Reviews/Consensus Reports/ADA Statements META-ANALYSIS

Quantifying the Effect of Treatment and Dose on Glycemic Control

1 4 JENNIFER A. HIRST, MSC NIA W. ROBERTS, MSC examining head-to-head trials of low versus 1 1 ANDREW J. FARMER, MD RICHARD J. STEVENS, PHD 2,3 high metformin doses to understand the ef- RAGHIB ALI, MSC fect metformin dose has on HbA1c reduction.

RESEARCH DESIGN AND d fi OBJECTIVE Metformin is the rst-line oral recommended for glycemic control METHODS in patients with type 2 . We reviewed the literature to quantify the effect of metformin treatment on glycated hemoglobin (HbA1c) levels in all types of diabetes and examine the impact Search strategy and study selection of differing doses on glycemic control. MEDLINE, EMBASE, and the RESEARCH DESIGN AND METHODSdMEDLINE, EMBASE, and the Cochrane Li- Central Register of Controlled Trials were brary were searched from 1950 to June 2010 for trials of at least 12 weeks’ duration in which searched from 1950 to June 2010. Ab- diabetic patients were treated with either metformin monotherapy or as an add-on therapy. Data stracts of identified articles were reviewed on change in HbA1c were pooled in a meta-analysis. Data from dose-comparison trials were by two reviewers, and full texts were exam- separately pooled. ined by two reviewers (J.A.H. and R.A.). fi RESULTSdA total of 35 trials were identified for the main analysis and 7 for the dose- For inclusion, trials were required to ful ll the following criteria: 1) be a randomized comparison analysis. Metformin monotherapy lowered HbA1c by 1.12% (95% CI 0.92–1.32; 2 2 I = 80%) versus placebo, metformin added to oral therapy lowered HbA1c by 0.95% (0.77–1.13; controlled design; ) report data on par- I2 = 77%) versus placebo added to oral therapy, and metformin added to therapy lowered ticipants with diabetes; 3) have a patient 2 HbA1c by 0.60% (0.30–0.91; I = 79.8%) versus insulin only. There was a significantly greater follow-up of at least 12 weeks; 4) have a reduction in HbA1c using higher doses of metformin compared with lower doses of metformin treatment group of metformin monother- with no significant increase in side effects. apy, or metformin as an add-on therapy; 5) have a placebo or background treat- CONCLUSIONSdEvidence supports the effectiveness of metformin therapy in a clinically ment comparator group; 6) randomize pa- important lowering of HbA1c used as monotherapy and in combination with other therapeutic fi 7 agents. There is potential for using higher doses of metformin to maximize glycemic control in tients to a xed dose of metformin; ) diabetic patients without increasing gastrointestinal effects. blind patients to oral ; 8) use the same metformin dose for each patient Diabetes Care 35:446–454, 2012 in the trial; and 9) use the same fixed dose of any other oral glucose-lowering medica- etformin is the most commonly review (8) suggested that this is an over- tion used in combination with metformin in Mprescribed antihyperglycemic estimate of effect, but the meta-analysis in- both the metformin and comparator arms. medication for diabetes in the U.S. cluded only seven trials of metformin, (1) and the U.K. (2) and is the recommen- and it did not separately examine metfor- Data extraction and quality ded first choice for oral therapy (2–4). The min use as a monotherapy or in combi- assessment roleofmetformininglucoseloweringhas nation with other antihyperglycemic Data were abstracted using standardized been associated with a reduction in car- medications. We therefore conducted a forms to include trial characteristics (de- diovascular outcomes (5,6). However, its systematic review and meta-analysis of sign and duration), interventions, trial effectiveness in glycemic control is not randomized controlled trials of metformin quality, patient characteristics, and out- well documented, although estimates with the aim of 1) quantifying its reduction come measures. The quality of trials was based on trials suggest that it reduces gly- in HbA , 2) exploring the different treat- assessed using items for selection bias, 1c treatments, outcome measurement statis- cated hemoglobin (HbA1c)by1–2% (11– ment effects when administered as a mon- 22 mmol/mol) (3,7). A recent systematic otherapy or as an add-on therapy, and 3) tical methods, and outcome assessment. Outcome measures were the change in ccccccccccccccccccccccccccccccccccccccccccccccccc HbA1c levels from baseline to the end of the trial, total adverse events, and gastric From the 1Department of Primary Care Health Sciences, University of Oxford, Oxford, U.K., and the National Institute for Health Research School for Primary Care Research, Oxford, U.K.; the 2Cancer Epidemiology adverse events ( and abdominal Unit, University of Oxford, Oxford, U.K.; the 3Department of Community Medicine, United Arab Emirates cramps). In 12 trials where change in 4 University, Al Ain, United Arab Emirates; and the Bodleian Health Care Libraries, University of Oxford, HbA1c was not reported, it was calculated Oxford, U.K. from baseline and end point data, and SD Corresponding author: Jennifer A. Hirst, [email protected]. of the change was estimated from baseline Received 3 August 2011 and accepted 31 October 2011. fi DOI: 10.2337/dc11-1465 and end point SDs (9). In ve trials, SD of This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 HbA1c was not given, and it was imputed .2337/dc11-1465/-/DC1. by averaging the SDs from trials in which it The views expressed by the authors may not necessarily reflect the views or policies of the National Institute for was reported (9). Trials in which data were Health Research. © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly estimated or imputed were excluded from cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ the meta-analysis in a sensitivity analysis. licenses/by-nc-nd/3.0/ for details. When a study had two metformin arms of

446 DIABETES CARE, VOLUME 35, FEBRUARY 2012 care.diabetesjournals.org Hirst and Associates

Table 1dIncluded studies

Duration of Length of Type Metformin Age diabetes Primary trial of Trial n Intervention dose (mg) Comparator (years) BMI (years) outcome (weeks) diabetes Monotherapy trials Fujioka 2005 379 Metformin 500, 2,000 Placebo 54.7 30.5 2.9 Change in 16 2 HbA1c Garber 1997 229 Metformin 500, 2,500 Placebo 57 32 d Change in 14 2 FPG Horton 2000 350 Metformin 500 Placebo 58.2 29.4 4.5 Change in 24 2 HbA1c Goldstein 2007 520 Metformin 1,000 Placebo 53.4 32.3 4.5 Change in 24 2 HbA1c Hallsten 2002 27 Metformin 1,000 Placebo 57.7 30 d Insulin 26 2 responsiveness in skeletal muscle Viljanen 2005 23 Metformin 1,000 Placebo 58.2 29.7 d 26 2 Iozzo 2003 21 Metformin 1,000 Placebo 58 29.8 1–3Hepatic 26 2 glucose uptake Chiasson 2001 163 Metformin 1,500 Placebo 57.8 30.9 6.3 Change in 30 2 HbA1c Natali 2004 50 Metformin 1,500 Placebo 58 29 5.0 Vascular 16 2 reactivity List 2009 110 Metformin 1,500 Placebo 53.5 32 d Change in 12 2 HbA1c Grant 1996 75 Metformin 1,500, 3,000 Placebo dd d Glycemic 26 2 control Wolever 2000 107 Metformin 1,500 Placebo 58.6 30.6 6.1 Serum folate 36 2 levels Hoffmann 1997 63 Metformin 1,700 Placebo 58.1 26.9 2.9 Change in 24 2 HbA1c DeFronzo 1995 289 Metformin 2,500 Placebo 53 29.5 6 Diabetes 24 2 control Damsbo 1998 18 Metformin 3,000 Placebo 52 32 Newly Glycogen 12 2 diagnosed synthase activity Combination trials Jadzinsky 658 Metformin + 500 52.1 30.2 1.6 Change in 24 2 2009 saxagliptin HbA1c Perez 2009 390 Metformin + 850 54.4 31 d Change in 24 2 pioglitazone HbA1c Bosi 2009 885 Metformin + 1,000, 2,000 52.9 31.2 2.0 Change in 24 2 vildagliptin HbA1c Lewin 2007 434 Metformin + 1,500, 2,000 53.3 34.5 5.3 Change in 24 2 sulfonylurea HbA1c Wolever 2000 92 Metformin + 1,500 58.2 30.3 5.0 Serum folate 36 2 miglitol levels Chiasson 2001 155 Metformin + 1,500 Miglitol 58.1 30.3 5.6 Change in 30 2 miglitol HbA1c Horton 2000 351 Metformin + 1,500 58.5 29.3 4.6 Change in 24 2 nateglinide HbA1c Moses 1999 55 Metformin + 1,750 58.8 32.2 6.5 Change in 12 2 repaglinide HbA1c DeFronzo 1995 422 Metformin + 2,500 Glyburide 55.5 29 8.2 Diabetes 24 2 glyburide control Continued on p. 448

care.diabetesjournals.org DIABETES CARE, VOLUME 35, FEBRUARY 2012 447 Metformin and glycemic control: a meta-analysis

Table 1dContinued

Duration of Length of Type Metformin Age diabetes Primary trial of Trial n Intervention dose (mg) Comparator (years) BMI (years) outcome (weeks) diabetes Derosa 2009 127 Metformin + 2,550 Pioglitazone 55.5 27.5 d Insulin 64 2 pioglitazone sensitivity Goldstein 2007 536 Metformin + 1,000, 2,000 53.6 31.8 4.4 Change in 24 2 sitagliptin HbA1c Williams- 406 Metformin + 1,000, 2,000 Sitagliptin 53.6 31.6 4.2 Change in 54 2 Herman sitagliptin HbA1c 2009 Insulin trials Robinson 1998 38 Metformin + 1,000 Placebo + 61.3 30.1 15 Glycemic 12 2 insulin insulin control Giugliano 1993 50 Metformin + 1,700 Placebo + 60.4 32.9 11.6 Glycemic 26 2 fixed-dose fixed-dose control insulin insulin Hermann 2001 35 Metformin + 1,700 Placebo + 57.6 33.1 13 Glycemic 52 2 fixed-dose fixed-dose control insulin insulin Meyer 2002 62 Metformin + 1,700 Placebo + 40.0 26.1 19.3 Blood glucose 26 1 insulin insulin control Ponssen 2000 31 Metformin + 1,700 Placebo + 61.8 28 10 Dose of insulin 20 2 insulin insulin required for glycemic control Douek 2005 175 Metformin + 2,000 Placebo + 58 31.2 9.5 Weight gain 52 2 insulin insulin Jacobsen 2009 24 Metformin + 2,000 Placebo + 40.4 29.4 19.1 Glycemic 24 1 insulin insulin control Lund 2008 98 Metformin + 2,000 Placebo + 45.5 26 28 Change in 52 1 insulin insulin HbA1c Ryysy 2001 41 Metformin + 2,000 Placebo + 58.4 28.7 .3 Glycemic 52 2 sulfonylurea + sulfonylurea + control insulin insulin Yki-Järvinen 1999 45 Metformin + 2,000 Placebo + 57.9 29.6 .3Weightgain522 glyburide + glyburide + insulin insulin Wulffelé 2002 353 Metformin + 2,163 Placebo + 61.0 29.7 13 Cardiovascular 16 2 insulin insulin morbidity Aviles Santa 43 Metformin + 2,500 Placebo + 53.9 d 9.7 Glycemic 16 2 1999 insulin insulin control Khan 2006 30 Metformin + 2,550 Placebo + 48 31.3 19 Blood glucose 16 1 insulin insulin control Dose-comparison trials Garber 1997 299 Metformin Metformin 58.3 d Change in 14 2 (2,257 mg) (1,255 mg) FPG Fujioka 2005 374 Metformin Metformin 56 2.9 Change in 16 2 (2,000 mg) (1,250 mg) HbA1c Goldstein 2007a 355 Metformin Metformin 53.3 4.5 Change in 24 2 (2,000 mg) (1,000 mg) HbA1c Goldstein 2007b 361 Metformin Metformin 53.7 4.5 Change in 24 2 (2,000 mg) + (1,000 mg) + HbA1c sitagliptin sitagliptin Williams- 251 Metformin Metformin 54.0 4.1 Change in 54 2 Herman (2,000 mg) (1,000 mg) HbA1c 2009a Continued on p. 449

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Table 1dContinued

Duration of Length of Type Metformin Age diabetes Primary trial of Trial n Intervention dose (mg) Comparator (years) BMI (years) outcome (weeks) diabetes Williams- 300 Metformin Metformin 53.7 4.4 Change in 54 2 Herman (2,000 mg) + (1,000 mg) + HbA1c 2009b sitagliptin sitagliptin Grant 1996 27 Metformin Metformin ddGlycemic 24 2 (3,000 mg) (1,500 mg) control Bosi 2009 585 Metformin Metformin 52.7 1.9 Change in 24 2 (2,000 mg) + (1,000 mg) + HbA1c vildagliptin vildagliptin Lewin 2007 290 Metformin Metformin 53.5 5.1 Change in 24 2 (2,000 mg) + (1,500 mg) + HbA1c sulfonylurea sulfonylurea References for all included trials are available in the Supplementary Data online. FPG, plasma glucose. a, comparison of metformin monotherapy. b, com- parison of metformin in combination with oral therapy.

different doses, we included both in the in HbA1c levels between the metformin dose-comparison analysis (2,842 partici- analysis and present results ordered by and comparator arms or high-dose versus pants). Details of the trial characteristics dose, splitting the comparator group into low-dose metformin. Adverse-events data are shown in Table 1. two to avoid covariance problems (9). were analyzed using the Mantel-Haenszel When a study had more than two metfor- method, with a random-effects model re- Quality of trials min arms, we selected the lowest and porting risk ratio under the approximating All of the included trials were double highest dose arms for inclusion in the assumption that adverse events occur in- blinded, with the exception of one trial analysis. Sensitivity analyses of trials of dependently. Heterogeneity was explored from the insulin subgroup (15) in which 24 weeks or longer were conducted to ver- using subgroup analyses and metaregres- the comparator group received an extra ify that the treatment effect observed was sion to look at the effect of type of diabe- insulin injection and, thus, was only sustained in the longer trials. tes, trial size, BMI, age, metformin dose, partially blinded. Of the 35 included A second review comparing head-to- baseline HbA levels, length of follow- 1c trials, only 8 stated the method of ran- head trials of two metformin doses was up, year of publication, country of trial, domization. conducted. The same inclusion criteria and change in HbA1c in the comparator were applied with the exception that the group. comparator arm included a different Metformin effectiveness dose of metformin to the intervention RESULTS All monotherapy and combination oral arm. In each multiarm trial, we pooled therapy trials were conducted on patients arms with metformin doses of 1,000 and Study characteristics with . In the metformin “ ” fi 1,500 mg into a single low-dose arm Searches identi ed 2,680 trials (Supple- monotherapy trials, HbA1c was reduced and arms with metformin dose .1,500 mentary Fig. A1). These were screened on by 1.12% (95% CI 0.92–1.32; P , mg into a single “high-dose” arm for title and abstract to give 293 articles re- 0.00001, I2 = 80.2%), corresponding comparisons. quiring examination of the full text. A total to a reduction of 12 mmol/mol more All of the trials covered in this review of 35 trials, representing 7,960 partici- with metformin than placebo (Fig. 1). reported HbA1c units as a percentage of pants, met inclusion criteria (a full list of When we restricted the analysis to trials total hemoglobin standardized to the references of included trials is given in of $24 weeks, the HbA1c in 10 trials was methods of the Diabetes Control and the Supplementary Data online). Of these, 1.19% lower (0.98–1.41; I2 =71.2%)in Complications Trial (DCCT). Results are 15 were receiving metformin monother- the metformin groups versus placebo. In therefore reported in DCCT units as a per- apy compared with placebo, no treatment, the trials of metformin as add-on to oral centage and have been converted into the or diet (2,424 participants); 12 were re- therapy, HbA1c was reduced by 0.95% new Standard International units using ceiving metformin treatment in combina- (0.77–1.13; P , 0.00001, I2 =77.1%), International Federation of Clinical Chem- tion with another oral antihyperglycemic corresponding to a reduction of 11 istry and Laboratory Medicine units of mil- medication compared with the other med- mmol/mol more with metformin than in limoles per mole of hemoglobin. ication (4,511 participants); and 13 were the comparator group. When we re- receiving metformin in combination with stricted the analysis to trials of $24 Statistical analysis insulin treatment compared with patients weeks, the HbA1c in 11 trials was Data analysis was performed in Stata 11.1 on insulin treatment only (1,025 partici- 0.94% lower (0.76–1.13; I2 = 78.6%) (Stata Corporation, College Station, TX) pants). Five trials with multiple arms (10– in the metformin groups versus compar- using a random-effects model based on the 14) were included in the meta-analysis of ator groups. DerSimonian and Laird method to pool the both monotherapy and metformin combi- In trials of metformin as add-on to data, reporting the mean difference in change nation. Seven trials were included in the insulin therapy, HbA1c was reduced by care.diabetesjournals.org DIABETES CARE, VOLUME 35, FEBRUARY 2012 449 Metformin and glycemic control: a meta-analysis

d Figure 1 Mean difference in change in HbA1c of metformin treatment versus comparator (boxes) and pooled estimates (diamonds) calculated by the random-effects DerSimonian and Laird method, stratified by metformin monotherapy and metformin added to an oral antidiabetes medication. Horizontal bars and diamond widths denote 95% CIs, and box sizes indicate relative weight in the analysis. (A high-quality color representation of this figure is available in the online issue.)

0.60% (95% CI 0.30–0.91; P = 0.0001, than patients on insulin alone. Patients which HbA1c was 0.79% lower (95% CI I2 = 79.8%), corresponding to a reduction with , however, showed 0.15–1.42; I2 = 83.4%) in metformin ver- of 6 mmol/mol more in the metformin no change in their HbA1c levels when met- sus comparator groups. groups than in the comparator group. A formin was added to their insulin treat- Metaregression, carried out to inves- 2 subgroup analysis of these trials per- ment (change in HbA1c 0.02% [95% tigate the effect of other variables and to formed on type of diabetes (Fig. 2) found CI 20.25 to 0.21]; P = 0.43, I2 =0%)in explore sources of heterogeneity, found that that patients with type 2 diabetes taking four trials. Restricting the analysis to trials no single factor could explain the hetero- metformin with their insulin treatment of $24 weeks included three trials of geneity. The I2 statistic for the insulin trials had HbA1c levels 0.83% lower (0.48–1.18; type 1 diabetes that gave no change in was reduced by 24.3% by mean BMI. Year 2 2 2 P = 0.000, I = 74.2%) in nine trials, cor- HbA1c (20.01% [20.22 to 0.25]; I = of publication reduced the I by 11.8% responding to HbA1c of 9 mmol/mol lower 0%) and five trials of type 2 diabetes in for metformin combination trials and

450 DIABETES CARE, VOLUME 35, FEBRUARY 2012 care.diabetesjournals.org Hirst and Associates

d Figure 2 Mean difference in change in HbA1c of metformin added on to insulin versus placebo and insulin comparator (boxes) and pooled estimates (diamonds) calculated by the random-effects DerSimonian and Laird method, stratified by type of diabetes. Horizontal bars and diamond widths denote 95% CIs, and box sizes indicate relative weight in the analysis. (A high-quality color representation of this figure is available in the online issue.)

18.5% for insulin trials. No other factor Adverse events metformin group and the comparator reduced heterogeneity by .10.4% in any The most commonly reported adverse group (2.37 [0.65–8.67]; I2 = 73%, P = of the analyses, even though year of pub- events were gastrointestinal events, such 0.19). There was no significant difference lication, metformin dose, mean BMI, as diarrhea, , vomiting, flatulence, in adverse events between higher and mean patient age, and mean duration of and abdominal pain, but also included lower dose in the dose-comparison trials diabetes were significantly associated were , dizziness, headache, (approximate risk ratio = 1.23, P =0.13). with the mean outcome in some of the urinary tract infection, hypertension, However, the assumption of independence analyses. coughing, and palpitations. The meta- was clearly an approximation (Supplemen- The dose-comparison review identi- analysis of reported adverse events tary Fig. A2). fied seven trials with head-to-head com- (Supplementary Fig. A2) found an in- An analysis of gastric adverse events parisons of two different metformin doses crease in the number of adverse events in (diarrhea and abdominal cramps) showed for inclusion, two of which could be used metformin-treated groups in comparison significantly more adverse events in the for more than one comparison, giving nine with comparator groups in the monother- metformin arms of the monotherapy trials comparisons. Meta-analysis of data from apy trials (with an approximate risk ratio (approximate risk ratio 2.26 [95% CI 1.60– these trials (Fig. 3) found significantly of 1.13 [95% CI 1.06–1.21]; I2 =3%,P = 3.20]; I2 = 0%) and combination trials 2 greater change in HbA1c in the higher- 0.0003), and in oral combination trials (1.55 [1.29–1.87]; I = 0%) and nonsignifi- 2 dose arms with a reduction in HbA1c of (1.03 [0.95–1.12]; I = 82%, P = 0.45). The cantly more adverse events in the metformin 0.26% (95% CI 0.14–0.38; P , 0.0001, number of adverse events in insulin trials arms of insulin trials (2.18 [0.68–7.01]; I2 =55.5%)moreinthesearms. was not significantly different between the I2 = 78%). There were also more gastric care.diabetesjournals.org DIABETES CARE, VOLUME 35, FEBRUARY 2012 451 Metformin and glycemic control: a meta-analysis

d Figure 3 Mean difference (boxes) in change in HbA1c of high dose metformin, combining trial arms allocated to at least 2,000 mg metformin, versus low dose metformin, combining trial arms allocated to 1,000–1,500 mg metformin, showing pooled estimates (diamonds) calculated by the random-effects DerSimonian and Laird method. Horizontal bars and diamond widths denote 95% CIs, and box sizes indicate relative weight in the analysis. (A high-quality color representation of this figure is available in the online issue.)

adverse events in the higher-dose trials with metformin did not reduce HbA1c.We glucose lowering, albeit a well-established compared with the lower-dose trials, al- have also clearly demonstrated that an in- surrogate on which treatment guidelines though this was not significant (1.18 crease in metformin dose results in a fur- are based (4,17,18), but it has the advantage 2 [0.98–1.42]; I =7%,P =0.08). ther modest reduction in HbA1c of 0.26% of an estimate based on more trials. This has in trials comparing lower doses to higher allowed us to examine subgroups, such as CONCLUSIONSdThis systematic doses up to a metformin dose of 2,000 mg. monotherapy, combination oral therapy, review of double-blinded, randomized, It was not possible to establish whether and insulin therapy, and to establish a controlled trials has separately examined there is further benefitwhenmetformin dose-response relationship. metformin treatment as a stand-alone dose is increased beyond this level because This is the most comprehensive sys- therapy and as an add-on therapy both there were too few trials with higher doses, tematic review to date on the effect of to other oral medications and to insulin to although the trial on which much of the metformin treatment on HbA1c levels. In quantify its effect on glycemic control. evidence for cardiovascular benefitis addition, to our knowledge, this is the fi Metformin monotherapy reduced HbA1c based, the UK Prospective Diabetes Study rst meta-analysis of metformin dose- by 1.12%, and metformin in combination (UKPDS) (16), used a median dose of comparison studies. Significant unexplained with other oral antihyperglycemic treat- 2,550 mg metformin. Establishing how heterogeneity observed between the trials, ments or insulin reduced HbA1c by 0.95 the dose-effect relationship may vary at however, is a limitation of this review and, and 0.83%, respectively, for type 2 diabe- different doses and what the maximum consequently, results need to be treated tes, and these effects were sustained at 24 effective dose may be is an area for future with caution. Our searches identified weeks. Of particular interest is that the ad- work. 5 times more trials than a previous review, dition of metformin treatment to insulin A previous systematic review found which examined the effect of metformin treatment improves glycemic control in lower rates of cardiovascular mortality in on glycemic control in seven trials (8). type 2 diabetes by a clinically significant people randomized to metformin in six This is partly explained by the other re- level despite protocol-permitted insulin trials of .11,000 patients (6). Compared viewer’s more stringent inclusion criteria, dose adjustments in both arms of these with that review, our analysis has the disad- which included a minimum of 50 subjects trials. Treatment of type 1 diabetic patients vantageofusingthesurrogateoutcomeof in each arm of the trial and an explicit

452 DIABETES CARE, VOLUME 35, FEBRUARY 2012 care.diabetesjournals.org Hirst and Associates statement that informed consent was ob- compared with lower doses. Metformin online], 2008. Available from http:// tained. Inclusion of a larger number of tri- use in type 1 diabetes may not, however, www.nice.org.uk/nicemedia/live/11983/ 40803/40803.pdf. Accessed 5 December als has made it possible to separately reduce HbA1c. Despite this, there may be analyze data from metformin monother- other indications for treating type 1 dia- 2011 apy, oral combination therapy, and insu- betic patients with metformin because a re- 5. Holman RR, Paul SK, Bethel MA, MatthewsDR,NeilHA.10-yearfollow- lin trials. The greatest reduction in HbA1c duction in insulin dose required in the up of intensive glucose control in type in our analysis was 1.1%, which is at the metformin arm of these trials was ob- – ’ 2 diabetes. N Engl J Med 2008;359: low end of the 1 2% estimated by Nathan served consistent with metformin srole 1577–1589 et al. (3). The results of our review suggest as an insulin sensitizer (21). 6. Selvin E, Bolen S, Yeh H-C, et al. Car- that these estimated reductions are most diovascular outcomes in trials of oral likely to be achieved with the highest met- diabetes medications: a systematic re- – formin doses. Previous trials that compared AcknowledgmentsdThis project was funded view. Arch Intern Med 2008;168:2070 different metformin doses from various by the U.K.’s National Health Services Di- 2080 fi 7. Nathan DM. Finding new treatments trials could not establish a dose-effect re- abetes. A.J.F. has received nancial support d lationship of metformin (8). By including from the National Institute of Health Research for diabetes how many, how fast... how good? N Engl J Med 2007;356:437– head-to-head trials of metformin in our sys- Oxford Biomedical Research Centre. 440 tematic review, we clearly demonstrate the No potential conflicts of interest relevant to fi this article were reported. 8. Sherifali D, Nerenberg K, Pullenayegum bene t of using a higher metformin dose to E, Cheng JE, Gerstein HC. The effect maximize HbA reduction, although there J.A.H. researched data and wrote the manu- 1c script. A.J.F. contributed to discussion and re- of oral antidiabetic agents on A1C levels: may be an associated increase in gastric side a systematic review and meta-analysis. viewed and edited the manuscript. R.A. and – effects. We have not been able to dem- N.W.R. researched data and reviewed and edited Diabetes Care 2010;33:1859 1864 onstrate a relationship between baseline the manuscript. R.J.S. researched data, contrib- 9. Higgins JPT, Deeks JJ, Altman DG, Eds (2011). Chapter 16: Special topics in HbA1c and change in HbA1c with treatment uted to discussion, and reviewed and edited the observed in other systematic reviews (8,19). manuscript. statistics. Cochrane Handbook for Sys- A previous systematic review of 61 trials of The authors thank Ben Cairns and Francesca tematic Reviews of Interventions [Inter- oral glucose-lowering therapy found an as- Crowe from the Epidemiology Unit, net], 2011, Version 5.1.0. The Cochrane Collaboration. Available from http:// sociation between baseline HbA1c and the University of Oxford; Clare Bankhead, Julie McLellan, Peter Rose, Rafael Perera, Annette www.cochrane-handbook.org/. Accessed change in HbA1c on treatment, but metfor- 5December2011 min was a randomized therapy in only Plüddemann, and Sian Harrison from the De- partment of Primary Care Health Sciences, 10. Chiasson JL, Naditch L; Miglitol Canadian seven of these trials (8). We were not able University Investigator Group. The syn- fi University of Oxford; and Angelyn Bethel from to nd such a relationship in 15 trials of the Diabetes Trials Unit, Oxford Centre for ergistic effect of miglitol plus metformin metformin monotherapy, 12 trials of met- Diabetes Endocrinology and Metabolism, Uni- combination therapy in the treatment of formin in combination with oral therapy, versity of Oxford, for their input in reviewing type 2 diabetes. Diabetes Care 2001;24: and 13 trials of metformin in combination 989–994 and screening the original articles. fi with insulin. However, our analysis is 11. DeFronzo RA, Goodman AM. Ef cacy of based on metaregression, which compares metformin in patients with non-insulin- dependent diabetes mellitus. The Multi- mean values across trials. The best data to References center Metformin Study Group. N Engl J address this question would make compar- 1. Alexander GC, Sehgal NL, Moloney RM, Med 1995;333:541–549 isons between individuals (20). These re- Stafford RS. 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