Professional Documents
Culture Documents
CO
PY
RE
PR (DI RI
O AB GH
DU E T
CT TES M
IO ) L ED
N IM IN
PR IT EW
O ED S
HI
BI
TE
D
Introduction
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
1
2
*Glucophage
273
HEALTHCARE MANAGEMENT
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
CO
PY
RE
PR (DI RI
O AB GH
DU E T
CT TES M
IO ) L ED
N IM IN
PR IT EW
O ED S
HI
BI
TE
D
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
274
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
HEALTHCARE MANAGEMENT
25
p<0.01
15
10
ia
rr
pe
ys
CO
PY
RE
PR (DI RI
O AB GH
DU E T
CT TES M
IO ) L ED
N IM IN
PR IT EW
O ED S
HI
BI
TE
D
a
se
au
rr
ia
D
ho
ny
A
ny
0
ps
ia
Fl
at
ul
en
ce
Co
ns
tip
at
io
A
bd
n
om
in
al
pa
in
5
0
ea
se
a
ys
pe
ps
A
ia
bd
o
di
st
en
si
on
Fl
at
ul
en
ce
Co
ns
tip
at
A
io
bd
n
om
in
al
pa
in
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 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)
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
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.
275
HEALTHCARE MANAGEMENT
80
Key:
p<0.0001
Immediate-release metformin
(pre-switch, n=78)
% patients
60
p=0.0014
Prolonged-release metformin
(pre-switch, n=78)
40
20
p=0.0143
Fl
at
ul
en
ce
CO
PY
RE
PR (DI RI
O AB GH
DU E T
CT TES M
IO ) L ED
N IM IN
PR IT EW
O ED S
HI
BI
TE
D
D
ys
pe
ps
ia
A
bd
om
in
al
pa
in
A
bd
o
di
st
en
si
on
N
au
se
a
D
ia
rr
ho
ea
A
ny
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
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-
276
HEALTHCARE MANAGEMENT
Key messages
1,500
1,000
500
0
0
CO
PY
RE
PR (DI RI
O AB GH
DU E T
CT TES M
IO ) L ED
N IM IN
PR IT EW
O ED S
HI
BI
TE
D
2,000
12
24
Conclusions
References
1. Howlett HC, Bailey CJ. A risk-benefit assessment of metformin in type 2
diabetes mellitus. Drug Saf 1999;20:489-503.
2. Campbell IW, Howlett HC. Worldwide experience of metformin as an
effective glucose-lowering agent: a meta-analysis. Diabetes Metab Rev
1995;11(suppl 1):S57-S62.
3. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood
glucose control with metformin on complications in overweight patients
with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.
277