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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 The online version of this article can be found at: can be found at:
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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 Introduction
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. diabetes
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: (placebo-corr
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 FPG (mmol/L)
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, (mmol/L)
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 Key messages
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 Conclusions
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.
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