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Review | Comparative Effectiveness Research

Systematic Review of the Benefits and Risks of Metformin in Treating Obesity in Children Aged 18 Years and Younger FREE

Marian S. McDonagh, PharmD1; Shelley Selph, MD1; Alp Ozpinar, BS2; Carolyn Foley, BA2
[+] Author Affiliations
1Department of Medical Informatics and Clinical Epidemiology, School of Medicine, Oregon Health & Science University, Portland, Oregon
2School of Medicine, Oregon Health & Science University, Portland, Oregon
JAMA Pediatr. 2014;168(2):178-184. doi:10.1001/jamapediatrics.2013.4200.
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Published online

Importance  Childhood obesity is an important public health problem with increasing prevalence. Because treatment often has limited success, new approaches must be identified.

Objective  To evaluate the effectiveness and safety of metformin for treating obesity in children aged 18 years and younger without a diagnosis of diabetes mellitus.

Evidence Review  We included randomized clinical trials identified through searches of MEDLINE, the Cochrane Library, and ClinicalTrials.gov. Our primary outcome measure was change in body mass index (BMI, calculated as weight in kilograms divided by height in meters squared). We assessed study quality, pooled data using a random-effects model, and performed subgroup and sensitivity analyses.

Findings  Fourteen randomized clinical trials were eligible. For BMI, moderate-strength evidence indicated a reduction of −1.38 (95% CI, −1.93 to −0.82) from baseline compared with control at 6 months. A similar, if less dramatic, effect was observed in studies less than 6 months, but the pooled estimate from studies of 1 year of treatment was not statistically significant. Subgroup analyses indicated smaller, but significant, effects for those with baseline BMI below 35, those of Hispanic ethnicity, those with acanthosis nigricans, those who had tried and failed diet and exercise programs, and in studies with more girls or higher mean age (adolescents). Moderate-strength evidence indicated that with metformin, 26% reported a gastrointestinal event compared with 13% in control groups (relative risk, 2.05; 95% CI, 1.19-3.54), although there was no difference in discontinuations due to adverse events. No serious adverse events were reported.

Conclusions and Relevance  Metformin provides a statistically significant, but very modest reduction in BMI when combined with lifestyle interventions over the short term. A large trial is needed to determine the benefits to subgroups or impacts of confounders. In the context of other options for treating childhood obesity, metformin has not been shown to be clinically superior.

Figures in this Article

Childhood obesity is one of the most prevalent and challenging health care concerns in the United States, with 16.9% of children found to be obese (>95th percentile of body mass index [BMI, calculated as weight in kilograms divided by height in meters squared] for age1) in 2008.2,3 Nearly 1 in 3 children are considered overweight (BMI ≥85th percentile for age).2,3 The incidence of type 2 diabetes mellitus among overweight adolescents has increased dramatically in the past 20 years.4 Obese children are more likely to become obese adults, develop type 2 diabetes mellitus, and have cardiovascular disease risk factors such as elevated blood pressure and serum lipids.47 While diet and exercise are the first-line weight-loss methods used, few patients achieve success.5 Since 2003, orlistat (Xenical) has been approved by the US Food and Drug Administration to treat obesity in children ages 12 to 16 years. In severe obesity, bariatric surgery can result in weight loss of 32 to 45 kg, but its use is limited to adults, except in extreme circumstances.68

While metformin is approved by the Food and Drug Administration for treating type 2 diabetes mellitus in adults and children older than 10 years of age, it has been used off label in recent years to treat childhood obesity.914 The most serious adverse effect associated with metformin is lactic acidosis, with kidney disease, heart failure, and alcoholism as known risk factors. Cases in children were not found in the literature.

A previous systematic review15 of this topic included studies published through 2008. We aimed to update this review on the comparative benefits and risks of metformin used to treat childhood obesity. We posed the following critical questions: (1) Does metformin use in overweight or obese nondiabetic children reduce BMI, weight, lipids, blood pressure, or the risk for associated comorbidities? (2) What are the adverse effects of metformin use in overweight or obese nondiabetic children? (3) Are results different across subpopulations of children (eg, comorbidities, races, or ethnicities)?

Inclusion Criteria

Studies eligible for this review included nondiabetic children or adolescents (aged ≤18 years) who were overweight or obese (BMI >25 or had BMI for age ≥85th percentile). We included randomized clinical trials of metformin compared with any intervention. Benefit outcomes included change in BMI or BMI-for-age percentile; weight loss (percentage and absolute); change in weight category (obese, overweight, and normal); change in serum lipids, blood pressure, or quality of life; exercise tolerance; cardiovascular events (eg, stroke); and onset of type 2 diabetes mellitus. Adverse event outcomes included discontinuation from study owing to adverse events and the type and incidence of adverse events including lactic acidosis and alterations in height growth. This systematic review did not require institutional review board approval nor patient consent.

Literature Search

We conducted literature searches in MEDLINE (1996 to September 2012 including in-process and nonindexed citations), the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. We used the search term metformin combined with overweight or obese combined with child. Searches were limited to human and English language (owing to resource limitations). Manual searches of reference lists of included studies were conducted.

Study Selection

Two reviewers independently screened titles and abstracts and then full-text publications by applying the inclusion criteria just described. Disagreements were resolved through consensus. We excluded studies of adolescent girls with polycystic ovary syndrome because it has been associated with weight gain and obesity and because many studies did not stratify results of teens from the women included.

Data Abstraction

The following data were abstracted from each included study: study design, eligibility criteria (eg, BMI), baseline characteristics (eg, failure of prior weight-loss interventions and insulin resistance), intervention (eg, drug, dosage, and length of treatment), control intervention, other permitted concurrent interventions, methods of outcome assessment, population demographics, sample size, loss to follow-up, and results. We recorded intention-to-treat (ITT) results when available. A second reviewer checked abstracted data.

Quality Assessment

Internal validity of included trials was independently graded as good, fair, or poor by 2 reviewers based on the methods of the Drug Effectiveness Review Project.16 Elements of internal validity included methods of randomization and allocation concealment, masking of drug intervention, ITT analysis, and loss to follow-up. According to these methods, good studies meet all criteria, poor studies fail to meet combinations of criteria thought to constitute a fatal flaw, and the rest are fair quality. Disagreements were resolved through consensus.

Analysis

We analyzed results qualitatively and quantitatively. Our primary outcome measure was mean change in BMI. We also analyzed mean change in other continuous variables (eg, change in BMI and blood pressure) and relative risk for events (eg, rates of adverse events). Where we had at least 2 trials reporting the same outcome, we conducted meta-analyses using a Mantel Haenszel random-effects model using Stata (StataCorp). For continuous variables, we analyzed databases on those who had both baseline and follow-up values (ie, not ITT), but for categorical variables, we analyzed based on number randomized (ITT). Statistical heterogeneity was assessed using the Q and the I2 statistics. We analyzed publication bias visually using a funnel plot. We conducted sensitivity analyses to explore the effect of study quality, duration, dose, percentage male, country of study, and presence of acanthosis nigricans.

Strength of Evidence and Applicability

We graded strength of the body of evidence for change in BMI, change in lipid and blood pressure parameters, and adverse events based on the GRADE method.17 This approach assesses 4 key domains: risk for bias, consistency, directness, and precision of the evidence. We separately reported the applicability of the body of evidence based on the descriptions of the populations, interventions, comparators, duration of study, and settings of the studies included.

Our searches identified 75 studies, from which we included 14 randomized clinical trials (Figure 1).1,1830 These small trials enrolled a total of 946 children and adolescents, ranging in age (mean) from 10 to 16 years, with baseline BMIs ranging from 26 to 41 (eTable in the Supplement). Only 3 studies used age-adjusted BMI of greater than the 95th percentile for inclusion.25,26,29 Of these, 1 study25 reported that at baseline, the participants were in the 98th percentile and had a mean BMI of 33. Ten studies documented insulin resistance at baseline (4 did not report on this characteristic). Two studies required that patients be normoglycemic or nondiabetic at baseline to enroll,18,29 and 8 reported participants were normoglycemic at baseline (6 did not report fasting glucose levels at baseline). Only 2 studies required that patients have tried and failed prior weight-loss efforts (eg, diet and exercise program) prior to enrolling in the study.26,28 Race and ethnicity distribution was not reported in a consistent manner across the studies, with 3 not reporting these data at all: 1 in Iran, 1 in Turkey, and 1 in Mexico.1,20,26 Three studies reported enrolling more than 90% white children,19,22,28 while the remainder reported a more mixed population including a study from Australia, where 64% were ethnically Indian subcontinent or Pacific Islanders. The balance of males and females ranged from 32% to 81% male across the studies, with a mean of 45% male.

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Figure 1.
Results of Literature Search
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Three trials were determined to be good quality,23,29,30 2 were poor quality,19,25 and the remainder were fair quality. The studies that were rated poor quality were open label (everyone involved was unblinded including those making assessments of outcomes), were unclear on the methods of randomization and allocation concealment, and either did not use an ITT analysis or had potentially important differences between groups at baseline. The other 12 studies used a placebo control. The study durations varied, with 4 being of short duration (<6 months), 8 lasting 6 months, and 2 being of long duration (≥1 year). Dosing of metformin ranged from 1000 to 2000 mg divided into twice daily doses, and once daily for the extended-release formulation. All but 1 study21 used some form of lifestyle intervention as background therapy in both groups, with 2 reporting intensive interventions.25,28

BMI

Inadequate reporting of mean percentage change in BMI or weight limited our analyses to mean absolute changes and 1 study did not report BMI as an outcome.22 Based on 13 trials,1,1820,2330 children taking metformin had reductions in BMI greater than those assigned to control groups (Figure 2). We graded the strength of this evidence as moderate, with reductions for limitations in study quality and a small amount of unexplained heterogeneity. For example, one clear exception to the finding of benefit with metformin was a study of 70 children conducted in Germany, randomized after failing to lose weight after 6 months of intensive lifestyle intervention.28 In this study, the reduction in BMI was slightly greater in the control group. Further examination of this study did not reveal reasons for this variation. One other study showed essentially no difference between groups. This was a very small study (N = 26), with a duration of only 3 months.20

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Figure 2.
Change in Body Mass Index With Metformin Compared With Control by Length of Follow-up

Body mass index is calculated as weight in kilograms divided by height in meters squared.

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Because the overall pooled estimate (−1.16; 95% CI, −1.60 to 0.73) resulted in a large amount of statistical heterogeneity (I2, 60%), we assessed the results stratified by duration of study (<6 months, 6 months, and >6 months; Figure 2 and Table). The largest difference (favoring metformin) was seen in the pooled estimate of 7 6-month trials (−1.38; 95% CI, −1.93 to −0.82; I2, 44%). Two studies with 1 year of treatment did not show a statistically significant difference. At the end of treatment, 1 study continued blinded follow-up for another 48 weeks, and both groups regressed toward baseline.29

Table Graphic Jump LocationTable.  Subgroup Analyses of BMI Change With Metformin Compared With Control

Subgroup analyses (Table) showed greater differences in BMI reduction in patients whose baseline BMI was 35 or more (−1.23; 95% CI, −1.66 to −0.79) than for those with BMI less than 35 (−1.05; 95% CI, −1.81 to −0.29), although both were statistically significant. Studies with greater proportions of girls had smaller decreases in BMI relative to studies with more boys, but both subgroup analyses were statistically significant. While the study reports did not allow an analysis based on pubescent/prepubescent status, analysis based on mean age indicated that younger children (aged ≤12 years; −1.56; 95% CI, −2.29 to −0.84) had greater reduction in BMI compared with adolescents (aged >14 years; − 0.96; 95% CI, −1.59 to −0.32). Analysis of metformin dose showed only a small difference in effect with 2000 mg per day compared with lower doses. Analysis of studies including children with insulin resistance or insulin sensitivity or those who were known to be normoglycemic did not result in any clear differences in effect on BMI. This was most likely because the comparison groups were studies that did not report these characteristics rather than studies of children without them. Children with acanthosis nigricans had smaller, but significant, decreases in BMI. Similarly, analyzing 2 studies of children who failed diet and exercise prior to enrollment resulted in a smaller decrease in BMI compared with 10 studies that did not have this criterion. Studies conducted only in the United States found a smaller mean change in BMI than studies conducted outside the United States, although this analysis resulted in a large amount of statistical heterogeneity.

Sensitivity analysis removing the 2 studies rated poor quality changed the overall estimate of effect from −1.16 to −1.09, but it remained statistically significant (95% CI, −1.54 to −0.63). We conducted an exploratory metaregression analysis of subgroup characteristics potentially associated with change in BMI. While there were too few studies to provide statistically significant results, our findings suggested that higher proportions of patients with Hispanic ethnicity or a history of failing lifestyle intervention in the past should be examined more closely in future studies as potential predictors of smaller change in BMI.

The funnel plot of our primary outcome measure (difference in change in BMI) indicates a potential for publication bias, given the gap in studies on the side of no effect/favoring placebo at the top of the plot (Figure 3).

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Figure 3.
Funnel Plot for Change in Body Mass Index
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Weight

Moderate-strength evidence, based on 8 studies, showed a statistically significant greater weight loss with metformin compared with control (−3.26; 95% CI, −4.23 to −2.30; I2, 0%).1,18,20,22,23,25,27,30 The largest difference in weight loss was seen at 6 months (−3.77; 95% CI, −5.03 to −2.51), while a year-long study found no significant difference between groups (0.70; 95% CI, −3.62 to 5.02; P = .75).23 The difference between groups was inversely associated with the intensity of the control intervention (low, medium, and high) but statistically significant for all 3 subgroups (data not shown). Similarly, greater differences in weight loss were found for patients whose BMI was 35 or more (−3.45; 95% CI, −4.23 to −2.30) than for those whose baseline BMI was less than 35 (−2.98; 95% CI, −4.61 to −1.36), although both were statistically significant. Stratifying by the percentage male or by metformin dose did not indicate important differences across groups.

Lipids and Blood Pressure

Pooled analysis of 7 trials showed slightly greater decrease in total cholesterol with metformin compared with control (−4.65 mg/dL; 95% CI, −8.90 to −0.41; I2, 0%; Figure 4).1,18,21,23,25,28,30 A small but significantly greater change in triglycerides was found with metformin (−17.42 mg/dL; 95% CI, −33.68 to −1.16); however, owing to statistical heterogeneity (I2, 81%), we rated this as low strength of evidence.1,18,19,2123,25,2830 Other lipid outcomes were not different between groups. Only 4 studies reported changes in blood pressure, but these changes were inconsistent across the studies, and pooled analyses did not result in statistically significant differences.1,18,25,28

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Figure 4.
Change in Total Cholesterol After Metformin Treatment
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Adverse Events and Discontinuations

In these studies, metformin was relatively well tolerated, with discontinuations owing to adverse events occurring in 1.6% of metformin patients overall and in 1.7% of control group patients. Evidence on the specific risks of metformin relative to placebo treatment was poorly reported in these studies. Ten of 14 reported limited details on specific adverse events stated during the trials, but none adequately reported how these events were ascertained. In these studies, there were no serious adverse events related to treatment and no cases of lactic acidosis reported. Likewise, alterations in height growth were not reported. The most commonly reported adverse events were gastrointestinal in nature. Moderate-strength evidence indicated that in metformin groups, 26% of patients reported some type of gastrointestinal event compared with 13% of those in the control groups (relative risk, 2.05; 95% CI, 1.19 to 3.54; I2, 35%). The types, frequency, and severity of events reported varied, and it was not clear that adverse events were ascertained equally in control group patients in all studies. Several studies noted that gastrointestinal adverse events generally resolved with time or dose reduction (often followed by slower dose increase). Other adverse events, such as increases in liver function tests, were reported inconsistently, but among those studies that did report values, differences between groups were not seen.

During the past decade, there has been interest in the potential benefits of metformin in obese children and adolescents, as evidenced by 14 trials examining various metabolic outcomes. Our focus was on the potential benefit in a primary health outcome for these children: reduction in BMI. Because the studies were generally small, ranging from 24 to 173 participants, a pooled analysis is ideal for determining the effectiveness with adequate statistical power. Our analysis indicated that metformin combined with lifestyle interventions is efficacious in helping obese children aged 10 to 16 years reduce their BMI and weight as compared with lifestyle interventions alone in the short term. However, the magnitude of change was small relative to known reductions needed to impart long-term health benefits. Our pooled analysis indicated a maximum reduction in BMI of 1.4 relative to lifestyle interventions alone in studies with durations of 6 to 12 months. Given that the mean BMI at study outset was 33, this reduction was only 3.6% greater than lifestyle interventions (mean [SD] change from baseline in these groups was close to zero [0.15]), less than the 5% or 10% goals often cited as a marker for meaningful weight loss. Similarly, weight change was 3.77 kg in studies limited to 6 months. Studies that lasted less than 6 months also showed a benefit, but the maximum effect was seen after 6 months of treatment. As with many weight-loss strategies, this weight-reduction benefit did not appear to be sustained over longer periods because weight and BMI changes were not clearly different between groups in studies with treatment durations of 1 year, although there were only 2 such studies (N = 77 and N = 173).

Evaluating treatments for obesity in children is complex and must consider the impact of normal growth and the effects of puberty, age, and sex differences. Our analysis of subgroups indicated that the beneficial effects of metformin may be smaller in those whose baseline BMI was below 35, in studies with more girls or higher mean age (adolescents), in those of Hispanic ethnicity, in those with acanthosis nigricans, and in those who have tried and failed diet and exercise programs in the past. However, for some of these important subgroups, the ability to stratify more accurately would greatly improve the clarity of the findings. To complete such analysis, individual patient data or a very large trial with a diverse population would be necessary. For example, while our analysis by age indicated that younger children (mean age ≤12 years and more likely to be prepubertal) had a better reduction in BMI (−1.56) compared with adolescents (age ≥14 years, assumed to be pubescent, and BMI loss of −0.96), there is certainly contamination in our groupings, reducing the accuracy of the results. For other subgroups (eg, acanthosis nigricans), larger sample sizes are needed.

The risk of giving children a medication for potentially long periods is concerning. In this case, metformin is a drug that has been used for multiple decades and has been used long term in children with type 2 diabetes mellitus. In these studies, it does not appear that children discontinued treatment owing to adverse effects. Gastrointestinal adverse effects accounted for most events reported, with twice as many patients reporting at least 1 event. While not well documented, several trial reports commented that these adverse effects resolved with time or dose reduction and titration.

Potential limitations of our study included the lack of having searched for studies not published in English and having imputed as standard deviation those variance measures that were not specifically identified as standard deviations or standard errors. Limitations of the evidence included that the efficacy measures included were continuous variables, where 14% of randomized patients did not provide data for the analyses. If all of these patients experienced less benefit, then our results may be an overestimation of effect. As previously noted, while the populations included were of mixed sex, race, and ethnicity, sufficient information on effects in specific subgroups is mostly lacking. Finally, there is a suggestion of publication bias, where studies that did not show metformin to be beneficial may not have been published. Inclusion of more negative studies is likely to shift the point estimate toward the null. Searches of ClinicalTrials.gov, the Food and Drug Administration website, or general Internet searches did not identify unpublished studies.

While our results indicate that some obese children and adolescents may benefit from short-term treatment with metformin combined with lifestyle interventions, these benefits were very modest, not achieving a 5% reduction in BMI based on mean response. Also, it was not clear that there was any benefit from longer-term treatment. Although these findings are based on statistically significant, moderate-strength evidence, the clinical benefit of such a small reduction in BMI is certainly questionable. Subgroup analyses suggest that there may be children who benefit more, for example, those with BMI greater than 35, age 12 years or younger, and who have not failed lifestyle interventions previously. Current evidence is insufficient to fully examine such subgroups or to fully account for some major potential confounding factors (eg, puberty). To determine whether there are specific patients who may have a clinical, and not just statistical, benefit from treatment with metformin, a large scale trial is needed. Such a trial should have adequate statistical power to allow examination of potential confounders and subgroups who may benefit more than the average, adequate duration to further examine the optimal duration of treatment, and an appropriate control group.

Accepted for Publication: August 8, 2013.

Corresponding Author: Marian S. McDonagh, PharmD, Department of Medical Informatics and Clinical Epidemiology, School of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Stop BICC, Portland, OR 97239 (mcdonagh@ohsu.edu).

Published Online: December 16, 2013. doi:10.1001/jamapediatrics.2013.4200.

Author Contributions: Dr McDonagh had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: McDonagh, Ozpinar, Foley.

Acquisition of data: McDonagh, Ozpinar, Foley.

Analysis and interpretation of data: McDonagh, Selph, Ozpinar.

Drafting of the manuscript: McDonagh, Ozpinar, Foley.

Critical revision of the manuscript for important intellectual content: McDonagh, Selph, Ozpinar.

Statistical analysis: McDonagh, Selph, Ozpinar.

Administrative, technical, or material support: McDonagh, Foley.

Study supervision: McDonagh.

Conflict of Interest Disclosures: None reported.

Additional Contributions: We thank David Do, BS, Gabriel Edwards, BA, Leah Fletchall, BS, Erika Sohlberg, BA, Nicole Stanley, BS, and Dallas Swanson, BS, for assistance with topic development and data collection. We also thank Leah Williams, BS, for assistance with editing and formatting of the manuscript. Ms Williams is affiliated with Oregon Health & Science University and was paid by the university for her editing assistance as part of her regular salary.

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Figures

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Figure 1.
Results of Literature Search
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Figure 2.
Change in Body Mass Index With Metformin Compared With Control by Length of Follow-up

Body mass index is calculated as weight in kilograms divided by height in meters squared.

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Figure 3.
Funnel Plot for Change in Body Mass Index
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Figure 4.
Change in Total Cholesterol After Metformin Treatment
Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Subgroup Analyses of BMI Change With Metformin Compared With Control

References

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