Abstract

Current guidelines for the management of type 2diabetes recommend initiating pharmacologicaltherapy with metformin, particularly inoverweight patients, but gastrointestinal side-effectsand a complex administration regimen sometimespresent barriers to its use. A novel, prolonged-releasemetformin formulation (Glucophage SR*), givenonce-daily in double-blind, randomised, placebo-controlled trials, was associated with fewergastrointestinal side-effects, than immediate-releasemetformin. A retrospective review of 468 metformin-treated patients in the USA found bettergastrointestinal tolerability with prolonged-releasemetformin in patients new to metformin, or switchedfrom the immediate-release formulation. The efficacy ofthe two formulations was similar. The improvedtolerability associated with prolonged-releasemetformin probably arises from the tablet design,which releases metformin into the upper intestine bydiffusion from a dual hydrophilic polymer matrix(GelShield diffusion system). This provides slower,smoother and longer drug delivery, without an initialrapid rise in plasma metformin. This novel metforminformulation may simplify the delivery of metformin-based therapy. Br J Diabetes Vasc Dis 2004;4:2737

Key words: metformin, type 2 diabetes, oral antidiabetictherapy, prolonged-release formulation, gastrointestinaltolerability, adherence.

IntroductionMetformin has been available for clinical use in its immediate-release formulation for more than four decades. While the effi-cacy of metformin in lowering blood glucose is similar to that ofthe other main classes of oral antidiabetic agents,1,2 metformin

has been shown to provide cardiovascular protection beyondthat expected from blood glucose control alone.3 Metformin isalso the only oral antidiabetic agent described as providing pro-tection from diabetic complications in its European labelling.Accordingly, current UK guidelines from NICE state that"In peo-ple who are overweight (BMI > 25.0 kg/m2) and whose bloodglucose is inadequately controlled using lifestyle interventionsalone, metformin should normally be used as the first-line glu-cose-lowering therapy".4 Other guidelines such as those fromthe Texas Diabetes Council in the USA also support the use ofmetformin as first-line therapy in type 2 diabetes.5,6

Gastrointestinal side-effects, especially diarrhoea, present themain tolerability issue with metformin, and occur in up to about20% of patients.1 These side-effects often resolve on continuedtreatment, and gastrointestinal tolerability also often improvesfollowing a reduction in the metformin dose, although clinicaltrial data indicate that the incidence of gastrointestinal side-effects with metformin is not strongly dose-related at total dailydosages above 500 mg.7 Overall, the gastrointestinal side-effectsof metformin are believed to cause discontinuation of therapy inonly about 5% of patients,8 but they are nevertheless trouble-some for some patients. Total daily dosages > 500 mg requiretwo or three tablet intakes each day, which can add to the com-plexity of the regimen, especially as the typical type 2 diabeticpatient is likely to be taking multiple medications for comorbidconditions. Given the well-known inverse relationship betweenfrequency of administration and the level of compliance withtreatment,9 the need for multiple tablet intakes per day providesa further barrier to achieving a successful treatment outcomewith metformin.

There is a clinical need for a formulation of metformin thathas improved gastrointestinal tolerability, with the potential foronce-daily dosing. Such a prolonged-release formulation,Glucophage SR, has been developed and evaluated in clinical tri-als. This review summarises clinical experience gained with thisnovel formulation of metformin.

Gastrointestinal tolerability of prolonged-releasemetforminControlled clinical trialsTwo double-blind, randomised, parallel-group clinical trials haveevaluated prolonged-release metformin in comparison with place-bo.10 In one study, 240 type 2 diabetic patients with hypergly-caemia despite diet and exercise were initially randomised in a 2:1

New prolonged-release metformin improvesgastrointestinal tolerabilityJAIME DAVIDSON1, HARRY HOWLETT2

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1University of Texas Southwestern Medical School, Dallas, Texas, USA.2Merck Pharma UK, Harrier House, West Drayton, Middlesex, UB7 7QG, UK.

Correspondence to: Dr Harry HowlettMerck UK, Harrier House, High Street, Yiewsley, West Drayton, Middlesex,UB7 7QG, UK. Tel: +44 (0)1895 452231; Fax: +44 (0)1895 452286 E-mail: hhowlett@merckpharma.co.uk

*Glucophage XR in most other areas.

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ratio to receive prolonged-release metformin 1,000 mg or placeboonce-daily for 12 weeks. Patients with HbA1C > 7% and < 8%after 12 weeks of treatment then received an additional pro-longed-release metformin tablet (total daily dose 1,500 mg) for afurther 12 weeks. The second study was a dose-ranging trial in 742

diet-failed patients randomised to receive placebo or prolonged-release metformin at doses of 500 mg, 1,000 mg, 1,500 mg, or2,000 mg once-daily, or 1,000 mg twice-daily for 16 weeks.

The incidence of diarrhoea or nausea and vomiting pooledfrom these two studies was approximately 50% lower than thecorresponding incidences from a parallel-group, placebo-con-trolled, 14-week dose ranging evaluation of immediate-releasemetformin in 451 diet-failed patients (figure 1).7 Furthermore,the rate of treatment withdrawal for gastrointestinal adverseevents (1.8%) was lower with prolonged-release metforminthan with immediate-release metformin in this study (5.9%),7

and in an additional double-blind, randomised parallel-group,placebo-controlled evaluation of immediate-release metformin

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Figure 2. Withdrawals for gastrointestinal side-effects pooled from two double-blind, randomised evaluations of prolonged-release metformin10 in comparison with data from two placebo-controlled evaluations of immediate-release metformin7,11

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Fujioka et al.10 Garber et al.7DeFronzo &Goodman11

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Placebo

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Figure 1. Treatment-related gastrointestinal adverse events pooled from A: two double-blind, placebo-controlled evaluations of prolonged-release metformin10

or B: from a double-blind, placebo-controlled dose-ranging evaluation of immediate-release metformin7

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Abdominal pain

Nausea or vomiting

Dyspepsia or heartburn

Key:

Abbreviations

BMI body mass indexHDL-c high density lipoprotein-cholesterolLDL-c low density lipoprotein-cholesterolNICE National Institute for Clinical Excellence

Data have been pooled for all dosages of metformin in each study.

Data have been pooled for all dosages of metformin in the studies of Fujioka et al. and Garber et al.

A B

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in 289 diet-failed patients treated for 29 weeks (7.7%) (figure2).11

A further double-blind, randomised study evaluated theeffects of switching patients from immediate-release metforminto the prolonged-release formulation.12 Following a 2-week lead-in on immediate-release metformin 500 mg b.i.d., 217 patientswere randomly assigned to continue on immediate-release met-formin, or to switch to prolonged-release metformin at a dose of1,0001,500 mg once-daily. Although the study was not pow-ered to detect differences in tolerability between treatmentgroups, the incidence of all-cause gastrointestinal adverse eventswas about 10% lower following treatment with prolonged-release metformin, compared with an equivalent dose of theimmediate-release formulation.

The incidence of gastrointestinal side-effects with once-dailyprolonged-release metformin in the dose-ranging study was notclearly dose-related at doses between 1,000 mg and 2,000 mg.10

These findings are similar to those from the double-blind, ran-domised study in 451 patients, in which the incidence of gas-trointestinal side-effects, and withdrawals for this reason, wasnot clearly dose-related at total daily dosages of metforminbetween 1,000 mg and 2,500 mg.7

Retrospective analysisA retrospective review of patients treatment records was under-taken at four centres in the USA to evaluate the gastrointestinaltolerability of the prolonged-release and immediate-release for-mulations of metformin in patients with type 2 diabetes.13 Thepatient population had started treatment with either formulationof metformin during the previous year. In all, data from 471patients were analysed, of which data from 468 patients weresufficiently complete for inclusion in the analysis. The primaryend points of the study were the overall incidence of gastroin-testinal side-effects, and the incidence of diarrhoea for each for-mulation during the first year of treatment.

The incidence of gastrointestinal adverse events was similar in

the immediate-release metformin and prolonged-release met-formin groups in the overall patient population (11.4% vs.11.9%). The incidence of individual gastrointestinal side-effectswas also similar between groups. It should be noted, however,that about one quarter of the prolonged-release metformincohort had been switched from immediate-release metforminwith the specific intention of relieving gastrointestinal adverseevents. The prolonged-release metformin cohort therefore con-tained a substantial proportion of patients with known sensitivi-ty to the gastrointestinal effects of metformin.

Sub-group analyses were conducted to provide a moremeaningful evaluation of tolerability. A comparison of the inci-dence of gastrointestinal side-effects in patients receiving met-formin for the first time is shown in figure 3. This analysis exclud-ed those patients from the immediate-release metformin cohortwho subsequently switched to prolonged-release metformin,and thus avoids the generation of an enriched population forsensitivity to metformin-induced gastrointestinal side-effects. Theincidence of diarrhoea in the prolonged-release metformincohort was less than half that reported by the immediate-releasemetformin cohort (3.1% vs. 7.6%), although the difference didnot achieve statistical significance in this smaller cohort.

Gastrointestinal tolerability was evaluated in 205 patientswho switched from immediate-release metformin to the pro-longed-release formulation in a further sub-group analysis. Theswitch to prolonged-release metformin was associated with asignificant reduction in the incidence of any gastrointestinal side-effect (26% vs. 11%, p=0.0006), and of diarrhoea (18% vs. 8%,p=0.008) (figure 4). The patients who switched to prolonged-release metformin were further subdivided according to the rea-son for the switch, where this was stated on the patients casenotes. The incidence of gastrointestinal side-effects in 78patients who were switched with the stated intention of improv-ing gastrointestinal tolerability is shown in figure 5. The switchwas associated with significant reductions in the incidence of anygastrointestinal side-effect and of diarrhoea.

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Figure 4. Gastrointestinal side-effects before and after a switch from immediate-release metformin to prolonged-release metformin13

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There are no additional tolerability issues with prolonged-release metformin. For example, data pooled from the double-blind, randomised studies described above show that only theincidence of all-cause gastrointestinal side-effects was markedlyhigher than placebo, as would be expected.10 In addition, therewas no increase in general side-effects after switching fromimmediate-release metformin to prolonged-release metformin.12

Efficacy of once-daily prolonged-release metforminMaintaining adequate glycaemic control is crucial for the pre-vention of long-term microvascular complications.14 It is impor-tant to ensure that improvements in tolerability with the pro-longed-release metformin formulation are not gained at theexpense of reduced antihyperglycaemic efficacy.

The dose-ranging study with prolonged-release metforminshows that the efficacy of this formulation given once-daily isdose-related, with a maximal effect at 1,5002,000 mg/day.10

Mean treatment differences versus placebo during once-dailytreatment in this study were -0.6% (500 mg), -0.7% (1,000 mg),-1.0% (1,500 mg), and -1.0% (2,000 mg). This study also eval-uated prolonged-release metformin given at a dose of 1,000 mgtwice-daily. The change in HbA1C in this group (mean reductionof 1.2%) was comparable with that observed in the grouprandomised to receive a dose of 2,000 mg once-daily (meanreduction of 1.0%). In addition, there was no loss of efficacyfollowing a switch from immediate-release metformin to theprolonged-release formulation.12

These data confirm that the antihyperglycaemic efficacy ofonce-daily prolonged-release metformin is comparable to that ofimmediate-release metformin given in divided doses. In addition,these data also support twice-daily administration of prolonged-release metformin, if preferred.

Lipid profiles generally improved, with significant reductionsfrom baseline in total and LDL-c observed in both parallel-group,placebo-controlled evaluations of prolonged-release metformin,and in the switch study.10,12 However, small, but statistically sig-

nificant increases in triglycerides occurred in these studies.HDL-c was unaffected. Prolonged-release metformin exerted lit-tle effect on body weight: mean changes in body weight weresmall (reductions of up to 1 kg) in the various treatment groupsin the placebo-controlled parallel-group evaluations of pro-longed-release metformin.10

How does the prolonged-release metformin formula-tion improve gastrointestinal tolerability?The improved gastrointestinal tolerability of prolonged-releasemetformin arises directly from its novel tablet design (figure 6).The metformin is contained within a dual hydrophilic polymermatrix system that meters metformin release by means of diffu-sion.15 An outer, continuous polymer (containing no metformin)surrounds inner particles of a different polymer that contains,overall, 500 mg of metformin per tablet. When the tablet is swal-lowed, it absorbs moisture and swells, forming a gel layer on theoutside of the tablet that meters the release of metformin intothe gut. Importantly, the rate at which metformin dissolves is notaffected by movement, or by variations in pH, which helps tominimise variations in metformin delivery between and withinpatients.

The absorption of metformin from the prolonged-releasetablet is slower and takes place over a longer period of time,compared with the immediate-release formulation.15,16 A phar-macokinetic study evaluated the prolonged-release tablet (2,000mg once-daily) in comparison with immediate-release metformin(1,000 mg b.i.d.) after each was dosed to steady state.15 The timeto maximal plasma concentration of metformin (Tmax) from theprolonged-release tablet was longer than with immediate-release metformin (seven-hour vs. three-hour), and the maximalplasma concentration (Cmax) was about 25% lower for the pro-longed-release formulation. The overall exposure of the patientto metformin was unaffected. Indeed, analysis of the area underthe plasma concentration-time curve demonstrated strict bio-equivalence between the formulations. Figure 7 shows plasma

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Figure 5. Gastrointestinal side-effects in patients switched from immediate-release metformin to prolonged-release metformin with the intention of improving tolerability13

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metformin-time curves for the two formulations, after dosing tosteady state.

The pharmacokinetic profile of metformin from the pro-longed-release tablet avoids the rapid initial rise in plasma met-formin concentrations seen with immediate-release metformin.This smoother delivery of metformin may help to avoid trigger-ing gastrointestinal side-effects, and may account for much ofthe improved tolerability demonstrated with the prolonged-release formulation.

ConclusionsThe extensive database of clinical experience with metformin hasestablished this agent as a foundation therapy for type 2 dia-betes. However, gastrointestinal side-effects with metformin arecommon and troublesome, and some patients may find the com-plex twice or three times daily administration regimen difficult tofollow in the setting of polypharmacy. A novel prolonged-releaseformulation of metformin (Glucophage SR), based on a dualpolymer matrix (the GelShield diffusion system) controls bloodglucose effectively following once-daily dosing, and has demon-strated improved gastrointestinal tolerability compared with theimmediate-release formulation. This new metformin tablet hasthe potential to improve patients adherence to metformin-based therapy.

References1. Howlett HC, Bailey CJ. A risk-benefit assessment of metformin in type 2

diabetes mellitus. Drug Saf 1999;20:489-503. 2. Campbell IW, Howlett HC. Worldwide experience of metformin as an

effective glucose-lowering agent: a meta-analysis. Diabetes Metab Rev1995;11(suppl 1):S57-S62.

3. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive bloodglucose control with metformin on complications in overweight patientswith type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.

4. National Institute for Clinical Excellence. Management of type 2 diabetes- Management of blood glucose - NICE summary. Available at NationalLibrary for Health website, http://www.nelh.nhs.uk/guidelinesdb/html/fulltext-guidelines/Bloodglucose.html, last accessed by authorJanuary 29 2004.

5. Davidson JA. The treatment of type II diabetes in Texas: current issues formanaged care and employers. Diabetes Care 1997;20:44-51.

6. Davidson J. Revised standards for the treatment of type 2 diabetes inTexas. Diabetes Care 1999;22:1219-20.

7. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of met-formin in type II diabetes: results of a double-blind, placebo-controlled,dose-response trial. Am J Med 1997;103:491-7.

8. Scarpello JHB. Optimal dosing strategies for maximising the clinicalresponse to metformin in type 2 diabetes. Br J Vasc Dis 2001;1:28-36.

9. Paes AHP, Bakker A, Soe-Agnie S-J. Impact of dosage frequency onpatient compliance. Diabetes Care 1997;20:1512-17.

10. Fujioka K, Bruce S, Joyal S, Swanink R, Pans M. Efficacy, dose-responserelationship and safety of once-daily extended-release metformin(Glucophage XR) in type 2 diabetic patients with inadequate glycemiccontrol despite prior treatment with diet and exercise: results from twodouble-blind, placebo-controlled studies. Diabetes Obes Metab 2004 (inpress).

11. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin dependent diabetes mellitus. N Engl J Med 1995;333:541-9.

12. Fujioka K, Joyal S, Bruce S. Type 2 diabetes patients switched from imme-diate-release metformin bid to an extended-release qd formulation in arandomized, controlled trial maintain comparable glycemic control. ClinTher 2003;25:515-29.

13. Blonde L, Dailey GE, Jabbour SA, Reasner CA, Mills DJ. Gastrointestinaltolerability of extended-release metformin tablets compared to immedi-ate-release metformin tablets results of a retrospective cohort study.Curr Med Res Opin 2004;20:565-72.

14. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucosecontrol with sulphonylureas or insulin compared with conventional treat-ment and risk of complications in patients with type 2 diabetes (UKPDS33). Lancet 1998;352:837-53.

15. Timmins P, Donahue S, Meeker J, Marathe P. Steady-state pharmacoki-netics of a novel extended-release metformin formulation. ClinPharmacokinet 2004 (in press).

16. Marathe P, Turner K. Steady-state pharmacokinetics of the metforminextended-release tablet versus immediate-release metformin in healthysubjects. Diabetes 2002;51(suppl 2):A474.

Key messages

Management guidelines for type 2 diabetes support theuse of metformin for initiation of pharmacologicalantidiabetic therapy.2 Gastrointestinal side-effects andcomplex administration may present barriers to the useof metformin

The new prolonged-release formulation of metformin(Glucophage SR) has the potential for once-dailydosing and improved gastrointestinal tolerabilitycompared with immediate-release metformin

Glucophage SR employs a dual matrix polymer (theGelShield diffusion system), which allows prolonged andsmoother absorption of metformin, avoiding the initialrapid rise in plasma concentrations with immediate-release metformin

Figure 7. Plasma-concentration-time relationships following once-daily dosing of extended-release metformin or twice-daily dosing of immediate-release metformin in 16 healthy volunteers

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Adapted from Timmins P. Clin Pharmacokinet 2004 (in press)15

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