The British Journal of Diabetes & Vascular Disease
Review: Optimal dosing strategies for maximising the clinical response to metformin in type 2 diabetes British Journal of Diabetes & Vascular Disease 2001 1: 28
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Optimal dosing strategies for maximising theclinical response to metformin in type 2 diabetes
Abstract Recently 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 Table 1. Targets for glycaemic management in Europe and in the USA metformin concentration. Intensification of metformin therapy within the dose range represents a rational and Fasting plasma glucose 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
type 2 diabetes reduces the risk of diabetic complications.1 As a
diabetes, dose-response relationships.
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).
The United Kingdom Prospective Diabetes Study (UKPDS) has
Meeting these goals requires a new paradigm for the man-
shown beyond doubt that improving glycaemia in patients with
agement of the person with type 2 diabetes. An ongoing surveyof current standards achieved in routine clinical practice fromSalford in the UK has shown that in a population of more than
six thousand patients, less than 20% achieved an annual HbA1C
Department of Diabetes and Endocrinology, City General Hospital,
< 7.0% over a six-year follow-up period (1993–1998).4
Achieving the new treatment targets requires optimisation of
Tel: +44 (0)1782 553425; Fax: +44 (0)1782 553427E-mail: [email protected]
dosing strategies for oral antidiabetic agents, including com-
Br J Diabetes Vasc Dis 2001;1:28–36
bined therapies. Maximum dosage of oral antidiabetic therapy inindividual patients is frequently limited by the risk-benefit profiles
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
Table 2. Improved clinical outcomes following intensive glycaemic Figure 1. Average metformin daily dosage in various countries
management with metformin compared with intensive glycaemic management with a sulphonylurea or insulin10
Metformin Sulphonylurea/insulin therapies
∆ risk* Metformin daily dose (mg)
a Majority of UKPDS patients allocated metformin received a dosage
*Compared with conventional therapy based on diet/exercise in overweight
>2000 mg/day.10 Prescription analysis data (mean doses) kindly supplied by
of individual therapies, for example weight gain and hypogly-
therefore lend support to the use of metformin at adequately
caemia associated with insulinotropic agents.5-7 Metformin is as
titrated doses in order to improve clinical outcomes in patients
effective as sulphonylureas,6,8,9 but its risk-benefit profile across
with type 2 diabetes. In contrast, evidence from the literature11,12
the full therapeutic dose range of 500–3000 mg/day is less well
and from the manufacturer of a branded form of metformin (fig-
ure 1) suggests that many patients may not achieve the expect-
In the UKPDS, significant improvements in macrovascular out-
ed benefit of metformin if it is not titrated to sufficient dosage.
comes leading to fewer deaths were reported for overweight
patients receiving metformin therapy for a median period of 10years.10 The reduction in morbidity and mortality was much
Dose-relationship of the efficacy of metformin in
greater than that reported for patients treated with sulphonyl-
ureas and insulin despite there being no overall difference in gly-
Most large clinical trials with metformin have employed prag-
caemic control. This landmark clinical trial emphasises the need to
matic study designs, with a flexible dose titration phase followed
optimise therapy with metformin, so that these benefits can be
by a period of long-term maintenance treatment.8-10 While these
more widely realised. This review explores the dose-relationship of
studies have optimised therapy in their patient populations, with-
the effects of metformin in patients with type 2 diabetes and sum-
in the dose ranges employed in each study, they tell us little of
marises the evidence that metformin administered at higher doses
the dose-relationship of the effects of metformin per se. Some
provides additional glycaemic control, without the burden of addi-
information about the relationship between the dose and anti-
hyperglycaemic efficacy of metformin in people with type 2 dia-betes can be acquired from smaller studies using either parallel-
Optimising oral antidiabetic therapy for type 2
group designs or titration within individual patients.
A double-blind study13 investigated the effects of metformin
Benefits of titrating up metformin dose in the United
in 75 patients with established type 2 diabetes and fasting plas-
ma glucose (FPG) ≥ 6 mmol/L, who were randomised to receive
The reductions in diabetic complications in metformin-treated
placebo or metformin at doses of 1500 mg or 3000 mg for six
patients in the UKPDS10 are summarised in table 2. Significant
months. FPG and glycated haemoglobin (HbA1C) increased in
improvements were observed with metformin in all cause mor-
placebo-treated patients over the six-month study period (figure.
tality (p=0.011), diabetes-related deaths (p=0.017), myocardial
2). In contrast, metformin significantly reduced both parameters.
infarction (p=0.01) and any diabetes-related end point
The higher dose of metformin was significantly more effective in
(p=0.0023). In contrast, no significant changes in these outcomes
reducing FPG compared with the lower dose (p=0.02). The
were observed in patients treated with insulin or a sulphonylurea,
improvement in mean HbA1C values was 1.8% between patients
despite similar improvements in glycaemic control (table 2).
receiving placebo and the higher dose of metformin (figure 2).
It is important to note that the benefits observed in the
A second parallel-group dose-response study14 randomised
UKPDS were achieved at a relatively high dose of metformin.
451 patients with FPG of at least 10 mmol/L (180 mg/dl) despite
Whilst more than half of the patients in the UKPDS received a
prior treatment with diet or sulphonylurea to therapy with met-
daily dosage of 2550 mg/day, more than three quarters of
formin at daily doses of 500 mg, 1000 mg, 1500 mg, 2000 mg
patients received at least 1700 mg/day. The results of the UKPDS
or 2500 mg for 11 weeks. Statistically significant reductions in
Figure 2. Effects of two doses of metformin on fasting plasma glucose Figure 3. Effects of metformin administered at doses between 500 and
2500 mg/day on glycaemic parameters in patients with type 2
Final daily dose of metformin (mmol/L) (% units) FPG (mmol/L) (placebo-corr Final daily dose of metformin
Mean changes from baseline are shown. Significance versus placebo:
Mean placebo-corrected differences from baseline are shown. FPG: fasting
FPG compared with placebo, occurred at doses of 1000 mg and
plasma glucose. Significance versus placebo: **p<0.01, ***p<0.001.
above, with the greatest effects occurring at 2000 mg and 2500mg/day. HbA1C was improved at all dosages studied. There wasa decrease in HbA1C of more than 1.5% at doses of 1500mg/day and above. Reductions in HbA1C and FPG increased withthe dose of metformin up to a dose of 2000 mg which corre-
Figure 4. Dose-related effects of metformin during dose titration in
sponded with reductions of 4.4 mmol/L and 2% respectively (fig-
ure 3). At the highest dose, 2500 mg, the net reduction in FPGand HbA1C was not significantly different from 2000 mg,
although some individual patients achieved additional glycaemic
Two other studies15,16 have evaluated the dose-response rela-
tionships of metformin within individual patients during dose
titration. One double-blind study included a group of 37 patientswith 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 onwhether the glycaemic target was achieved after three titration
Metformin daily dose (mg)
steps, or whether only two titration steps were needed. Not sur-prisingly, the patients requiring more than two titration steps had
Mean values of fasting plasma glucose (FPG) are shown. Patients were
more severe diabetes at baseline, as indicated by a higher mean
divided into those able to achieve a glycaemic target of FPG ≤ 6.7 mmol/Lafter two dose titration steps, and those who required at least three titration
FPG (figure 4). In both groups progressive increases in antihy-
perglycaemic efficacy were observed with each dose incre-ment, including titration to the maximum dose of 3000 mg/day(figure 4).
Figure 4 also shows that mean FPG in patients receiving more
use the full dose range of metformin particularly if this is unlike-
titration steps remained in excess of 9 mmol/L despite the maxi-
ly to achieve the glycaemic target. In the latter situation, the
mum therapeutic dose of metformin. The observed improve-
dosage should revert to the lowest dose to achieve the maximum
ment in glycaemia of between 25–30% is consistent with other
effect and consideration given to combination therapy.19
metformin studies which have employed doses of up to 3000
Metformin-based combination therapy has proved to be a ratio-
mg per day. 8,17,18 It must be noted that it may not be practical to
nal and effective strategy for enhancing glycaemic control in
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
Figure 5. Mean 24-hour plasma glucose profiles during titration of the Figure 6. Effects of increasing doses of metformin on fasting plasma
dose of metformin in nine patients with type 2 diabetes16
glucose (FPG, left-hand ordinate) and on 24-hour plasma glucose (right-hand ordinate) in patients with type 2 diabetes16
Baseline Metformin 500 mg/day Metformin 1500 mg/day Metformin 3000 mg/day (AUC) (mmol.h/l) FPG (mmol/L) 24-hour plasma glucose Plasma glucose (mmol/L) Daily dose of metformin (mg)
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 glucose-
patients with type 2 diabetes20 and more than 60% of patients
Figure 7. Dose-relationship of effects of metformin on postprandial
in this study switched to metformin-glibenclamide combinations
glucose in a single-dose study in patients with type 2
went on to achieve FPG ≤ 6.7 mmol/L.
A further study compared the effects on glycaemia of esca-
lating doses of metformin in nine patients with type 2 dia-
betes.16 The metformin daily dose was commenced at 500 mgand then increased in a stepwise manner at two-weekly inter-
vals to 1500 mg and then 3000 mg. FBG, 24-hour glucose
profiles and glucose utilisation rates were evaluated at the endof each two week treatment period. The twenty-four hour glu-
cose profiles demonstrated a clear dose-response relationship,
with reduced plasma glucose concentrations with each
increase in the dose of metformin (figure 5). Measurements of
Postprandial plasma glucose
mean FBG and mean 24-hour plasma glucose, measured as thearea under the glucose concentration–time curve, confirm this
observation (figure 6). Both parameters were significantly
Dose of metformin (mg)
reduced at all metformin doses, compared with baseline(p<0.01). Whilst the 1500 mg and 3000 mg doses of met-formin were significantly more effective than the 500 mg dose
Means + SEM are shown. Postprandial glucose was measured during theperiod 1–3 hours after lunch and changes in this parameter are shown
in reducing both fasting and 24-hour plasma glucose concen-
relative to fasting plasma glucose; *p<0.05 versus placebo.
trations (p<0.02), the benefits observed with 3000 mg/daywere not statistically significantly greater than with 1500mg/day (figures 5 and 6).
Metformin at 3000 mg, but not at lower doses, significant-
13.3±2.4 µmol/kg/min, respectively.
ly reduced the magnitude of the plasma glucose excursion fol-
Other studies confirm the improvement of postprandial glu-
lowing breakfast (p<0.05), although no significant effects of
cose by higher doses of metformin (1500–2550 mg/day).21-24
metformin were observed at other meal times. The greater
One of these studies included an evaluation of the effects of
effect of metformin on plasma glucose at higher doses was
different single doses of metformin on postprandial glucose.22
reflected in an increased rate of glucose utilisation during stud-
The effect on postprandial glucose increased with increasing
ies employing the euglycaemic hyperinsulinaemic glucose
dose, achieving statistical significance at doses of 1700 mg and
clamp. Glucose uptake rates at baseline and following treat-
2550 mg (figure 7). Larger improvements in postprandial glu-
ment with metformin at doses of 500 mg, 1500 mg and 3000
cose were observed following five days of treatment with met-
mg were (means ± SEM) 10.3±1.5, 11.1±2.8, 12.7±2.2 and
formin at a dose of 2550 mg/day. Interestingly, postprandial
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
Table 3. Gastrointestinal adverse events and treatment discontinuations for gastrointestinal adverse events in patients receiving different doses of metformin14 Final daily dose of metformin
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 versusplacebo (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
administration with meals (table 3).
This lack of association between metformin dosage and drug
It is likely, therefore, that reductions in postprandial glucose
related side-effects confirms the findings of one of the earlier
contribute to the improvements in HbA1C observed during treat-
studies15 but is in contrast to the observations of another.13 A
ment with higher metformin doses. Since postprandial glucose is
questionnaire-based study of 285 randomly selected type 2 out-
an independent risk factor for the development of diabetic com-
patients11 provides further evidence for the lack of dose-response
plications, including coronary heart disease, retinopathy or renal
for gastrointestinal side-effects. Although 20% of responders
dysfunction,25-27 this might be one mechanism whereby met-
receiving metformin complained of diarrhoea, there were no dif-
formin proved so effective in the UKPDS trial.
ferences in incidence between patients receiving low and highdoses. In the case of patients with intractable symptoms, tran-
sient reduction in the dose and subsequent gradual re-titration
can lead to improved tolerance.31 The drug is best withdrawn in
The majority of adverse events associated with metformin ther-
apy are gastrointestinal, and usually appear soon after the ini-tiation of therapy. They can lead to discontinuation of therapy
in up to 5% of patients.17 These effects are usually transient,
A relatively high incidence of lactic acidosis led to the with-
and tend to subside over several months of continued thera-
drawal of the biguanide phenformin in most countries, and an
py.28 The impact of gastrointestinal adverse events during initi-
association between this adverse event and biguanides in gen-
ation of metformin therapy may be minimised by titrating from
eral has often been made in reviews of oral antidiabetic thera-
an initial dose of 500 mg, and by taking metformin with or
py. The incidence of lactic acidosis with metformin is very rare
immediately after food. The biological mechanism underlying
and reported as between 3–9 cases per 100 000 patient-years
metformin-induced gastrointestinal side-effects has not been
of treatment with 2–4 deaths/100 000 patient-years and is up
fully elucidated, but increased colonic concentrations of bile
to 20 times lower than the incidence described in patients
salts29 and increased intestinal 5-hydroxytryptamine (serotonin)
Several reports indicate increased lactate production during
The tolerability of different doses of metformin was
metformin treatment in type 2 diabetes patients, although this
analysed in detail in the parallel-group study in 451 patients,14
has not been observed in all studies.35-37 There is good evidence
described above. Table 3 shows the incidence of gastrointesti-
that neither plasma metformin nor lactate concentrations are
nal adverse events from this study, and the percentages of
of any help in predicting clinical outcomes, even in patients
patients discontinuing therapy as a result. Above 500 mg/day,
with very high lactate levels.37-39 Due to the co-morbidity asso-
there is no clear evidence of a dose relationship for either the
ciated with type 2 diabetes, it is anticipated that some cases of
incidence of individual or pooled gastrointestinal side-effects,
lactic acidosis in patients receiving metformin are unrelated to
or for treatment discontinuations arising from an adverse drug
event. In this study, the good tolerance to metformin was
A review of all published cases of lactic acidosis in patients
attributed to gradual dose escalation at weekly intervals, and
receiving metformin has recently been published.38 Twenty-one
reports over a five-year period, including information on 26
Clinical implications of optimising metformin therapy
patients, are included in this review. Four cases did not fit cri-
Risk versus benefit of higher doses of metformin
teria for true lactic acidosis (arterial lactate > 5 mmol/L, blood
Taken together, the four dose ranging studies described above
pH ≤ 7.35), lactic acidosis was not associated with metformin
indicate that the antihyperglycaemic efficacy of metformin is
accumulation in another eight, and was of uncertain origin in
dose-related, and that this relationship extends to daily doses of
a further two cases. Metformin accumulation was considered
metformin at the upper limits of the recommended daily dosage
to have contributed to the development of lactic acidosis in 12
( > 2000 mg/day ). On the other hand, the evidence suggests
cases, of whom all had acute or chronic renal dysfunction.
that increasing the metformin dose beyond 1500–2000 mg/day
Importantly, the true aetiology of the lactic acidosis strongly
does not markedly increase the risk of gastrointestinal side-
influenced the eventual clinical outcomes of these patients. Of
effects or lactic acidosis, and fear of these side-effects should not
the eight cases of documented lactic acidosis that were not
prevent the achievement of optimal dosage levels in patients
associated with metformin, seven patients died. In contrast, the
only death among the 12 patients with lactic acidosis consid-
The additional efficacy available from higher metformin
ered to be metformin-related occurred as a result of the
doses is potentially important in the prevention of long-term dia-
patient’s refusal to undergo renal dialysis.
betic complications. Evidence from the UKPDS indicates that
Although a link is often drawn between metformin accu-
each 1% decrease in HbA1C is likely to yield clinically important
mulation and lactic acidosis, the plasma concentration of met-
reductions in the risk of diabetic complications, including dia-
formin is of no prognostic benefit in patients with this condi-
betes related death (by 21%), myocardial infarction (by 14%),
tion. In a study of 49 metformin-treated patients with lactic aci-
peripheral vascular disease (by 43%), microvascular disease (by
dosis, the median metformin plasma concentration in 27
37%) and cataract extraction (by 19%).1 It is therefore most
patients who survived (20.6 mg/l) was considerably higher than
important that HbA1C is controlled adequately. Importantly, the
the corresponding concentration in 22 patients who died (6.3
intensive glycaemic management of patients receiving met-
mg/l).39 Given that the maximal plasma concentration of met-
formin achieved by UKPDS can be realised in routine clinical
formin achieved after an 850 mg oral dose is in the range
management of such patients, as demonstrated by a three-year
1.5–2.0 mg/l,17 it follows that even metformin concentrations
community-based study which reduced baseline HbA1C by
well above the normal therapeutic range were not associated
with a poorer outcome in these patients.
In addition to being an effective antihyperglycaemic agent,
The development of lactic acidosis during metformin therapy
metformin improves other cardiovascular risk factors related to
therefore often results from the presence of intercurrent disease,
the insulin resistance syndrome, also referred to as ‘metabolic
rather than from the use of metformin itself. Furthermore, the
syndrome’ or ‘syndrome X’, in diabetic patients.9,17,32 For example,
incidence of genuine metformin-related lactic acidosis appears
dose-related improvements in fibrinolytic parameters (plasmino-
to be lower than that cited in the literature. Nevertheless, it
gen activator inhibitor-1 [PAI-1] activity, PAI-1 antigen, tissue
remains important to minimise the risk of lactic acidosis with
plasminogen activator [tPA] activity and tPA antigen) were
metformin by paying careful attention to the contraindications
observed after six months of metformin therapy at doses of up
and special precautions associated with metformin use, espe-
to 3000 mg/day.13 Improved fibrinolysis is likely to reduce the risk
cially with regard to renal or hepatic impairment and alcohol
of intravascular thrombotic events, such as myocardial infarction,
abuse. Conditions precluding the use of metformin are not
and may contribute to the beneficial cardiovascular effects of
uncommon in type 2 diabetic patients42 and evidence from sur-
metformin in type 2 diabetic patients.45,46 Metformin also
veys suggests that a substantial proportion of patients who have
improves lipid profiles in many patients, including beneficial
received metformin have absolute contraindications, intercurrent
effects on LDL, VLDL and HDL cholesterol, free fatty acids and
conditions or other risk factors incompatible with metformin
therapy, although no cases of lactic acidosis were reported inthese surveys.43,44
Maintained quality of life during intensive metformin
The risk of lactic acidosis with metformin is low if the pre-
scribing instructions for metformin are followed correctly.34,37
The impact of intensive glycaemic management and of the pres-
Careful assessment of patients at the time of initiation of met-
ence or absence of diabetic complications on quality of life was
formin therapy, and regular surveillance of patients to detect
measured in the UKPDS.47 Individual questionnaires were used to
the development of contraindications to metformin form an
evaluate patients’ quality of life relating to satisfaction with
essential part of successful long-term management of type 2
work, mood, symptoms and cognitive function, while the gener-
diabetes with metformin. Vigilance is required at the time of
ic EQ5D questionnaire was used to explore patients’ general
radiological investigations involving intravascular administra-
tion of iodinated contrast materials as these agents can precipi-
There were no significant differences in the scores for any
tate renal failure. Metformin therapy should be discontinued at
dimension of quality of life in patients receiving intensive thera-
the time of the procedure, withheld for a minimum of 48 hours,
py with metformin, compared with patients receiving conven-
and reinstated only after renal function is confirmed as normal.32
tional, diet-based therapy. In contrast, the presence of macrovas-
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
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 lifein patients with type 2 diabetes, while intensive glycaemic
● 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
Polypharmacy, defined as the long-term use of two or more
drug with meals to reduce GI side effects
pharmacologic therapies, is common, especially in elderlypatients with diabetes who are at increased risk of other dis-
● Metformin offers benefits against cardiovascular disease
eases of ageing, such as hypertension, ischaemic heart disease
or arthritis. Indeed, age and diabetes have been shown to behighly significant risk factors for receiving polypharmacy(p=0.0002 and p=0.0001, respectively) in a study of data from1,544 patients over a three-year period.48
It is well accepted that polypharmacy is a clinically signifi-
The UKPDS showed that metformin improves clinical outcomes
cant barrier to good compliance with therapeutic regimens,
in type 2 diabetic patients by controlling glycaemia, and through
especially where patients take several doses of medication per
additional as yet undefined cardiovascular protective effects.
day, and non-adherence to therapy is common among patients
Metformin is therefore established as the first line component of
with diabetes.49,50 This has been demonstrated quantitatively in
oral antidiabetic therapy for patients without contraindications
patients with type 2 diabetes, by the Diabetes Audit and
to this drug. We also know from the UKPDS that the degree of
Research in Tayside, Scotland (DARTS) Study, which recorded
protection from complications is determined by the magnitude
the medication details of 2,920 patients for 12 months.51 Data
of the reduction in HbA1C. The efficacy of metformin in control-
on prescriptions were used to define an Adherence Index,
ling glycaemia is related to dose, generally requiring titration up
which provided an estimate of the proportion of the year for
to 2000 mg/day or above to achieve optimal effect. Therapy
which patients had adequate therapeutic cover from their
should however be individualised, and with this objective the full
medication. Adequate adherence to therapy was defined as an
therapeutic dose range of metformin should be exploited where
Adherence Index of 90% or greater, after adjustment for hos-
appropriate in order to optimise the benefits of therapy. At all
times vigilance should be maintained to ensure safety of use dur-
The median Adherence Indices in patients receiving either
ing intensification of metformin therapy. The recently introduced
of two oral antidiabetic monotherapies were 300 and 302
1000 mg metformin tablet will facilitate the use of higher doses
days. When the agents were given together as a free combina-
of metformin with the potential to improve compliance.
tion, involving an increase in the number of tablets taken perday, the Adherence Index fell to 266 days (p<0.01 for the dif-
ference between monotherapy and combination therapy). It
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THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
Vivostat®PRF® for the treatment of hard to heal ischemic diabetic ulcer. Pascal Steenvoorde MD MSc*1,2, Louk P. van Doorn MA2, Jacques Oskam MD Phd1,2From the department of Surgery1 Rijnland Hospital Leiderdorp and the Rijnland Wound We have asked the patient for permission to use this material. The patient agreed. However publication rights are with the authors; therefore before
Hermann Memorial Library, Sullivan County Community College The rules for citing the most frequently used source types are given below: printed books of all kinds, including reference books; periodicals; and lastly, sources found on the World Wide Web. This list of rules and examples is not exhaustive. Students should refer to the following book, which is always on hand in the Ready Reference Are