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HEALTHCARE MANAGEMENT

New prolonged-release metformin improves


gastrointestinal tolerability
JAIME DAVIDSON1, HARRY HOWLETT2
Abstract

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urrent guidelines for the management of type 2


diabetes recommend initiating pharmacological
therapy with metformin, particularly in
overweight patients, but gastrointestinal side-effects
and a complex administration regimen sometimes
present barriers to its use. A novel, prolonged-release
metformin formulation (Glucophage SR*), given
once-daily in double-blind, randomised, placebocontrolled trials, was associated with fewer
gastrointestinal side-effects, than immediate-release
metformin. A retrospective review of 468 metformintreated patients in the USA found better
gastrointestinal tolerability with prolonged-release
metformin in patients new to metformin, or switched
from the immediate-release formulation. The efficacy of
the two formulations was similar. The improved
tolerability associated with prolonged-release
metformin probably arises from the tablet design,
which releases metformin into the upper intestine by
diffusion from a dual hydrophilic polymer matrix
(GelShield diffusion system). This provides slower,
smoother and longer drug delivery, without an initial
rapid rise in plasma metformin. This novel metformin
formulation may simplify the delivery of metforminbased therapy.
Br J Diabetes Vasc Dis 2004;4:2737
Key words: metformin, type 2 diabetes, oral antidiabetic
therapy, prolonged-release formulation, gastrointestinal
tolerability, adherence.

Introduction

has been shown to provide cardiovascular protection beyond


that expected from blood glucose control alone.3 Metformin is
also the only oral antidiabetic agent described as providing protection from diabetic complications in its European labelling.
Accordingly, current UK guidelines from NICE state that "In people who are overweight (BMI > 25.0 kg/m2) and whose blood
glucose is inadequately controlled using lifestyle interventions
alone, metformin should normally be used as the first-line glucose-lowering therapy".4 Other guidelines such as those from
the Texas Diabetes Council in the USA also support the use of
metformin as first-line therapy in type 2 diabetes.5,6
Gastrointestinal side-effects, especially diarrhoea, present the
main tolerability issue with metformin, and occur in up to about
20% of patients.1 These side-effects often resolve on continued
treatment, and gastrointestinal tolerability also often improves
following a reduction in the metformin dose, although clinical
trial data indicate that the incidence of gastrointestinal sideeffects with metformin is not strongly dose-related at total daily
dosages above 500 mg.7 Overall, the gastrointestinal side-effects
of metformin are believed to cause discontinuation of therapy in
only about 5% of patients,8 but they are nevertheless troublesome for some patients. Total daily dosages > 500 mg require
two or three tablet intakes each day, which can add to the complexity of the regimen, especially as the typical type 2 diabetic
patient is likely to be taking multiple medications for comorbid
conditions. Given the well-known inverse relationship between
frequency of administration and the level of compliance with
treatment,9 the need for multiple tablet intakes per day provides
a further barrier to achieving a successful treatment outcome
with metformin.
There is a clinical need for a formulation of metformin that
has improved gastrointestinal tolerability, with the potential for
once-daily dosing. Such a prolonged-release formulation,
Glucophage SR, has been developed and evaluated in clinical trials. This review summarises clinical experience gained with this
novel formulation of metformin.

Metformin has been available for clinical use in its immediaterelease formulation for more than four decades. While the efficacy of metformin in lowering blood glucose is similar to that of
the other main classes of oral antidiabetic agents,1,2 metformin

University of Texas Southwestern Medical School, Dallas, Texas, USA.


Merck Pharma UK, Harrier House, West Drayton, Middlesex, UB7 7QG, UK.

1
2

Correspondence to: Dr Harry Howlett


Merck UK, Harrier House, High Street, Yiewsley, West Drayton, Middlesex,
UB7 7QG, UK.
Tel: +44 (0)1895 452231; Fax: +44 (0)1895 452286
E-mail: hhowlett@merckpharma.co.uk

Gastrointestinal tolerability of prolonged-release


metformin
Controlled clinical trials
Two double-blind, randomised, parallel-group clinical trials have
evaluated prolonged-release metformin in comparison with placebo.10 In one study, 240 type 2 diabetic patients with hyperglycaemia despite diet and exercise were initially randomised in a 2:1

*Glucophage

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XR in most other areas.

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Figure 1. Treatment-related gastrointestinal adverse events pooled from A: two double-blind, placebo-controlled evaluations of prolonged-release metformin10
or B: from a double-blind, placebo-controlled dose-ranging evaluation of immediate-release metformin7

20

20

Key:

15
% patients

% patients

15

10

Diarrhoea
Nausea or vomiting

10

Abdominal pain
Dyspepsia or heartburn

0
Placebo

Prolonged-release
metformin

Placebo

Immediate-release
metformin

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Data have been pooled for all dosages of metformin in each study.

Figure 2. Withdrawals for gastrointestinal side-effects pooled from two double-blind, randomised evaluations of prolonged-release metformin10 in
comparison with data from two placebo-controlled evaluations of immediate-release metformin7,11

Immediate-release metformin

Prolonged-release
metformin
Fujioka et al.10

Withdrawals for
GI side-effects (%)

5.9

DeFronzo &
Goodman11

Garber et al.7

1.8
1.0

Any GI AE

0.6

4.0

0.0

Diarrhoea

0.0
0
Any GI AE

7.7

0.0

Key:
Prolonged-release
metformin
Immediate-release
metformin
Placebo

1.4

Diarrhoea

Any GI AE
(mainly diarrhoea)

Data have been pooled for all dosages of metformin in the studies of Fujioka et al. and Garber et al.

Abbreviations
BMI
HDL-c
LDL-c
NICE

body mass index


high density lipoprotein-cholesterol
low density lipoprotein-cholesterol
National Institute for Clinical Excellence

ratio to receive prolonged-release metformin 1,000 mg or placebo


once-daily for 12 weeks. Patients with HbA1C > 7% and < 8%
after 12 weeks of treatment then received an additional prolonged-release metformin tablet (total daily dose 1,500 mg) for a
further 12 weeks. The second study was a dose-ranging trial in 742

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diet-failed patients randomised to receive placebo or prolongedrelease metformin at doses of 500 mg, 1,000 mg, 1,500 mg, or
2,000 mg once-daily, or 1,000 mg twice-daily for 16 weeks.
The incidence of diarrhoea or nausea and vomiting pooled
from these two studies was approximately 50% lower than the
corresponding incidences from a parallel-group, placebo-controlled, 14-week dose ranging evaluation of immediate-release
metformin in 451 diet-failed patients (figure 1).7 Furthermore,
the rate of treatment withdrawal for gastrointestinal adverse
events (1.8%) was lower with prolonged-release metformin
than with immediate-release metformin in this study (5.9%),7
and in an additional double-blind, randomised parallel-group,
placebo-controlled evaluation of immediate-release metformin

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25

p<0.01

Prolonged-release metformin (n=65)

15
10

ia
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pe
ys

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a
se
au

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ho

ny
A

ny

0
ps
ia
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0

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Prolonged-release metformin
(post-switch, n=205)

20

ho
ea

% patients

Key:
Immediate-release metformin
(pre-switch, n=205)

p<0.001

au

10
% patients

30

Key:
Immediate-release metformin (n=158)

12

Figure 4. Gastrointestinal side-effects before and after a switch from


immediate-release metformin to prolonged-release
metformin13

Figure 3. Gastrointestinal tolerability in patients receiving prolongedrelease metformin or immediate-release metformin for the
first time13 (excludes patients switched from immediaterelease metformin to prolonged-release metformin)

in 289 diet-failed patients treated for 29 weeks (7.7%) (figure


2).11
A further double-blind, randomised study evaluated the
effects of switching patients from immediate-release metformin
to the prolonged-release formulation.12 Following a 2-week leadin on immediate-release metformin 500 mg b.i.d., 217 patients
were randomly assigned to continue on immediate-release metformin, or to switch to prolonged-release metformin at a dose of
1,0001,500 mg once-daily. Although the study was not powered to detect differences in tolerability between treatment
groups, the incidence of all-cause gastrointestinal adverse events
was about 10% lower following treatment with prolongedrelease metformin, compared with an equivalent dose of the
immediate-release formulation.
The incidence of gastrointestinal side-effects with once-daily
prolonged-release metformin in the dose-ranging study was not
clearly dose-related at doses between 1,000 mg and 2,000 mg.10
These findings are similar to those from the double-blind, randomised study in 451 patients, in which the incidence of gastrointestinal side-effects, and withdrawals for this reason, was
not clearly dose-related at total daily dosages of metformin
between 1,000 mg and 2,500 mg.7

Retrospective analysis
A retrospective review of patients treatment records was undertaken at four centres in the USA to evaluate the gastrointestinal
tolerability of the prolonged-release and immediate-release formulations of metformin in patients with type 2 diabetes.13 The
patient population had started treatment with either formulation
of metformin during the previous year. In all, data from 471
patients were analysed, of which data from 468 patients were
sufficiently complete for inclusion in the analysis. The primary
end points of the study were the overall incidence of gastrointestinal side-effects, and the incidence of diarrhoea for each formulation during the first year of treatment.
The incidence of gastrointestinal adverse events was similar in

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the immediate-release metformin and prolonged-release metformin groups in the overall patient population (11.4% vs.
11.9%). The incidence of individual gastrointestinal side-effects
was also similar between groups. It should be noted, however,
that about one quarter of the prolonged-release metformin
cohort had been switched from immediate-release metformin
with the specific intention of relieving gastrointestinal adverse
events. The prolonged-release metformin cohort therefore contained a substantial proportion of patients with known sensitivity to the gastrointestinal effects of metformin.
Sub-group analyses were conducted to provide a more
meaningful evaluation of tolerability. A comparison of the incidence of gastrointestinal side-effects in patients receiving metformin for the first time is shown in figure 3. This analysis excluded those patients from the immediate-release metformin cohort
who subsequently switched to prolonged-release metformin,
and thus avoids the generation of an enriched population for
sensitivity to metformin-induced gastrointestinal side-effects. The
incidence of diarrhoea in the prolonged-release metformin
cohort was less than half that reported by the immediate-release
metformin cohort (3.1% vs. 7.6%), although the difference did
not achieve statistical significance in this smaller cohort.
Gastrointestinal tolerability was evaluated in 205 patients
who switched from immediate-release metformin to the prolonged-release formulation in a further sub-group analysis. The
switch to prolonged-release metformin was associated with a
significant reduction in the incidence of any gastrointestinal sideeffect (26% vs. 11%, p=0.0006), and of diarrhoea (18% vs. 8%,
p=0.008) (figure 4). The patients who switched to prolongedrelease metformin were further subdivided according to the reason for the switch, where this was stated on the patients case
notes. The incidence of gastrointestinal side-effects in 78
patients who were switched with the stated intention of improving gastrointestinal tolerability is shown in figure 5. The switch
was associated with significant reductions in the incidence of any
gastrointestinal side-effect and of diarrhoea.

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Figure 5. Gastrointestinal side-effects in patients switched from


immediate-release metformin to prolonged-release
metformin with the intention of improving tolerability13

Figure 6. Schematic representation of the prolonged-release


metformin tablet
Key:

80
Key:

p<0.0001

Immediate-release metformin
(pre-switch, n=78)

% patients

60
p=0.0014

Prolonged-release metformin
(pre-switch, n=78)

Outer polymer matrix


(does not contain metformin)
Inner polymer matrix
Metformin molecules

40

20

p=0.0143

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There are no additional tolerability issues with prolongedrelease metformin. For example, data pooled from the doubleblind, randomised studies described above show that only the
incidence of all-cause gastrointestinal side-effects was markedly
higher than placebo, as would be expected.10 In addition, there
was no increase in general side-effects after switching from
immediate-release metformin to prolonged-release metformin.12

nificant increases in triglycerides occurred in these studies.


HDL-c was unaffected. Prolonged-release metformin exerted little effect on body weight: mean changes in body weight were
small (reductions of up to 1 kg) in the various treatment groups
in the placebo-controlled parallel-group evaluations of prolonged-release metformin.10

Efficacy of once-daily prolonged-release metformin

How does the prolonged-release metformin formulation improve gastrointestinal tolerability?

Maintaining adequate glycaemic control is crucial for the prevention of long-term microvascular complications.14 It is important to ensure that improvements in tolerability with the prolonged-release metformin formulation are not gained at the
expense of reduced antihyperglycaemic efficacy.
The dose-ranging study with prolonged-release metformin
shows that the efficacy of this formulation given once-daily is
dose-related, with a maximal effect at 1,5002,000 mg/day.10
Mean treatment differences versus placebo during once-daily
treatment in this study were -0.6% (500 mg), -0.7% (1,000 mg),
-1.0% (1,500 mg), and -1.0% (2,000 mg). This study also evaluated prolonged-release metformin given at a dose of 1,000 mg
twice-daily. The change in HbA1C in this group (mean reduction
of 1.2%) was comparable with that observed in the group
randomised to receive a dose of 2,000 mg once-daily (mean
reduction of 1.0%). In addition, there was no loss of efficacy
following a switch from immediate-release metformin to the
prolonged-release formulation.12
These data confirm that the antihyperglycaemic efficacy of
once-daily prolonged-release metformin is comparable to that of
immediate-release metformin given in divided doses. In addition,
these data also support twice-daily administration of prolongedrelease metformin, if preferred.
Lipid profiles generally improved, with significant reductions
from baseline in total and LDL-c observed in both parallel-group,
placebo-controlled evaluations of prolonged-release metformin,
and in the switch study.10,12 However, small, but statistically sig-

The improved gastrointestinal tolerability of prolonged-release


metformin arises directly from its novel tablet design (figure 6).
The metformin is contained within a dual hydrophilic polymer
matrix system that meters metformin release by means of diffusion.15 An outer, continuous polymer (containing no metformin)
surrounds inner particles of a different polymer that contains,
overall, 500 mg of metformin per tablet. When the tablet is swallowed, it absorbs moisture and swells, forming a gel layer on the
outside of the tablet that meters the release of metformin into
the gut. Importantly, the rate at which metformin dissolves is not
affected by movement, or by variations in pH, which helps to
minimise variations in metformin delivery between and within
patients.
The absorption of metformin from the prolonged-release
tablet is slower and takes place over a longer period of time,
compared with the immediate-release formulation.15,16 A pharmacokinetic study evaluated the prolonged-release tablet (2,000
mg once-daily) in comparison with immediate-release metformin
(1,000 mg b.i.d.) after each was dosed to steady state.15 The time
to maximal plasma concentration of metformin (Tmax) from the
prolonged-release tablet was longer than with immediaterelease metformin (seven-hour vs. three-hour), and the maximal
plasma concentration (Cmax) was about 25% lower for the prolonged-release formulation. The overall exposure of the patient
to metformin was unaffected. Indeed, analysis of the area under
the plasma concentration-time curve demonstrated strict bioequivalence between the formulations. Figure 7 shows plasma

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Figure 7. Plasma-concentration-time relationships following


once-daily dosing of extended-release metformin or twicedaily dosing of immediate-release metformin in 16 healthy
volunteers
Key:
Once-daily 2,000 mg prolonged-release metformin
Twice-daily 1,000 mg immediate-release metformin

Key messages

Management guidelines for type 2 diabetes support the


use of metformin for initiation of pharmacological
antidiabetic therapy.2 Gastrointestinal side-effects and
complex administration may present barriers to the use
of metformin

The new prolonged-release formulation of metformin


(Glucophage SR) has the potential for once-daily
dosing and improved gastrointestinal tolerability
compared with immediate-release metformin

Glucophage SR employs a dual matrix polymer (the


GelShield diffusion system), which allows prolonged and
smoother absorption of metformin, avoiding the initial
rapid rise in plasma concentrations with immediaterelease metformin

1,500

1,000

500

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Plasma metformin (ng/mL)

2,000

12

24

Time post-dose (h)

Adapted from Timmins P. Clin Pharmacokinet 2004 (in press)15

metformin-time curves for the two formulations, after dosing to


steady state.
The pharmacokinetic profile of metformin from the prolonged-release tablet avoids the rapid initial rise in plasma metformin concentrations seen with immediate-release metformin.
This smoother delivery of metformin may help to avoid triggering gastrointestinal side-effects, and may account for much of
the improved tolerability demonstrated with the prolongedrelease formulation.

Conclusions

The extensive database of clinical experience with metformin has


established this agent as a foundation therapy for type 2 diabetes. However, gastrointestinal side-effects with metformin are
common and troublesome, and some patients may find the complex twice or three times daily administration regimen difficult to
follow in the setting of polypharmacy. A novel prolonged-release
formulation of metformin (Glucophage SR), based on a dual
polymer matrix (the GelShield diffusion system) controls blood
glucose effectively following once-daily dosing, and has demonstrated improved gastrointestinal tolerability compared with the
immediate-release formulation. This new metformin tablet has
the potential to improve patients adherence to metforminbased therapy.

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