial respiratory
chain system.
10
Pharmacokinetic studies of the conventional
immediate-release formulation of metformin (MIR) have
shown that this agent is absorbed into the upper
gastrointestinal tract, with only minimal absorption
occurring in the colon.
11
An extended-release (MXR)
formulation was approved in October 2000 to allow
once-daily dosing. This newer formulation releases the
active drug through hydrated polymers, which expand
after uptake of fluid. This prolongs gastric residence time,
which produces slower drug absorption in the upper
gastrointestinal tract and allows once-daily dosing.
12
To
analyse whether a switch from thrice daily MIR to once
Department of Endocrinology and Metabolism, Postgraduate
Institute of Medical Education and Research, Chandigarh,
India.
Received : 7.4.2004; Revised: 25.12.2004;Accepted : 28.3.2005
INTRODUCTION
T
he oral antihyperglycemic agent metformin is well
established as a therapeutic agent in patients with
type-2 diabetes mellitus (T2DM).
1,2
Metformin has been
available in Europe since the 1950s but was not
approved by the US Food and Drug Administration until
December 30, 1994.
3
It is indicated for the treatment
T2DM as an adjunct to diet and exercise, either as a
single oral agent or in combination with sulfonylureas,
alpha-glucosidase inhibitors, or insulin.
4
Metformin
produces clinically significant improvements in
glycemic control in patients with T2DM through its
insulin-sensitizing actions on both the liver, where it
442 www.japi.org JAPI VOL. 53 MAY 2005
or twice daily MXR would achieve comparable degrees
of glycemic control in patients with T2DM, we conducted
a study of the efficacy and tolerability of MXR in patients
with T2DM who had achieved moderate or good
glycemic control with MIR alone or in combination with
other antihyperglycemic agents.
MATERIAL AND METHODS
We conducted a clinical trial involving 50 patients
with T2DM who were on at least on one gram of MIR
with or without other antihyperglycemic agents.
Eligibility criteria included an age of at least 40 years, a
body mass index (the weight in kilograms divided by
the square of the height in meters) of 20 or higher, HbA1c
of 8.5% and a fasting capillary glucose of 120 mg/dl.
Patients were required to be free of symptomatic
T2DM, significant renal dysfunction (serum creatinine
level >1.5 mg/dL for men, >1.4 mg/dL for women),
hepatic dysfunction, congestive heart failure, major
psychiatric disorders, alcohol and/or substance abuse,
seizure disorders, or a history of malignancy or steroid
intake. Pregnant or breast-feeding women were excluded
from the study. Patients could be receiving long-term
insulin therapy or any other antihyperglycemic therapy
apart from MIR. After a lead-in period of 3 months,
during which patients were on American Diabetes
Association weight-maintenance diet and 1000 to 2000
mg of MIR (in 2 or 3 divided doses), all patients who
were at least 80% compliant with drug treatment (as
determined by tablet counts and interviews) were entered
in the study. The institutional review board approved
the protocol, and all participants gave written informed
consent.
At the start of trial (Visit 0), all eligible patients with
T2DM were switched over to one particular brand of
MIR (Glycomet, USV India Ltd.) while the dose of MIR
and other hypoglycemic agents were kept the same.
Baseline measurements included a four point glucose
profile (fasting, 2-h post-breakfast, post-lunch and post-
dinner glucose levels), HbA1c, serum lipid profile (total
cholesterol [TC], low-density lipoprotein cholesterol
[LDL-C], high-density lipoprotein cholesterol [HDL-C],
and triglyceride [Tg] concentrations), standard
laboratory tests (hematology, serum chemistry profile,
urinalysis), and electrocardiography (ECG). A record of
body weight, blood pressure and other vital signs was
maintained. After one month (Visit 1) all subjects were
assessed and then switched over to 500 mg lesser dose
of MXR (Glycomet SR

) which was given in the form of a

single dose after dinner whereas the other
antihyperglycemic agents were continued (Fig. 1).
Patients were subsequently called for 3 more visits at
monthly intervals as shown in Figure 1. Where the total
dose of MXR was 1500mg/day, 500 mg were given after
breakfast and 1000 mg of MXR given after dinner. During
reassessment, at each visit, patients were particularly
Fig. 1 : Algorithm showing study protocol
asked about any possible new side-effects in addition to
change in dosage schedule as per protocol. At each visit
four-point blood glucose estimation was done. Ten
patients were excluded from the study which included
7 patients who did not follow till end of study, 2 who
had poor compliance and one who discontinued MXR
because of skin rash. The data from remaining 40 subjects
was analysed for results. The baseline characteristics of
10 excluded patients were not significantly different
from those of study subjects.
Capillary blood glucose was measured with Glucose
Monitor (Advantage, Nicholas Piramal India Ltd.) based
on glucose oxidase method. Standardization of the
equipment was frequently done with the help of quality
controls of known concentrations provided with the
instrument. Fasting serum triglycerides, total cholesterol
and HDL cholesterol were measured with commercially
available standardized kits (Boehringer Ingelheim,
Germany), and low density lipoprotein cholesterol was
calculated according to the Friedewald formula.
13
HbA1c
was measured by calorimetric method. All fasting
estimations were conducted after a minimum fast of 8
hours. Compliance was assessed by reviewing the tablet
counts conducted at each study visit. Additionally,
patients were asked to confirm their compliance with
therapy at each visit. Acceptable compliance was defined
as >80% of expected study drug consumption.
Statistical Analysis: Statistical Package for Social
Sciences (SPSS) for windows (Release 10.0.1, 1999) from
SPSS Inc. Chicago IL was used for data analysis. Efficacy
of the drug was assessed by comparing the mean change
in four point glucose profile at each visit and HbA1c at
the end of study period by using Wilcoxon Signed Ranks
Test. A P value of <0.05 was taken as statistically
JAPI VOL. 53 MAY 2005 www.japi.org 443
significant.
RESULTS
The demographic and baseline clinical characteristics
of study subjects are summarized in Table 1. Age of the
patients ranged from 40 to 74 years with 12 (30%)
patients having age of 65 years or more. Duration of
diabetes ranged from 3 months to 22 years with 23 (58%)
having diabetes of 10 years duration or more. Majority
of patients were obese; 22 (55%) had a BMI of 25 or more.
History of hypertension was observed in 31 (77.5%) with
45% having a BP of 140/90 mmHg or more. Of all 40
patients, 33 (82.5%) were on other antihyperglycemic
agents which included insulin in 10 (25%) patients and
sulfonylureas in 23 (57.5%). Of 10 patients on insulin,
two were also on 15 mg/d of pioglitazone in addition.
Sulfonylureas used were glipizide (3 patients),
glimepiride (9 patients) and gliclazide (11 patients).
Initial assessment revealed peripheral neuropathy in 30
(75%), retinopathy in 16 (40%), nephropathy in 10 (25%),
coronary artery disease (CAD) in 4 (10%), and previous
stroke in 2 (5%). Of 16 patients with retinopathy, 10 had
proliferative retinopathy. Nine patients had a proteinuria
of 300 mg per 24 hours. Majority of patients had a fair
control of diabetes with 20 (50%) having an HbA1c of
7% or less.
Figure 2 shows fasting, post-breakfast, post-lunch and
post-dinner glucose profile of the study subjects at visits
1, 2, 3 and 4. Fasting glucose was <120 mg /dl in 80%,
63%, 73% and 70%, and mean postprandial glucose was
<180 mg/dl in 90%, 75%, 73% and 90% at visits 1, 2, 3
and 4 respectively though these differences were not
statistically significant. Table 2 shows comparative blood
glucose levels with different metformin regimen used in
one monthly sequence. As is evident from the table, mean
levels of both fasting as well postprandial glucose levels
increased significantly after patients were switched to
Fig. 2 : Fasting, post-breakfast, post-lunch and post-dinner glucose
profile of the study subjects
Table 1 : Baseline characteristics of the study population
Characteristic Value
Mean age, y 57.3 (10.2)*
Mean duration of diabetes, y 10.3 (6.5)
Mean BMI, Kg/m
2
25.6 (3.0)
Mean Systolic BP, mmHg 134.6 (19.2)
Mean Diastolic BP, mmHg 75.4 (8.6)
Mean HbA1c, % 6.9 (0.9)
Mean fasting glucose, mg/dl 103 (15)
Mean postprandial glucose, mg/dl 148 (31)
Post-Breakfast 161 (40)
Post-Lunch 137 (38)
Post-Dinner 147 (32)
Mean creatinine, mg/dl 0.9 (0.2)
Lipid profile, mg/dl
Mean TC 181 (27)
Mean LDL-C 114 (23)
Mean HDL-C 44 (8)
Mean Tg 117 (35)
BMI : Body mass index; TC : Total cholesterol; LDL-C : Low-
density lipoprotein cholesterol; HDL-C : High-density lipoprotein
cholesterol; Tg : triglycerides; * Figures in parenthesis indicate
SD
Table 2 : Mean fasting and postprandial glucose levels with 4 different regimen of metformin, each prescribed for one
month
Mean* Mean Mean Mean Mean
fasting post-breakfast post-lunch post-dinner postprandial
glucose glucose glucose glucose glucose
Visit 1 102 (20) 149 (40) 130 (44) 138 (39) 139 (33)
Visit 2 114 (31) 165 (45) 154 (47) 161 (57) 160 (43)
P=0. 008

P=0. 009

P=0. 003

P=0. 020

P=0. 001

Visit 3 110 (25) 158 (43) 151 (47) 138 (33) 149 (33)
P=0. 067 P=0. 159 P=0. 012

P=0. 967 P=0. 065

Visit 4 109 (20) 159 (49) 138 (31) 128 (31) 142 (30)
P=0. 029

P=0.111 P=0. 076 P=0. 264 P=0. 289

* mg/dl (SD),

significant vs. Visit 1. Visits were monthly, after taking MIR (Glycomet ) in a dose of 1-2 g/day (Visit 1); MXR with
dose 0.5 g less than baseline dose of MIR (Visit 2); MXR, 1-2 g/day with dose same as baseline MIR (Visit 3); and MXR, 1-2 g/day in
two divided doses with dose same as baseline MIR (Visit 4)
444 www.japi.org JAPI VOL. 53 MAY 2005
MXR when the dose was 500 mg lesser than prior used
dose of MIR. However, glucose profile was again
comparable to baseline (except post-lunch glucose) when
dose of MXR was increased back to original dose of MIR
after 1 month. At visit 4, when patients were on two-
split doses of MXR for 1 month, mean fasting glucose
was 10920 mg/dl compared to baseline value of 10220
(P=0.029) but all postprandial values were comparable
to baseline values of visit 1. Mean HbA1c done after 3
months of MXR was 6.3% compared to baseline HbA1c
of 6.9% with MIR (P=0.008). Mean weight at the end of 3
months of MXR was 68.710.2 as compared to 69.610.8
kg at baseline (P=0.020). Lipid profile after 3 months of
MXR including Mean TC (18229 mg/dl), LDL-C
(11326 g/dl), HDL-C (458 mg/dl) and Tg (11955 mg/
dl) was not significantly different from that of baseline.
There were not many new side effects with any regimen
of MXR; two patients complained of diarrhea and one
had loss of appetite and flatulence that settled
spontaneously. Only one patient required reduction in
insulin doses due to minor hypoglycemic episodes. No
patient in the trial required medical assistance to manage
hypoglycemia.
DISCUSSION
We conducted this study to determine the efficacy and
tolerability of extended release metformin (MXR) in
patients with T2DM who had achieved moderate or good
glycemic control with immediate release metformin
(MIR) alone or in combination with other
antihyperglycemic agents. In this relatively small group
of patients with T2DM, MXR and MIR had nearly
identical efficacy in reducing plasma glucose
concentrations. Our data suggest that MXR is more
convenient and well tolerated with insignificant rates
of adverse gastrointestinal adverse reactions.
Metformin is a biguanide that has been used
worldwide for the treatment of the T2DM for last 4
decades. It has been used increasingly as a first-line
agent for the treatment of T2DM, both as monotherapy
and as a component of combination regimens.
l,2
It
improves glycemic control by enhancing insulin
sensitivity in liver and muscle. It is not associated with
hypoglycemia. Improved metabolic control with
metformin does not cause weight gain and may lead to
weight loss. Metformin also has beneficial effects on
several cardiovascular risk factors such as dyslipidemia,
elevated plasma plasminogen activator inhibitor, other
fibrinolytic abnormalities, and hyperinsulinaemia and
insulin resistance.
14
Metformin is not metabolized by the
liver and excreted intact in urine. Elimination is
characterized by a rapid initial phase during which
~90% appears in the urine within ~ 812 h and a slower
elimination phase with a half-life of ~ 1220 h.
15,16
Metformin is generally given in divided doses two to
three times a day. The usual starting dose is 500 mg
twice daily. The dose is increased or decreased by 250
500 mg/d every 2 weeks until the desired level of
glycemic control is achieved or a maximum dose of 2000
mg/d is reached.
17
Until recently, the conventional MIR
formulation administered twice or thrice daily has been
used as first-line therapy, but this formulation may be
less than optimal in terms of patient compliance with
daily therapy. Taking into consideration its importance
in therapeutics and its pharmacodynamic advantages
over other agents, the sustained release preparation of
metformin not only should offer improved patients
compliance but also might improve the pathophysiology
of the disease.
Our study was designed to assess glycemic control,
as measured by change in HbA1c from baseline to week
12, after a switch from MIR to MXR. The design of this
study was also to determine tolerability of a single dose
of MXR given at bedtime versus two divided dosed of
MXR It is understandable that a monthly fructosamine
estimation would have been a better index of glycemic
control when we changed dosage schedule of MXR.
However, we do not consider this a serious limitation of
the study as we wanted to determine mainly the effect
on tolerability when we changed the dosage schedule of
MXR. Patients enrolled in the study had established
T2DM, an HbA1c value <8.5% while receiving MIR 1000
to 2000 mg per day, BID or TID, for >12 weeks, and a
mean fasting glucose of less than 120 mg/dL. Patients
when switched to MXR 1000 or 1500 mg once daily
achieved indices of glycemic control that were
comparable to those of patients who continued MIR
therapy. However, when MXR was given 500 mg lesser
at visit 1 than earlier dose of MIR, the glycemic control
worsened suggesting that switching over to MXR offers
only convenience but not dose reduction. Monthly
changes in dose schedule were done on the assumption
that maximum effect of any metformin regimen would
occur by 2 weeks.
Persistence with medications is a key element in
effective management of any chronic disease, and this is
particularly important in diabetes. A product that has to
be taken once daily should enhance administration
convenience for the patient and may offer persistence
advantages. Research on combination products in
diabetes
18,19
has shown that patients who receive a single
treatment are more adherent to therapy than patients
who take more complex regimens. By analogy, the MXR
formulation could be expected to enhance patient
compliance and persistence
20
and, by extension, glycemic
control and clinical outcomes.
Although the current study did not examine long-
term safety, concern has been raised based on increase
in weight with good glycemic control with any
hypoglycemic therapy. After 3 months of MXR the mean
weight in our patients decreased significantly by 0.9 Kg
from the baseline. This happened in spite of a decrease
in HbA1c by 0.6% (P=0.008) at the end of 3 months.
JAPI VOL. 53 MAY 2005 www.japi.org 445
Whether improvement in HbA1c was as a result of MXR
or a better compliance because of constant medical
supervision can not be determined with certainty.
In summary, once- or twice daily extended release
formulation of metformin tablets provides comparable
efficacy in patients with T2DM receiving thrice daily
formulation of conventional, immediate release
metformin. Therapy with MXR offers patients the benefit
of having to take lesser number of tablets with fewer GI
adverse events. Therefore, MXR is a safe and effective
choice as a once-daily therapy in patients with T2DM.
Acknowledgements
We acknowledge with gratitude the support we
received from USV India Ltd. in carrying out this study
whose brand Glycomet and Glycomet SR was used in
the study.
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Announcement
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