Download Optimal dosing strategies for maximising the clinical response to

REVIEW
Optimal dosing strategies for maximising the
clinical response to metformin in type 2
diabetes
JOHN HB SCARPELLO
Abstract
R
ecently revised consensus targets for glycaemic
management in patients with type 2 diabetes are
challenging and require optimisation of dosing
strategies for oral antidiabetic therapies. The
demonstration of significant cardiovascular outcome
benefits in metformin-treated type 2 diabetic patients
enrolled in the United Kingdom Prospective Diabetes
Study has established this agent as the first line oral
therapy after diet failure in newly presenting
overweight people with type 2 diabetes mellitus. The
antihyperglycaemic efficacy of metformin increases with
increasing daily doses between 500 mg and the upper
limits of the recommended daily dosage ( ≥ 2000
mg/day). Although metformin is associated with
gastrointestinal side-effects in up to 20% of patients,
this is not generally dose related. Transient dose
reduction, slower titration and taking the dose with
meals may ameliorate the problem. Risk of lactic
acidosis due to metformin is negligible when this agent
is prescribed correctly, and is unrelated to the plasma
metformin concentration. Intensification of metformin
therapy within the dose range represents a rational and
practical therapeutic strategy for optimising glycaemic
control in patients who are suitable for, and tolerant of,
metformin treatment. The recently introduced 1000 mg
metformin tablet should facilitate the use of higher
doses and may help treatment compliance.
Key words: metformin, oral antidiabetic therapy, type 2
diabetes, dose-response relationships.
Introduction
The United Kingdom Prospective Diabetes Study (UKPDS) has
shown beyond doubt that improving glycaemia in patients with
Correspondence to: Dr John Scarpello
Department of Diabetes and Endocrinology, City General Hospital,
Stoke on Trent, ST4 6QG, UK
Tel: +44 (0)1782 553425; Fax: +44 (0)1782 553427
E-mail: [email protected]
Br J Diabetes Vasc Dis 2001;1:28–36
28
John Scarpello
Table 1. Targets for glycaemic management in Europe and in the USA
International Diabetes Federation
(Europe)2
American Diabetes Association
(USA)3
Fasting plasma glucose
HbA1C
≤ 6 mmol/L
≤ 6.5%
< 6.7 mmol/L
< 7%
type 2 diabetes reduces the risk of diabetic complications.1 As a
result, challenging new targets for fasting plasma glucose (FPG)
and glycated haemoglobin (HbA1C) in patients with diabetes
have been agreed for routine clinical practice2,3 (table 1).
Meeting these goals requires a new paradigm for the management of the person with type 2 diabetes. An ongoing survey
of current standards achieved in routine clinical practice from
Salford in the UK has shown that in a population of more than
six thousand patients, less than 20% achieved an annual HbA1C
< 7.0% over a six-year follow-up period (1993–1998).4
Achieving the new treatment targets requires optimisation of
dosing strategies for oral antidiabetic agents, including combined therapies. Maximum dosage of oral antidiabetic therapy in
individual patients is frequently limited by the risk-benefit profiles
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
REVIEW
ce
an
ai
n
Fr
Sp
l
ga
rtu
UK
nd
la
er
Po
y
an
m
itz
14%
0
A
21%
Sw
41%
7%
er
39%
US
32%
1000
G
0.19
0.49
0.46
0.11
0.6
8%
m
20%
iu
0.017
0.011
0.0023
0.01
0.13
36%
lg
42%
ly
p
value
Be
∆ risk*
ria
p
value
Metformin dose - UKPDS a
2000
st
∆ risk*
3000
Au
Diabetes-related deaths
All cause mortality
Any diabetes-related endpoint
Myocardial infarction
Stroke
Sulphonylurea/insulin
therapies
Metformin daily dose (mg)
Metformin
therapy
Figure 1. Average metformin daily dosage in various countries
Ita
Table 2. Improved clinical outcomes following intensive glycaemic
management with metformin compared with intensive glycaemic
management with a sulphonylurea or insulin10
Majority of UKPDS patients allocated metformin received a dosage
>2000 mg/day.10 Prescription analysis data (mean doses) kindly supplied by
Merck-Lipha
a
*Compared with conventional therapy based on diet/exercise in overweight
patients.
of individual therapies, for example weight gain and hypoglycaemia associated with insulinotropic agents.5-7 Metformin is as
effective as sulphonylureas,6,8,9 but its risk-benefit profile across
the full therapeutic dose range of 500–3000 mg/day is less well
described.
In the UKPDS, significant improvements in macrovascular outcomes leading to fewer deaths were reported for overweight
patients receiving metformin therapy for a median period of 10
years.10 The reduction in morbidity and mortality was much
greater than that reported for patients treated with sulphonylureas and insulin despite there being no overall difference in glycaemic control. This landmark clinical trial emphasises the need to
optimise therapy with metformin, so that these benefits can be
more widely realised. This review explores the dose-relationship of
the effects of metformin in patients with type 2 diabetes and summarises the evidence that metformin administered at higher doses
provides additional glycaemic control, without the burden of additional side-effects.
Optimising oral antidiabetic therapy for type 2
diabetes
Benefits of titrating up metformin dose in the United
Kingdom Prospective Diabetes Study
The reductions in diabetic complications in metformin-treated
patients in the UKPDS10 are summarised in table 2. Significant
improvements were observed with metformin in all cause mortality (p=0.011), diabetes-related deaths (p=0.017), myocardial
infarction (p=0.01) and any diabetes-related end point
(p=0.0023). In contrast, no significant changes in these outcomes
were observed in patients treated with insulin or a sulphonylurea,
despite similar improvements in glycaemic control (table 2).
It is important to note that the benefits observed in the
UKPDS were achieved at a relatively high dose of metformin.
Whilst more than half of the patients in the UKPDS received a
daily dosage of 2550 mg/day, more than three quarters of
patients received at least 1700 mg/day. The results of the UKPDS
VOLUME 1 ISSUE 1 . AUGUST 2001
therefore lend support to the use of metformin at adequately
titrated doses in order to improve clinical outcomes in patients
with type 2 diabetes. In contrast, evidence from the literature11,12
and from the manufacturer of a branded form of metformin (figure 1) suggests that many patients may not achieve the expected benefit of metformin if it is not titrated to sufficient dosage.
(figure 1).
Dose-relationship of the efficacy of metformin in
patients with type 2 diabetes
Most large clinical trials with metformin have employed pragmatic study designs, with a flexible dose titration phase followed
by a period of long-term maintenance treatment.8-10 While these
studies have optimised therapy in their patient populations, within the dose ranges employed in each study, they tell us little of
the dose-relationship of the effects of metformin per se. Some
information about the relationship between the dose and antihyperglycaemic efficacy of metformin in people with type 2 diabetes can be acquired from smaller studies using either parallelgroup designs or titration within individual patients.
A double-blind study13 investigated the effects of metformin
in 75 patients with established type 2 diabetes and fasting plasma glucose (FPG) ≥ 6 mmol/L, who were randomised to receive
placebo or metformin at doses of 1500 mg or 3000 mg for six
months. FPG and glycated haemoglobin (HbA1C) increased in
placebo-treated patients over the six-month study period (figure.
2). In contrast, metformin significantly reduced both parameters.
The higher dose of metformin was significantly more effective in
reducing FPG compared with the lower dose (p=0.02). The
improvement in mean HbA1C values was 1.8% between patients
receiving placebo and the higher dose of metformin (figure 2).
A second parallel-group dose-response study14 randomised
451 patients with FPG of at least 10 mmol/L (180 mg/dl) despite
prior treatment with diet or sulphonylurea to therapy with metformin at daily doses of 500 mg, 1000 mg, 1500 mg, 2000 mg
or 2500 mg for 11 weeks. Statistically significant reductions in
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Figure 2. Effects of two doses of metformin on fasting plasma glucose
(FPG) and HbA1C in patients with type 2 diabetes13
FPG 1
HbA1c
-0.5
-1
-3
***
FPG (mmol/L)
(placebo-corrected)
-2
0
-1.5
***
500
(n=73)
0
Placebo (n=23)
Metformin, 1500 mg/day (n=25)
Metformin, 3000 mg/day (n=27)
Mean changes from baseline are shown. Significance versus placebo:
***p=0.001.
Final daily dose of metformin
1500
2000
1000
(n=76)
(n=73)
(n=73)
-2
**
-3
***
-4
***
-5
***
0
500
(n=73)
Final daily dose of metformin
1000
1500
2000
(n=73)
(n=76)
(n=73)
30
2500 (mg)
(n=77)
-0.5
-1.0
-1.5
***
***
-2.0
***
***
-2.5
***
Mean placebo-corrected differences from baseline are shown. FPG: fasting
plasma glucose. Significance versus placebo: **p<0.01, ***p<0.001.
Figure 4. Dose-related effects of metformin during dose titration in
patients with type 2 diabetes15
3 dose titration
13
2 dose titration
12
11
FPG (mmol/L)
FPG compared with placebo, occurred at doses of 1000 mg and
above, with the greatest effects occurring at 2000 mg and 2500
mg/day. HbA1C was improved at all dosages studied. There was
a decrease in HbA1C of more than 1.5% at doses of 1500
mg/day and above. Reductions in HbA1C and FPG increased with
the dose of metformin up to a dose of 2000 mg which corresponded with reductions of 4.4 mmol/L and 2% respectively (figure 3). At the highest dose, 2500 mg, the net reduction in FPG
and HbA1C was not significantly different from 2000 mg,
although some individual patients achieved additional glycaemic
benefit at the higher dose (figure 3).
Two other studies15,16 have evaluated the dose-response relationships of metformin within individual patients during dose
titration. One double-blind study included a group of 37 patients
with type 2 diabetes (FPG ≥ 6.7 mmol/L after two months of diet
therapy) randomised to monotherapy with metformin, given as
an initial daily dose of 1000 mg.15 The dose of metformin was
increased in two further titration steps, at two-weekly intervals,
to a maximum of 3000 mg/day if FPG remained at or above 6.7
mmol/L. Patients were divided into two groups depending on
whether the glycaemic target was achieved after three titration
steps, or whether only two titration steps were needed. Not surprisingly, the patients requiring more than two titration steps had
more severe diabetes at baseline, as indicated by a higher mean
FPG (figure 4). In both groups progressive increases in antihyperglycaemic efficacy were observed with each dose increment, including titration to the maximum dose of 3000 mg/day
(figure 4).
Figure 4 also shows that mean FPG in patients receiving more
titration steps remained in excess of 9 mmol/L despite the maximum therapeutic dose of metformin. The observed improvement in glycaemia of between 25–30% is consistent with other
metformin studies which have employed doses of up to 3000
mg per day. 8,17,18 It must be noted that it may not be practical to
2500 (mg)
(n=77)
-1
***
HbA1c (%)
(placebo-corrected)
-1
-4
1
0.5
(% units)
(mmol/L)
0
Figure 3. Effects of metformin administered at doses between 500 and
2500 mg/day on glycaemic parameters in patients with type 2
diabetes14
10
9
8
7
6
0
1000
2000
3000
Metformin daily dose (mg)
Mean values of fasting plasma glucose (FPG) are shown. Patients were
divided into those able to achieve a glycaemic target of FPG ≤ 6.7 mmol/L
after two dose titration steps, and those who required at least three titration
steps, as indicated.
use the full dose range of metformin particularly if this is unlikely to achieve the glycaemic target. In the latter situation, the
dosage should revert to the lowest dose to achieve the maximum
effect and consideration given to combination therapy.19
Metformin-based combination therapy has proved to be a rational and effective strategy for enhancing glycaemic control in
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
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Baseline
Metformin 500 mg/day
Metformin 1500 mg/day
Metformin 3000 mg/day
300
15
FPG (mmol/L)
20
Plasma glucose (mmol/L)
Figure 6. Effects of increasing doses of metformin on fasting plasma
glucose (FPG, left-hand ordinate) and on 24-hour plasma
glucose (right-hand ordinate) in patients with type 2 diabetes16
15
10
*
*
*† *†
10
*† *†
100
5
5
B
L
200
3000
0
500
1500
Daily dose of metformin (mg)
D
24-hour plasma glucose
(AUC) (mmol.h/l)
Figure 5. Mean 24-hour plasma glucose profiles during titration of the
dose of metformin in nine patients with type 2 diabetes16
0
0
6
12
18
24
Hours
B = breakfast; L = lunch; D = dinner.
patients with type 2 diabetes20 and more than 60% of patients
in this study switched to metformin-glibenclamide combinations
went on to achieve FPG ≤ 6.7 mmol/L.
A further study compared the effects on glycaemia of escalating doses of metformin in nine patients with type 2 diabetes.16 The metformin daily dose was commenced at 500 mg
and then increased in a stepwise manner at two-weekly intervals to 1500 mg and then 3000 mg. FBG, 24-hour glucose
profiles and glucose utilisation rates were evaluated at the end
of each two week treatment period. The twenty-four hour glucose profiles demonstrated a clear dose-response relationship,
with reduced plasma glucose concentrations with each
increase in the dose of metformin (figure 5). Measurements of
mean FBG and mean 24-hour plasma glucose, measured as the
area under the glucose concentration–time curve, confirm this
observation (figure 6). Both parameters were significantly
reduced at all metformin doses, compared with baseline
(p<0.01). Whilst the 1500 mg and 3000 mg doses of metformin were significantly more effective than the 500 mg dose
in reducing both fasting and 24-hour plasma glucose concentrations (p<0.02), the benefits observed with 3000 mg/day
were not statistically significantly greater than with 1500
mg/day (figures 5 and 6).
Metformin at 3000 mg, but not at lower doses, significantly reduced the magnitude of the plasma glucose excursion following breakfast (p<0.05), although no significant effects of
metformin were observed at other meal times. The greater
effect of metformin on plasma glucose at higher doses was
reflected in an increased rate of glucose utilisation during studies employing the euglycaemic hyperinsulinaemic glucose
clamp. Glucose uptake rates at baseline and following treatment with metformin at doses of 500 mg, 1500 mg and 3000
mg were (means ± SEM) 10.3±1.5, 11.1±2.8, 12.7±2.2 and
32
Means + SEM are shown. Significance of results: *p<0.01 versus 0 mg/day;
†p<0.02 versus 500 mg/day. AUC: area under the 24-hour plasma glucosetime curve.
Figure 7. Dose-relationship of effects of metformin on postprandial
glucose in a single-dose study in patients with type 2
diabetes22
4
Postprandial plasma glucose
(mmol/L)
0
3
*
2
*
1
0
Placebo
850
1700
2550
Dose of metformin (mg)
Means + SEM are shown. Postprandial glucose was measured during the
period 1–3 hours after lunch and changes in this parameter are shown
relative to fasting plasma glucose; *p<0.05 versus placebo.
13.3±2.4 µmol/kg/min, respectively.
Other studies confirm the improvement of postprandial glucose by higher doses of metformin (1500–2550 mg/day).21-24
One of these studies included an evaluation of the effects of
different single doses of metformin on postprandial glucose.22
The effect on postprandial glucose increased with increasing
dose, achieving statistical significance at doses of 1700 mg and
2550 mg (figure 7). Larger improvements in postprandial glucose were observed following five days of treatment with metformin at a dose of 2550 mg/day. Interestingly, postprandial
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
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Table 3. Gastrointestinal adverse events and treatment discontinuations for gastrointestinal adverse events in patients receiving different doses of metformin14
Final daily dose of metformin
Placebo
n=79
Abdominal pain
Diarrhoeaa
Nausea
Dyspepsia
Anorexia
Combined digestive
disturbancesa,b
500 mg
n=73
1000 mg
n=73
1500 mg
n=76
2000 mg
n=73
2500 mg
n=77
I
D
I
D
I
D
I
D
I
D
I
D
0%
5%
5%
1%
1%
0%
0%
0%
0%
0%
3%
8%
7%
1%
0%
0%
0%
0%
0%
0%
1%
21%
10%
1%
1%
1%
4%
3%
0%
0%
4%
12%
8%
9%
3%
1%
3%
3%
0%
0%
0%
19%
1%
3%
1%
0%
3%
1%
0%
0%
3%
14%
12%
4%
5%
0%
5%
5%
3%
1%
13%
0%
16%
0%
29%
5%
24%
3%
23%
4%
29%
10%
Figures show the incidence of gastrointestinal adverse events (I) and rates of discontinuation (D) for this reason; a significantly different (p<0.05) for metformin versus
placebo (all doses); b includes diarrhoea, dyspepsia, nausea and anorexia (abdominal pain was classified as a ‘whole body’ adverse event).
glucose was more sensitive to the effects of metformin than
FPG in this study (figure 7).
It is likely, therefore, that reductions in postprandial glucose
contribute to the improvements in HbA1C observed during treatment with higher metformin doses. Since postprandial glucose is
an independent risk factor for the development of diabetic complications, including coronary heart disease, retinopathy or renal
dysfunction,25-27 this might be one mechanism whereby metformin proved so effective in the UKPDS trial.
Safety and tolerability
Gastrointestinal adverse events
The majority of adverse events associated with metformin therapy are gastrointestinal, and usually appear soon after the initiation of therapy. They can lead to discontinuation of therapy
in up to 5% of patients.17 These effects are usually transient,
and tend to subside over several months of continued therapy.28 The impact of gastrointestinal adverse events during initiation of metformin therapy may be minimised by titrating from
an initial dose of 500 mg, and by taking metformin with or
immediately after food. The biological mechanism underlying
metformin-induced gastrointestinal side-effects has not been
fully elucidated, but increased colonic concentrations of bile
salts29 and increased intestinal 5-hydroxytryptamine (serotonin)
release30 appear to be involved.
The tolerability of different doses of metformin was
analysed in detail in the parallel-group study in 451 patients,14
described above. Table 3 shows the incidence of gastrointestinal adverse events from this study, and the percentages of
patients discontinuing therapy as a result. Above 500 mg/day,
there is no clear evidence of a dose relationship for either the
incidence of individual or pooled gastrointestinal side-effects,
or for treatment discontinuations arising from an adverse drug
event. In this study, the good tolerance to metformin was
attributed to gradual dose escalation at weekly intervals, and
VOLUME 1 ISSUE 1 . AUGUST 2001
administration with meals (table 3).
This lack of association between metformin dosage and drug
related side-effects confirms the findings of one of the earlier
studies15 but is in contrast to the observations of another.13 A
questionnaire-based study of 285 randomly selected type 2 outpatients11 provides further evidence for the lack of dose-response
for gastrointestinal side-effects. Although 20% of responders
receiving metformin complained of diarrhoea, there were no differences in incidence between patients receiving low and high
doses. In the case of patients with intractable symptoms, transient reduction in the dose and subsequent gradual re-titration
can lead to improved tolerance.31 The drug is best withdrawn in
patients with persistent diarrhoea.
Lactic acidosis
A relatively high incidence of lactic acidosis led to the withdrawal of the biguanide phenformin in most countries, and an
association between this adverse event and biguanides in general has often been made in reviews of oral antidiabetic therapy. The incidence of lactic acidosis with metformin is very rare
and reported as between 3–9 cases per 100 000 patient-years
of treatment with 2–4 deaths/100 000 patient-years and is up
to 20 times lower than the incidence described in patients
treated with phenformin.32-34
Several reports indicate increased lactate production during
metformin treatment in type 2 diabetes patients, although this
has not been observed in all studies.35-37 There is good evidence
that neither plasma metformin nor lactate concentrations are
of any help in predicting clinical outcomes, even in patients
with very high lactate levels.37-39 Due to the co-morbidity associated with type 2 diabetes, it is anticipated that some cases of
lactic acidosis in patients receiving metformin are unrelated to
the therapy with this agent.40-41
A review of all published cases of lactic acidosis in patients
receiving metformin has recently been published.38 Twenty-one
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reports over a five-year period, including information on 26
patients, are included in this review. Four cases did not fit criteria for true lactic acidosis (arterial lactate > 5 mmol/L, blood
pH ≤ 7.35), lactic acidosis was not associated with metformin
accumulation in another eight, and was of uncertain origin in
a further two cases. Metformin accumulation was considered
to have contributed to the development of lactic acidosis in 12
cases, of whom all had acute or chronic renal dysfunction.
Importantly, the true aetiology of the lactic acidosis strongly
influenced the eventual clinical outcomes of these patients. Of
the eight cases of documented lactic acidosis that were not
associated with metformin, seven patients died. In contrast, the
only death among the 12 patients with lactic acidosis considered to be metformin-related occurred as a result of the
patient’s refusal to undergo renal dialysis.
Although a link is often drawn between metformin accumulation and lactic acidosis, the plasma concentration of metformin is of no prognostic benefit in patients with this condition. In a study of 49 metformin-treated patients with lactic acidosis, the median metformin plasma concentration in 27
patients who survived (20.6 mg/l) was considerably higher than
the corresponding concentration in 22 patients who died (6.3
mg/l).39 Given that the maximal plasma concentration of metformin achieved after an 850 mg oral dose is in the range
1.5–2.0 mg/l,17 it follows that even metformin concentrations
well above the normal therapeutic range were not associated
with a poorer outcome in these patients.
The development of lactic acidosis during metformin therapy
therefore often results from the presence of intercurrent disease,
rather than from the use of metformin itself. Furthermore, the
incidence of genuine metformin-related lactic acidosis appears
to be lower than that cited in the literature. Nevertheless, it
remains important to minimise the risk of lactic acidosis with
metformin by paying careful attention to the contraindications
and special precautions associated with metformin use, especially with regard to renal or hepatic impairment and alcohol
abuse. Conditions precluding the use of metformin are not
uncommon in type 2 diabetic patients42 and evidence from surveys suggests that a substantial proportion of patients who have
received metformin have absolute contraindications, intercurrent
conditions or other risk factors incompatible with metformin
therapy, although no cases of lactic acidosis were reported in
these surveys.43,44
The risk of lactic acidosis with metformin is low if the prescribing instructions for metformin are followed correctly.34,37
Careful assessment of patients at the time of initiation of metformin therapy, and regular surveillance of patients to detect
the development of contraindications to metformin form an
essential part of successful long-term management of type 2
diabetes with metformin. Vigilance is required at the time of
radiological investigations involving intravascular administration of iodinated contrast materials as these agents can precipitate renal failure. Metformin therapy should be discontinued at
the time of the procedure, withheld for a minimum of 48 hours,
and reinstated only after renal function is confirmed as normal.32
34
Clinical implications of optimising metformin therapy
Risk versus benefit of higher doses of metformin
Taken together, the four dose ranging studies described above
indicate that the antihyperglycaemic efficacy of metformin is
dose-related, and that this relationship extends to daily doses of
metformin at the upper limits of the recommended daily dosage
( > 2000 mg/day ). On the other hand, the evidence suggests
that increasing the metformin dose beyond 1500–2000 mg/day
does not markedly increase the risk of gastrointestinal sideeffects or lactic acidosis, and fear of these side-effects should not
prevent the achievement of optimal dosage levels in patients
with type 2 diabetes.
The additional efficacy available from higher metformin
doses is potentially important in the prevention of long-term diabetic complications. Evidence from the UKPDS indicates that
each 1% decrease in HbA1C is likely to yield clinically important
reductions in the risk of diabetic complications, including diabetes related death (by 21%), myocardial infarction (by 14%),
peripheral vascular disease (by 43%), microvascular disease (by
37%) and cataract extraction (by 19%).1 It is therefore most
important that HbA1C is controlled adequately. Importantly, the
intensive glycaemic management of patients receiving metformin achieved by UKPDS can be realised in routine clinical
management of such patients, as demonstrated by a three-year
community-based study which reduced baseline HbA1C by
1.5%.12
In addition to being an effective antihyperglycaemic agent,
metformin improves other cardiovascular risk factors related to
the insulin resistance syndrome, also referred to as ‘metabolic
syndrome’ or ‘syndrome X’, in diabetic patients.9,17,32 For example,
dose-related improvements in fibrinolytic parameters (plasminogen activator inhibitor-1 [PAI-1] activity, PAI-1 antigen, tissue
plasminogen activator [tPA] activity and tPA antigen) were
observed after six months of metformin therapy at doses of up
to 3000 mg/day.13 Improved fibrinolysis is likely to reduce the risk
of intravascular thrombotic events, such as myocardial infarction,
and may contribute to the beneficial cardiovascular effects of
metformin in type 2 diabetic patients.45,46 Metformin also
improves lipid profiles in many patients, including beneficial
effects on LDL, VLDL and HDL cholesterol, free fatty acids and
triglycerides.32
Maintained quality of life during intensive metformin
therapy
The impact of intensive glycaemic management and of the presence or absence of diabetic complications on quality of life was
measured in the UKPDS.47 Individual questionnaires were used to
evaluate patients’ quality of life relating to satisfaction with
work, mood, symptoms and cognitive function, while the generic EQ5D questionnaire was used to explore patients’ general
well-being.
There were no significant differences in the scores for any
dimension of quality of life in patients receiving intensive therapy with metformin, compared with patients receiving conventional, diet-based therapy. In contrast, the presence of macrovas-
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
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cular complications significantly impaired general well-being,
and the presence of microvascular complications significantly
impaired quality of life relating to mood and symptoms.
Therefore, the presence of complications impairs quality of life
in patients with type 2 diabetes, while intensive glycaemic
management with metformin does not.
Compliance issues
Polypharmacy, defined as the long-term use of two or more
pharmacologic therapies, is common, especially in elderly
patients with diabetes who are at increased risk of other diseases of ageing, such as hypertension, ischaemic heart disease
or arthritis. Indeed, age and diabetes have been shown to be
highly significant risk factors for receiving polypharmacy
(p=0.0002 and p=0.0001, respectively) in a study of data from
1,544 patients over a three-year period.48
It is well accepted that polypharmacy is a clinically significant barrier to good compliance with therapeutic regimens,
especially where patients take several doses of medication per
day, and non-adherence to therapy is common among patients
with diabetes.49,50 This has been demonstrated quantitatively in
patients with type 2 diabetes, by the Diabetes Audit and
Research in Tayside, Scotland (DARTS) Study, which recorded
the medication details of 2,920 patients for 12 months.51 Data
on prescriptions were used to define an Adherence Index,
which provided an estimate of the proportion of the year for
which patients had adequate therapeutic cover from their
medication. Adequate adherence to therapy was defined as an
Adherence Index of 90% or greater, after adjustment for hospitalisation.
The median Adherence Indices in patients receiving either
of two oral antidiabetic monotherapies were 300 and 302
days. When the agents were given together as a free combination, involving an increase in the number of tablets taken per
day, the Adherence Index fell to 266 days (p<0.01 for the difference between monotherapy and combination therapy). It
follows, therefore, that increasing the dose of oral antidiabetic
therapy could hinder patient compliance with therapy if this
involved the administration of a greater number of tablets
per day.
The benefits of simplifying the dosage regimen for metformin have been demonstrated in a crossover study involving
some 64 patients.52 Patients stabilised and maintained on
1500–2000 mg per day of metformin were switched to 850
mg twice-daily, whilst those on 2500–3000 mg were converted to 850 mg three times daily. Three months after conversion,
no significant changes were noted in glycaemic control, and
some 90% of patients reported nothing untoward and were
willing to continue medication with the high dosage strength.
Simplifying the antidiabetic regimen to reduce the number of
metformin tablets per day would therefore seem practical,
straightforward and safe. The recently introduced 1000 mg
tablet should, in principle, allow the delivery of higher doses of
metformin without adding to the already arduous burden of
polypharmacy in these patients.
VOLUME 1 ISSUE 1 . AUGUST 2001
Key messages
●
UKPDS has established metformin as a preferred
first line agent for pharmacological treatment of type 2
diabetes
●
Adequate titration of metformin is required, taking the
drug with meals to reduce GI side effects
●
Metformin offers benefits against cardiovascular disease
in type 2 diabetes
Conclusions
The UKPDS showed that metformin improves clinical outcomes
in type 2 diabetic patients by controlling glycaemia, and through
additional as yet undefined cardiovascular protective effects.
Metformin is therefore established as the first line component of
oral antidiabetic therapy for patients without contraindications
to this drug. We also know from the UKPDS that the degree of
protection from complications is determined by the magnitude
of the reduction in HbA1C. The efficacy of metformin in controlling glycaemia is related to dose, generally requiring titration up
to 2000 mg/day or above to achieve optimal effect. Therapy
should however be individualised, and with this objective the full
therapeutic dose range of metformin should be exploited where
appropriate in order to optimise the benefits of therapy. At all
times vigilance should be maintained to ensure safety of use during intensification of metformin therapy. The recently introduced
1000 mg metformin tablet will facilitate the use of higher doses
of metformin with the potential to improve compliance.
References
1. Stratton IM, Adler AI, Neil HAW et al. Association of glycaemia with
macrovascular and microvascular complications of type 2 diabetes
(UKPDS 35): prospective observational study. BMJ 2000;321:405-12.
2. European Diabetes Policy Group. A desktop guide to type 2 diabetes
mellitus. Diabet Med 1999;16:716-30.
3. American Diabetes Association. Clinical Practice Recommendations.
Diabetes Care 1999;22(Suppl 1):S1-114.
4. New JP, Hollis S, Campbell F et al. Measuring clinical performance and
outcomes from diabetes information systems: an observational study.
Diabetologia 2000;43:836-43.
5. Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral
antidiabetic agents. Drug Saf 1994;11:223-41.
6. Bailey CJ. Antidiabetic Drugs. Br J Cardiol 2000;7:350-60.
7. Schatz H. Preclinical and clinical studies on the safety and tolerability of
repaglinide. Clin Exp Endocrinol Diabetes 1999;107(Suppl 4):S144-8.
8. Campbell IW, Howlett HC. Worldwide experience of metformin as an
effective glucose-lowering agent: a meta-analysis. Diabetes Metab Rev
1995;11(Suppl 1):S57-62.
9. Johansen K. Efficacy of metformin in the treatment of NIDDM. Metaanalysis. Diabetes Care 1999;22:33-7.
10. UK Prospective Diabetes Study 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.
11. Dandona P, Fonseca V, Mier A, Beckett AG. Diarrhea and metformin in a
diabetic clinic. Diabetes Care 1983;6:472-4.
35
REVIEW
12. Stades AM, Heikens JT, Holleman F, Hoekstra JB. Effect of metformin on
glycaemic control in type 2 diabetes in daily practice: a retrospective
study. Neth J Med 2000;56:86-90.
13. Grant PJ. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care
1996;19:64-6.
14. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled,
dose-response trial. Am J Med 1997;103:491-7.
15. Hermann LS, Schersten B, Melander A. Antihyperglycaemic efficacy,
response prediction and dose-response relations of treatment with metformin and sulphonylurea, alone and in primary combination. Diabet Med
1994;11:953-60.
16. McIntyre HD, Ma A, Bird DM, Paterson CA, Ravenscroft PJ, Cameron DP.
Metformin increases insulin sensitivity and basal glucose clearance in type
2 (non-insulin dependent) diabetes mellitus. Aust NZ J Med 1991;
21:714-9.
17. Cusi K, DeFronzo RA. Metformin: a review of its metabolic effects.
Diabetes Reviews 1998;6:89-131.
18. Davidson MB, Peters AL. An overview of metformin in the treatment of
type 2 diabetes mellitus. Am J Med 1997;102:99-110.
19. Garber AJ. Using dose-response characteristics of therapeutic agents for
treatment decisions in type 2 diabetes. Diabetes, Obesity and Metabolism
2000;2:139-47.
20. Campbell IW. Need for intensive, early glycaemic control in patients with
type 2 diabetes. Br J Cardiol 2000;7:625-31.
21. Leatherdale BA, Bailey CJ. Acute antihyperglycaemic effect of metformin
without alteration of gastric emptying. IRCS Med Sci 1986;14:1086-6.
22. Sambol NC, Chiang J, O’Conner M et al. Pharmacokinetics and pharmacodynamics of metformin in healthy subjects and patients with noninsulin-dependent diabetes mellitus. J Clin Pharmacol 1996;36:1012-21.
23. Hollenbeck CB, Johnston P, Varasteh BB, Chen Y-DI, Reaven GM. Effects
of metformin on glucose, insulin and lipid metabolism in patients with
mild hypertriglyceridaemia and non-insulin dependent diabetes mellitus
by glucose tolerance test criteria. Diabete & Metabolisme (Paris)
1991;17:483-9.
24. Jeppesen J, Chen Y-DI, Zhou M-Y, Reaven GM. Effect of metformin on
postprandial lipemia in patients with fairly to poorly controlled NIDDM.
Diabetes Care 1994;17:1093-9.
25. Turner RC, Millns H, Neil HAW et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom
prospective diabetes study (UKPDS 23). BMJ 1998;316:823-8.
26. Klein R, Klein BE, Moss SE, Cruickshanks KJ. Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy. Arch Intern Med 1994;154:2169-78.
27. Klein R, Klein BE, Moss SE, Cruickshanks KJ. Ten-year incidence of gross
proteinuria in people with diabetes. Diabetes 1995;44:916-23.
28. Haupt E, Knick B, Koschinsky T, Liebermeister H, Schneider J, Hirche H.
Oral antidiabetic combination therapy with sulphonylureas and metformin. Diabete Metab 1991;17:224-31.
29. Scarpello JH, Hodgson E, Howlett HC. Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus. Diabet Med
1998;15:651-6.
30. Cubeddu LX, Bonisch H, Gothert M et al. Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors. Naunyn
36
Schmiedebergs Arch Pharmacol 2000;361:85-91.
31. Bailey CJ. Biguanides and NIDDM. Diabetes Care 1992;15:755-72.
32. Howlett HC, Bailey CJ. A risk-benefit assessment of metformin in type 2
diabetes mellitus. Drug Saf 1999;20:489-503.
33. Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidosis in
metformin users. Diabetes Care 1999;22:925-7.
34. Chan NN, Brain HPS, Feher MD. Metformin-associated lactic acidosis: a
rare or very rare clinical entity. Diabet Med 1999;16:273-81.
35. Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in non insulin-dependent diabetes mellitus.
J Clin Endocrinol Metab 1996;81:4059-67.
36. Fery F, Plat L, Balasse EO. Effects of metformin on the pathways of glucose utilization after oral glucose in non-insulin-dependent diabetes mellitus patients. Metabolism 1997;46:227-33.
37. Lalau JD, Race JM. Lactic acidosis in metformin therapy: searching for a
link with metformin in reports of ‘metformin-associated lactic acidosis’.
Diabetes, Obesity and Metabolism 2000;2:1-7.
38. Lalau JD, Race JM. Lactic acidosis in metformin therapy. Drugs
1999;58(Suppl 1):55-60.
39. Lalau JD, Race JM. Lactic acidosis in metformin-treated patients.
Prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf 1999;20:377-84.
40. Bailey CJ, Turner RC. Drug therapy: Metformin. N Engl J Med 1996;334:
574-9.
41. Brown JB, Pedula K, Barzilay J et al. Lactic acidosis rates in type 2 diabetes. Diabetes Care 1998;21:1659-63.
42. Sulkin TV, Bosman D, Krentz AJ. Contraindications to metformin therapy
in patients with NIDDM. Diabetes Care 1997;20:925-8.
43. Emslie-Smith AM, Boyle DIR, Evans JMM et al. Contraindications to metformin therapy in patients with Type 2 diabetes - a population-based
study of adherence to prescribing guidelines. Diabet Med 2001;18:483-8.
44. Holstein A, Nahrwold D, Hinze S, Egberts E-H. Contra-indications to metformin are largely disregarded. Diabet Med 1999;16:692-6.
45. Grant PJ, Stickland MH, Booth NA, Prentice CR. Metformin causes a
reduction in basal and post-venous occlusion plasminogen activator
inhibitor-1 in type 2 diabetic patients. Diabet Med 1991;8:361-5.
46. Landin-Wilhelmsen K. Metformin and blood pressure. J Clin Pharm Ther
1992;17:75-9.
47. UK Prospective Diabetes Study Group. Quality of life in type 2 diabetic
patients is affected by complications but not by intensive policies to
improve blood glucose or blood pressure control (UKPDS 37). Diabetes
Care 1999;22:1125-36.
48. Veehof L, Stewart R, Haaijer-Ruskamp F, Jong BM. The development of
polypharmacy. A longitudinal study. Fam Pract 2000;17:261-7.
49. Paes AHP, Bakker A, Soe-Agnie S-J. Impact of dosage frequency on
patient compliance. Diabetes Care 1997;20:1512-17.
50. Brown JB, Nichols GA, Glauber HS, Bakst A. Ten-year follow-up of antidiabetic drug use, nonadherence, and mortality in a defined population
with type 2 diabetes mellitus. Clin Ther 1999;21:1045-57.
51. Morris AD, Brennan GM, Macdonald TM, Donnan PT. Population-Based
Adherence to Prescribed Medication in Type 2 Diabetes: A Cause for
Concern. Diabetes 2000;49(Suppl 1):A76.
52. Menzies DG, Campbell I, McBain A, Brown IRF. Metformin efficacy and
tolerance in obese non-insulin dependent diabetics: a comparison of two
dosage schedules. Curr Med Res Opin 1989;11:273-8.
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