Optimal dosing strategies for maximising the clinical response to metformin in type 2 diabetes
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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 John Scarpello
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 HbA1C
practical therapeutic strategy for optimising glycaemic International Diabetes Federation
control in patients who are suitable for, and tolerant of, (Europe)2 ≤ 6 mmol/L ≤ 6.5%
American Diabetes Association
metformin treatment. The recently introduced 1000 mg
(USA)3 < 6.7 mmol/L < 7%
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 survey
of current standards achieved in routine clinical practice from
Salford in the UK has shown that in a population of more than
Correspondence to: Dr John Scarpello 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
Stoke on Trent, ST4 6QG, UK
Tel: +44 (0)1782 553425; Fax: +44 (0)1782 553427
Achieving the new treatment targets requires optimisation of
E-mail: jhbscarpello@hotmail.com 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 in
individual patients is frequently limited by the risk-benefit profiles
28 THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASEREVIEW
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 3000
Metformin daily dose (mg)
therapy therapies
Metformin dose - UKPDS a
2000
∆ risk* p ∆ risk* p
value value
1000
Diabetes-related deaths 42% 0.017 20% 0.19
All cause mortality 36% 0.011 8% 0.49
Any diabetes-related endpoint 32% 0.0023 7% 0.46
0
Myocardial infarction 39% 0.01 21% 0.11
nd
y
UK
ria
ly
m
A
l
n
ce
ga
an
ai
Ita
US
iu
an
Stroke 41% 0.13 14% 0.6
st
la
rtu
Sp
m
lg
Au
er
Fr
er
Be
Po
itz
G
Sw
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
patients. Merck-Lipha
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-
described. 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 (figure 1).
patients receiving metformin therapy for a median period of 10
years.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- patients with type 2 diabetes
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-
tional side-effects. 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-
Kingdom Prospective Diabetes Study 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
VOLUME 1 ISSUE 1 . AUGUST 2001 29REVIEW
Figure 2. Effects of two doses of metformin on fasting plasma glucose Figure 3. Effects of metformin administered at doses between 500 and
(FPG) and HbA1C in patients with type 2 diabetes13 2500 mg/day on glycaemic parameters in patients with type 2
diabetes14
FPG 1 HbA1c 1
Final daily dose of metformin
500 1000 1500 2000 2500 (mg)
0 0.5 (n=73) (n=73) (n=76) (n=73) (n=77)
0
(placebo-corrected)
(% units)
(mmol/L)
0
FPG (mmol/L)
-1 -1
-2
-2 -0.5 **
-3 ***
-1
-4
-3 ***
***
-5 ***
***
-4 *** -1.5 Final daily dose of metformin
500 1000 1500 2000 2500 (mg)
Placebo (n=23) (n=73) (n=73) (n=76) (n=73) (n=77)
0
(placebo-corrected)
Metformin, 1500 mg/day (n=25)
-0.5
HbA1c (%)
Metformin, 3000 mg/day (n=27)
-1.0
-1.5 ***
Mean changes from baseline are shown. Significance versus placebo: ***
***p=0.001. -2.0
*** ***
-2.5 ***
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: **pREVIEW
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
20
24-hour plasma glucose
Metformin 1500 mg/day 300
15 *
(AUC) (mmol.h/l)
Metformin 3000 mg/day *
Plasma glucose (mmol/L)
*† *†
FPG (mmol/L)
15 *† *† 200
10
10
5 100
5
0
0 500 1500 3000
B L D
Daily dose of metformin (mg)
0
0 6 12 18 24
Hours Means + SEM are shown. Significance of results: *pREVIEW
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 500 mg 1000 mg 1500 mg 2000 mg 2500 mg
n=79 n=73 n=73 n=76 n=73 n=77
I D I D I D I D I D I D
Abdominal pain 0% 0% 3% 0% 1% 1% 4% 1% 0% 0% 3% 0%
Diarrhoeaa 5% 0% 8% 0% 21% 4% 12% 3% 19% 3% 14% 5%
Nausea 5% 0% 7% 0% 10% 3% 8% 3% 1% 1% 12% 5%
Dyspepsia 1% 0% 1% 0% 1% 0% 9% 0% 3% 0% 4% 3%
Anorexia 1% 0% 0% 0% 1% 0% 3% 0% 1% 0% 5% 1%
Combined digestive
disturbancesa,b 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 (pREVIEW
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 with type 2 diabetes.
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 1.5%.12
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 triglycerides.32
therapy, although no cases of lactic acidosis were reported in
these surveys.43,44 Maintained quality of life during intensive metformin
The risk of lactic acidosis with metformin is low if the pre- therapy
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- well-being.
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-
34 THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASEREVIEW
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 life
in patients with type 2 diabetes, while intensive glycaemic ● UKPDS has established metformin as a preferred
management with metformin does not. first line agent for pharmacological treatment of type 2
diabetes
Compliance issues ● 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 elderly
● Metformin offers benefits against cardiovascular disease
patients with diabetes who are at increased risk of other dis-
eases of ageing, such as hypertension, ischaemic heart disease in type 2 diabetes
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 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
pitalisation. 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 per
day, the Adherence Index fell to 266 days (pREVIEW
12. Stades AM, Heikens JT, Holleman F, Hoekstra JB. Effect of metformin on Schmiedebergs Arch Pharmacol 2000;361:85-91.
glycaemic control in type 2 diabetes in daily practice: a retrospective 31. Bailey CJ. Biguanides and NIDDM. Diabetes Care 1992;15:755-72.
study. Neth J Med 2000;56:86-90. 32. Howlett HC, Bailey CJ. A risk-benefit assessment of metformin in type 2
13. Grant PJ. The effects of high- and medium-dose metformin therapy on car- diabetes mellitus. Drug Saf 1999;20:489-503.
diovascular risk factors in patients with type II diabetes. Diabetes Care 33. Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidosis in
1996;19:64-6. metformin users. Diabetes Care 1999;22:925-7.
14. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of met- 34. Chan NN, Brain HPS, Feher MD. Metformin-associated lactic acidosis: a
formin in type II diabetes: results of a double-blind, placebo-controlled, rare or very rare clinical entity. Diabet Med 1999;16:273-81.
dose-response trial. Am J Med 1997;103:491-7. 35. Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glu-
15. Hermann LS, Schersten B, Melander A. Antihyperglycaemic efficacy, cose and lactate metabolism in non insulin-dependent diabetes mellitus.
response prediction and dose-response relations of treatment with met- J Clin Endocrinol Metab 1996;81:4059-67.
formin and sulphonylurea, alone and in primary combination. Diabet Med 36. Fery F, Plat L, Balasse EO. Effects of metformin on the pathways of glu-
1994;11:953-60. cose utilization after oral glucose in non-insulin-dependent diabetes mel-
16. McIntyre HD, Ma A, Bird DM, Paterson CA, Ravenscroft PJ, Cameron DP. litus patients. Metabolism 1997;46:227-33.
Metformin increases insulin sensitivity and basal glucose clearance in type 37. Lalau JD, Race JM. Lactic acidosis in metformin therapy: searching for a
2 (non-insulin dependent) diabetes mellitus. Aust NZ J Med 1991; link with metformin in reports of ‘metformin-associated lactic acidosis’.
21:714-9. Diabetes, Obesity and Metabolism 2000;2:1-7.
17. Cusi K, DeFronzo RA. Metformin: a review of its metabolic effects. 38. Lalau JD, Race JM. Lactic acidosis in metformin therapy. Drugs
Diabetes Reviews 1998;6:89-131. 1999;58(Suppl 1):55-60.
18. Davidson MB, Peters AL. An overview of metformin in the treatment of 39. Lalau JD, Race JM. Lactic acidosis in metformin-treated patients.
type 2 diabetes mellitus. Am J Med 1997;102:99-110. Prognostic value of arterial lactate levels and plasma metformin concen-
19. Garber AJ. Using dose-response characteristics of therapeutic agents for trations. Drug Saf 1999;20:377-84.
treatment decisions in type 2 diabetes. Diabetes, Obesity and Metabolism 40. Bailey CJ, Turner RC. Drug therapy: Metformin. N Engl J Med 1996;334:
2000;2:139-47. 574-9.
20. Campbell IW. Need for intensive, early glycaemic control in patients with 41. Brown JB, Pedula K, Barzilay J et al. Lactic acidosis rates in type 2 dia-
type 2 diabetes. Br J Cardiol 2000;7:625-31. betes. Diabetes Care 1998;21:1659-63.
21. Leatherdale BA, Bailey CJ. Acute antihyperglycaemic effect of metformin 42. Sulkin TV, Bosman D, Krentz AJ. Contraindications to metformin therapy
without alteration of gastric emptying. IRCS Med Sci 1986;14:1086-6. in patients with NIDDM. Diabetes Care 1997;20:925-8.
22. Sambol NC, Chiang J, O’Conner M et al. Pharmacokinetics and pharma- 43. Emslie-Smith AM, Boyle DIR, Evans JMM et al. Contraindications to met-
codynamics of metformin in healthy subjects and patients with nonin- formin therapy in patients with Type 2 diabetes - a population-based
sulin-dependent diabetes mellitus. J Clin Pharmacol 1996;36:1012-21. study of adherence to prescribing guidelines. Diabet Med 2001;18:483-8.
23. Hollenbeck CB, Johnston P, Varasteh BB, Chen Y-DI, Reaven GM. Effects 44. Holstein A, Nahrwold D, Hinze S, Egberts E-H. Contra-indications to met-
of metformin on glucose, insulin and lipid metabolism in patients with formin are largely disregarded. Diabet Med 1999;16:692-6.
mild hypertriglyceridaemia and non-insulin dependent diabetes mellitus 45. Grant PJ, Stickland MH, Booth NA, Prentice CR. Metformin causes a
by glucose tolerance test criteria. Diabete & Metabolisme (Paris) reduction in basal and post-venous occlusion plasminogen activator
1991;17:483-9. inhibitor-1 in type 2 diabetic patients. Diabet Med 1991;8:361-5.
24. Jeppesen J, Chen Y-DI, Zhou M-Y, Reaven GM. Effect of metformin on 46. Landin-Wilhelmsen K. Metformin and blood pressure. J Clin Pharm Ther
postprandial lipemia in patients with fairly to poorly controlled NIDDM. 1992;17:75-9.
Diabetes Care 1994;17:1093-9. 47. UK Prospective Diabetes Study Group. Quality of life in type 2 diabetic
25. Turner RC, Millns H, Neil HAW et al. Risk factors for coronary artery dis- patients is affected by complications but not by intensive policies to
ease in non-insulin dependent diabetes mellitus: United Kingdom improve blood glucose or blood pressure control (UKPDS 37). Diabetes
prospective diabetes study (UKPDS 23). BMJ 1998;316:823-8. Care 1999;22:1125-36.
26. Klein R, Klein BE, Moss SE, Cruickshanks KJ. Relationship of hyper- 48. Veehof L, Stewart R, Haaijer-Ruskamp F, Jong BM. The development of
glycemia to the long-term incidence and progression of diabetic retinopa- polypharmacy. A longitudinal study. Fam Pract 2000;17:261-7.
thy. Arch Intern Med 1994;154:2169-78. 49. Paes AHP, Bakker A, Soe-Agnie S-J. Impact of dosage frequency on
27. Klein R, Klein BE, Moss SE, Cruickshanks KJ. Ten-year incidence of gross patient compliance. Diabetes Care 1997;20:1512-17.
proteinuria in people with diabetes. Diabetes 1995;44:916-23. 50. Brown JB, Nichols GA, Glauber HS, Bakst A. Ten-year follow-up of antidi-
28. Haupt E, Knick B, Koschinsky T, Liebermeister H, Schneider J, Hirche H. abetic drug use, nonadherence, and mortality in a defined population
Oral antidiabetic combination therapy with sulphonylureas and met- with type 2 diabetes mellitus. Clin Ther 1999;21:1045-57.
formin. Diabete Metab 1991;17:224-31. 51. Morris AD, Brennan GM, Macdonald TM, Donnan PT. Population-Based
29. Scarpello JH, Hodgson E, Howlett HC. Effect of metformin on bile salt cir- Adherence to Prescribed Medication in Type 2 Diabetes: A Cause for
culation and intestinal motility in type 2 diabetes mellitus. Diabet Med Concern. Diabetes 2000;49(Suppl 1):A76.
1998;15:651-6. 52. Menzies DG, Campbell I, McBain A, Brown IRF. Metformin efficacy and
30. Cubeddu LX, Bonisch H, Gothert M et al. Effects of metformin on intesti- tolerance in obese non-insulin dependent diabetics: a comparison of two
nal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors. Naunyn dosage schedules. Curr Med Res Opin 1989;11:273-8.
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